maura ruzhnikov

All Publications

• SUCCESSFUL CARDIAC TRANSPLANTATION AND LONG-TERM FOLLOW-UP IN DNAJC19-ASSOCIATED DILATED CARDIOMYOPATHY WITH ATAXIA Tahata, S., Tise, C., Floyd, B., Cusmano-Ozog, K., Ruzhnikov, M., Enns, G. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2022: 302

  View details for Web of Science ID 000772339900104

• Accelerated identification of disease-causing variants with ultra-rapid nanopore genome sequencing. Nature biotechnology Goenka, S. D., Gorzynski, J. E., Shafin, K., Fisk, D. G., Pesout, T., Jensen, T. D., Monlong, J., Chang, P. C., Baid, G., Bernstein, J. A., Christle, J. W., Dalton, K. P., Garalde, D. R., Grove, M. E., Guillory, J., Kolesnikov, A., Nattestad, M., Ruzhnikov, M. R., Samadi, M., Sethia, A., Spiteri, E., Wright, C. J., Xiong, K., Zhu, T., Jain, M., Sedlazeck, F. J., Carroll, A., Paten, B., Ashley, E. A. 2022

  Abstract

  Whole-genome sequencing (WGS) can identify variants that cause genetic disease, but the time required for sequencing and analysis has been a barrier to its use in acutely ill patients. In the present study, we develop an approach for ultra-rapid nanopore WGS that combines an optimized sample preparation protocol, distributing sequencing over 48 flow cells, near real-time base calling and alignment, accelerated variant calling and fast variant filtration for efficient manual review. Application to two example clinical cases identified a candidate variant in <8 h from sample preparation to variant identification. We show that this framework provides accurate variant calls and efficient prioritization, and accelerates diagnostic clinical genome sequencing twofold compared with previous approaches.

  View details for DOI 10.1038/s41587-022-01221-5

  View details for PubMedID 35347328

• Ultra-Rapid Nanopore Whole Genome Genetic Diagnosis of Dilated Cardiomyopathy in an Adolescent With Cardiogenic Shock. Circulation. Genomic and precision medicine Gorzynski, J. E., Goenka, S. D., Shafin, K., Jensen, T. D., Fisk, D. G., Grove, M. E., Spiteri, E., Pesout, T., Monlong, J., Bernstein, J. A., Ceresnak, S., Chang, P., Christle, J. W., Chubb, H., Dunn, K., Garalde, D. R., Guillory, J., Ruzhnikov, M. R., Wright, C., Wusthoff, C. J., Xiong, K., Hollander, S. A., Berry, G. J., Jain, M., Sedlazeck, F. J., Carroll, A., Paten, B., Ashley, E. A. 2022: CIRCGEN121003591

  View details for DOI 10.1161/CIRCGEN.121.003591

  View details for PubMedID 35133172

• Ultrarapid Nanopore Genome Sequencing in a Critical Care Setting. The New England journal of medicine Gorzynski, J. E., Goenka, S. D., Shafin, K., Jensen, T. D., Fisk, D. G., Grove, M. E., Spiteri, E., Pesout, T., Monlong, J., Baid, G., Bernstein, J. A., Ceresnak, S., Chang, P. C., Christle, J. W., Chubb, H., Dalton, K. P., Dunn, K., Garalde, D. R., Guillory, J., Knowles, J. W., Kolesnikov, A., Ma, M., Moscarello, T., Nattestad, M., Perez, M., Ruzhnikov, M. R., Samadi, M., Setia, A., Wright, C., Wusthoff, C. J., Xiong, K., Zhu, T., Jain, M., Sedlazeck, F. J., Carroll, A., Paten, B., Ashley, E. A. 2022

  View details for DOI 10.1056/NEJMc2112090

  View details for PubMedID 35020984

• Delineating the Epilepsy Phenotype of NGLY1 Deficiency. Journal of inherited metabolic disease Levy, R. J., Frater, C. H., Gallentine, W. B., Phillips, J. M., Ruzhnikov, M. R. 2022

  Abstract

  To delineate the phenotypic spectrum of epilepsy in individuals with NGLY1 deficiency from an international cohort.We collected detailed clinical and electroencephalographic data from 29 individuals with bi-allelic (likely) pathogenic variants in NGLY1 as part of an ongoing prospective natural history study. Participants were evaluated in-person at a single center and/or remotely. Historical medical records were reviewed. Published cases were included for comprehensive phenotyping.Of 29 individuals (mean 11.4 years, range 3-27 years), 17 (58.6%) participants had a history of epilepsy. Seizure onset was in early childhood (mean 43 months, range 2 months to 19 years). The most common seizure types were myoclonic and atonic. Epilepsy course was variable, but 35.2% (6/17) of participants with epilepsy achieved seizure freedom. The most common medications included levetiracetam, valproate, lamotrigine, and clobazam. EEGs were abnormal in 80% (12/15) of participants with or without epilepsy, though encephalopathy was uncommon. There was a trend in neurodevelopmental outcomes that participants with epilepsy had more developmental delays.Epilepsy is common in NGLY1 deficiency. Over half of the participants had a history of epilepsy and nearly all had EEG abnormalities indicating an increased risk of epilepsy. This work expands the electroclinical phenotype of NGLY1 deficiency and supports a high clinical suspicion for seizures. Some of the more common seizure types (epileptic spasms, myoclonic, and atonic seizures) can be subtle and require counseling to ensure early recognition and treatment to ensure the best possible outcomes. Despite transient liver enzyme abnormalities in this disorder, hepatically metabolized medications were well tolerated. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/jimd.12494

  View details for PubMedID 35243670

• UNCOMMON NEUROIMAGING FINDINGS IN INBORN ERRORS OF METABOLISM Morales, J. A., Velez-Bartolomei, F. P., Ruzhnikov, M., Enns, G. M. BMJ PUBLISHING GROUP. 2022: 194

  View details for DOI 10.1136/jim-2022-WRMC.162

  View details for Web of Science ID 000737295900183

• Biallelic CACNA2D1 loss-of-function variants cause early-onset developmental epileptic encephalopathy. Brain : a journal of neurology Dahimene, S., von Elsner, L., Holling, T., Mattas, L. S., Pickard, J., Lessel, D., Pilch, K. S., Kadurin, I., Pratt, W. S., Zhulin, I. B., Dai, H., Hempel, M., Ruzhnikov, M. R., Kutsche, K., Dolphin, A. C. 2022

  Abstract

  Voltage-gated calcium (CaV) channels form three sub-families (CaV1-3). The CaV1 and CaV2 channels are heteromeric, consisting of an α1 pore-forming subunit, associated with auxiliary CaVβ and α2δ subunits. The α2δ subunits are encoded in mammals by four genes, CACNA2D1-4. They play important roles in trafficking and function of the CaV channel complexes. Here we report biallelic variants in CACNA2D1, encoding the α2δ-1 protein, in two unrelated individuals showing a developmental and epileptic encephalopathy (DEE). Patient 1 has a homozygous frameshift variant c.818_821dup/p.(Ser275Asnfs*13) resulting in nonsense-mediated mRNA decay of the CACNA2D1 transcripts, and absence of α2δ-1 protein detected in patient-derived fibroblasts. Patient 2 is compound heterozygous for an early frameshift variant c.13_23dup/p.(Leu9Alafs*5), highly likely representing a null allele, and a missense variant c.626G>A/p.(Gly209Asp). Our functional studies show that this amino-acid change severely impairs the function of α2δ-1 as a calcium channel subunit, with strongly reduced trafficking of α2δ-1G209D to the cell surface, and a complete inability of α2δ-1G209D to increase the trafficking and function of CaV2 channels. Thus biallelic loss-of-function variants in CACNA2D1 underlie the severe neurodevelopmental disorder in these two patients. Our results demonstrate the critical importance and non-interchangeability of α2δ-1 and other α2δ proteins for normal human neuronal development.

  View details for DOI 10.1093/brain/awac081

  View details for PubMedID 35293990

• Biochemical Studies in Fibroblasts to Interpret Variants of Unknown Significance in the ABCD1 Gene. Genes van de Stadt, S. I., Mooyer, P. A., Dijkstra, I. M., Dekker, C. J., Vats, D., Vera, M., Ruzhnikov, M. R., van Haren, K., Tang, N., Koop, K., Willemsen, M. A., Hui, J., Vaz, F. M., Ebberink, M. S., Engelen, M., Kemp, S., Ferdinandusse, S. 1800; 12 (12)

  Abstract

  Due to newborn screening for X-linked adrenoleukodystrophy (ALD), and the use of exome sequencing in clinical practice, the detection of variants of unknown significance (VUS) in the ABCD1 gene is increasing. In these cases, functional tests in fibroblasts may help to classify a variant as (likely) benign or pathogenic. We sought to establish reference ranges for these tests in ALD patients and control subjects with the aim of helping to determine the pathogenicity of VUS in ABCD1. Fibroblasts from 36 male patients with confirmed ALD, 26 healthy control subjects and 17 individuals without a family history of ALD, all with an uncertain clinical diagnosis and a VUS identified in ABCD1, were included. We performed a combination of tests: (i) a test for very-long-chain fatty acids (VLCFA) levels, (ii) a D3-C22:0 loading test to study the VLCFA metabolism and (iii) immunoblotting for ALD protein. All ALD patient fibroblasts had elevated VLCFA levels and a reduced peroxisomal SS-oxidation capacity (as measured by the D3-C16:0/D3-C22:0 ratio in the D3-C22:0 loading test) compared to the control subjects. Of the VUS cases, the VLCFA metabolism was not significantly impaired (most test results were within the reference range) in 6/17, the VLCFA metabolism was significantly impaired (most test results were within/near the ALD range) in 9/17 and a definite conclusion could not be drawn in 2/17 of the cases. Biochemical studies in fibroblasts provided clearly defined reference and disease ranges for the VLCFA metabolism. In 15/17 (88%) VUS we were able to classify the variant as being likely benign or pathogenic. This is of great clinical importance as new variants will be detected.

  View details for DOI 10.3390/genes12121930

  View details for PubMedID 34946879

• Variable clinical severity in TANGO2 deficiency: Case series and literature review. American journal of medical genetics. Part A Schymick, J., Leahy, P., Cowan, T., Ruzhnikov, M. R., Gates, R., Fernandez, L., Pramanik, G., Undiagnosed Diseases Network, Yarlagadda, V., Wheeler, M., Bernstein, J. A., Enns, G. M., Lee, C. 2021

  Abstract

  Biallelic pathogenic variants in the TANGO2 (transport and Golgi organization 2 homolog) gene have been identified as causing a rare metabolic disorder characterized by susceptibility to recurrent rhabdomyolysis, lactic acidosis, encephalopathy, and life-threatening tachyarrhythmias. Recently published reports suggest variable clinical severity and phenotypes. This study details five new patients from two families with biallelic pathogenic variants in the TANGO2 gene identified by whole exome sequencing and includes the largest number of affected individuals from a single family reported to date. We document significant intrafamilial variability and highlight that milder phenotypes may be underrecognized. We present biochemical and clinical data to help highlight the features that aid in consideration of this condition in the differential with disorders of fatty acid oxidation. We also present a comprehensive literature review summarizing the molecular, clinical, and biochemical findings for 92 individuals across 13 publications. Of the 27 pathogenic variants reported to date, the recurrent exons 3-9 deletion represents the most common variant seen in 42% of individuals with TANGO2 deficiency. Common clinical features seen in >70% of all individuals include acute metabolic crisis, rhabdomyolysis, neurologic abnormalities, developmental delay, and intellectual disability. Findings such as elevated creatine kinase, hypothyroidism, ketotic hypoglycemia, QT prolongation, or abnormalities of long-chain acylcarnitines and urine dicarboxylic acids should raise clinical suspicion for this life-threatening condition.

  View details for DOI 10.1002/ajmg.a.62543

  View details for PubMedID 34668327

• Corrigendum to eP296-The yield of thorough record review in the Undiagnosed Diseases Network, Volume 132, Supplement 1, April 2021, Page S187, https://doi.org/10.1016/S1096-7192(21)00378-4. Molecular genetics and metabolism Findley, L., Mulvihill, J. J., Bentley, A., Bernstein, J. A., Bican, A., Botto, L., Briere, L., Butte, M. J., Cope, H., Fogel, B. L., Hom, J., Kravets, E., Mak, B. C., Martin, M. G., Martinez-Agosto, J. A., Nelson, S. F., Newman, J., Palmer, C. G., Parker, N. H., Rosenfeld, J. A., Ruzhnikov, M., Schoch, K., Spillmann, R., Undiagnosed Diseases Network 2021

  View details for DOI 10.1016/j.ymgme.2021.08.007

  View details for PubMedID 34663553

• A Prospective Study of Epilepsy in NGLY1 Deficiency Levy, R., Frater, C., Gallentine, W., Ruzhnikov, M. WILEY. 2021: S67-S68

  View details for Web of Science ID 000700182700061

• Genetic counselor roles in the undiagnosed diseases network research study: Clinical care, collaboration, and curation. Journal of genetic counseling Kohler, J. N., Kelley, E. G., Boyd, B. M., Sillari, C. H., Marwaha, S., Undiagnosed Diseases Network, Wheeler, M. T., Acosta, M. T., Adam, M., Adams, D. R., Agrawal, P. B., Alejandro, M. E., Alvey, J., Amendola, L., Andrews, A., Ashley, E. A., Azamian, M. S., Bacino, C. A., Bademci, G., Baker, E., Balasubramanyam, A., Baldridge, D., Bale, J., Bamshad, M., Barbouth, D., Bayrak-Toydemir, P., Beck, A., Beggs, A. H., Behrens, E., Bejerano, G., Bennet, J., Berg-Rood, B., Bernstein, J. A., Berry, G. T., Bican, A., Bivona, S., Blue, E., Bohnsack, J., Bonnenmann, C., Bonner, D., Botto, L., Boyd, B., Briere, L. C., Brokamp, E., Brown, G., Burke, E. A., Burrage, L. C., Butte, M. J., Byers, P., Byrd, W. E., Carey, J., Carrasquillo, O., Chang, T. C., Chanprasert, S., Chao, H., Clark, G. D., Coakley, T. R., Cobban, L. A., Cogan, J. D., Coggins, M., Sessions Cole, F., Colley, H. A., Cooper, C. M., Cope, H., Craigen, W. J., Crouse, A. B., Cunningham, M., D'Souza, P., Dai, H., Dasari, S., Davis, J., Dayal, J. G., Deardorff, M., Dell'Angelica, E. C., Dhar, S. U., Dipple, K., Doherty, D., Dorrani, N., Doss, A. L., Douine, E. D., Draper, D. D., Duncan, L., Earl, D., Eckstein, D. J., Emrick, L. T., Eng, C. M., Esteves, C., Falk, M., Fernandez, L., Ferreira, C., Fieg, E. L., Findley, L. C., Fisher, P. G., Fogel, B. L., Forghani, I., Fresard, L., Gahl, W. A., Glass, I., Gochuico, B., Godfrey, R. A., Golden-Grant, K., Goldman, A. M., Goldrich, M. P., Goldstein, D. B., Grajewski, A., Groden, C. A., Gutierrez, I., Hahn, S., Hamid, R., Hanchard, N. A., Hassey, K., Hayes, N., High, F., Hing, A., Hisama, F. M., Holm, I. A., Hom, J., Horike-Pyne, M., Huang, A., Huang, Y., Huryn, L., Isasi, R., Jamal, F., Jarvik, G. P., Jarvik, J., Jayadev, S., Karaviti, L., Kennedy, J., Kiley, D., Kobren, S. N., Kohane, I. S., Kohler, J. N., Krakow, D., Krasnewich, D. M., Kravets, E., Korrick, S., Koziura, M., Krier, J. B., Lalani, S. R., Lam, B., Lam, C., LaMoure, G. L., Lanpher, B. C., Lanza, I. R., Latham, L., LeBlanc, K., Lee, B. H., Lee, H., Levitt, R., Lewis, R. A., Lincoln, S. A., Liu, P., Liu, X. Z., Longo, N., Loo, S. K., Loscalzo, J., Maas, R. L., MacDowall, J., Macnamara, E. F., MacRae, C. A., Maduro, V. V., Majcherska, M. M., Mak, B. C., Maclidan, M. C., Mamounas, L. A., Manolio, T. A., Mao, R., Maravilla, K., Markello, T. C., Marom, R., Marth, G., Martin, B. A., Martin, M. G., Martinez-Agosto, J. A., Marwaha, S., McCauley, J., McConkie-Rosell, A., McCormack, C. E., McCray, A. T., McGee, E., Mefford, H., Lawrence Merritt, J., Might, M., Mirzaa, G., Morava, E., Moretti, P. M., Mosbrook-Davis, D., Mulvihill, J. J., Murdock, D. R., Nagy, A., Nakano-Okuno, M., Nath, A., Nelson, S. F., Newman, J. H., Nicholas, S. K., Nickerson, D., Nieves-Rodriguez, S., Novacic, D., Oglesbee, D., Orengo, J. P., Pace, L., Pak, S., Carl Pallais, J., Palmer, C. G., Papp, J. C., Parker, N. H., Phillips, J. A., Posey, J. E., Potocki, L., Power, B., Pusey, B. N., Quinlan, A., Raskind, W., Raja, A. N., Rao, D. A., Renteria, G., Reuter, C. M., Rives, L., Robertson, A. K., Rodan, L. H., Rosenfeld, J. A., Rosenwasser, N., Rossignol, F., Ruzhnikov, M., Sacco, R., Sampson, J. B., Samson, S. L., Saporta, M., Ron Scott, C., Schaechter, J., Schedl, T., Schoch, K., Scott, D. A., Shashi, V., Shin, J., Signer, R., Silverman, E. K., Sinsheimer, J. S., Sisco, K., Smith, E. C., Smith, K. S., Solem, E., Solnica-Krezel, L., Solomon, B., Spillmann, R. C., Stoler, J. M., Sullivan, J. A., Sullivan, K., Sun, A., Sutton, S., Sweetser, D. A., Sybert, V., Tabor, H. K., Tan, A. L., Tan, Q. K., Tekin, M., Telischi, F., Thorson, W., Thurm, A., Tifft, C. J., Toro, C., Tran, A. A., Tucker, B. M., Urv, T. K., Vanderver, A., Velinder, M., Viskochil, D., Vogel, T. P., Wahl, C. E., Wallace, S., Walley, N. M., Walsh, C. A., Walker, M., Wambach, J., Wan, J., Wang, L., Wangler, M. F., Ward, P. A., Wegner, D., Wener, M., Wenger, T., Perry, K. W., Westerfield, M., Wheeler, M. T., Whitlock, J., Wolfe, L. A., Woods, J. D., Yamamoto, S., Yang, J., Yousef, M., Zastrow, D. B., Zein, W., Zhao, C., Zuchner, S. 2021

  Abstract

  Genetic counselors (GCs) are increasingly filling important positions on research study teams, but there is limited literature describing the roles of GCs in these settings. GCs on the Undiagnosed Diseases Network (UDN) study team serve in a variety of roles across the research network and provide an opportunity to better understand genetic counselor roles in research. To quantitatively characterize the tasks regularly performed and professional fulfillment derived from these tasks, two surveys were administered to UDN GCs in a stepwise fashion. Responses from the first, free-response survey elicited the scope of tasks which informed development of a second structured, multiple-select survey. In survey 2, respondents were asked to select which roles they performed. Across 19 respondents, roles in survey 2 received a total of 947 selections averaging approximately 10 selections per role. When asked to indicate what roles they performed, respondent selected a mean of 50 roles (range 22-70). Survey 2 data were analyzed via thematic coding of responses and hierarchical cluster analysis to identify patterns in responses. From the thematic analysis, 20 non-overlapping codes emerged in seven categories: clinical interaction and care, communication, curation, leadership, participant management, research, and team management. Three themes emerged from the categories that represented the roles of GCs in the UDN: clinical care, collaboration, and curation. Cluster analyses showed that responses were more similar among individuals at the same institution than between institutions. This study highlights the ways GCs apply their unique skill set in the context of a clinical translational research network. Additionally, findings from this study reinforce the wide applicability of core skills that are part of genetic counseling training. Clinical literacy, genomics expertise and analysis, interpersonal, psychosocial and counseling skills, education, professional practice skills, and an understanding of research processes make genetic counselors well suited for such roles and poised to positively impact research experiences and outcomes for participants.

  View details for DOI 10.1002/jgc4.1493

  View details for PubMedID 34374469

• Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome. Genetics in medicine : official journal of the American College of Medical Genetics Weerts, M. J., Lanko, K., Guzman-Vega, F. J., Jackson, A., Ramakrishnan, R., Cardona-Londono, K. J., Pena-Guerra, K. A., van Bever, Y., van Paassen, B. W., Kievit, A., van Slegtenhorst, M., Allen, N. M., Kehoe, C. M., Robinson, H. K., Pang, L., Banu, S. H., Zaman, M., Efthymiou, S., Houlden, H., Jarvela, I., Lauronen, L., Maatta, T., Schrauwen, I., Leal, S. M., Ruivenkamp, C. A., Barge-Schaapveld, D. Q., Peeters-Scholte, C. M., Galehdari, H., Mazaheri, N., Sisodiya, S. M., Harrison, V., Sun, A., Thies, J., Pedroza, L. A., Lara-Taranchenko, Y., Chinn, I. K., Lupski, J. R., Garza-Flores, A., McGlothlin, J., Yang, L., Huang, S., Wang, X., Jewett, T., Rosso, G., Lin, X., Mohammed, S., Merritt, J. L., Mirzaa, G. M., Timms, A. E., Scheck, J., Elting, M. W., Polstra, A. M., Schenck, L., Ruzhnikov, M. R., Vetro, A., Montomoli, M., Guerrini, R., Koboldt, D. C., Mosher, T. M., Pastore, M. T., McBride, K. L., Peng, J., Pan, Z., Willemsen, M., Koning, S., Turnpenny, P. D., de Vries, B. B., Gilissen, C., Pfundt, R., Lees, M., Braddock, S. R., Klemp, K. C., Vansenne, F., van Gijn, M. E., Quindipan, C., Deardorff, M. A., Hamm, J. A., Putnam, A. M., Baud, R., Walsh, L., Lynch, S. A., Baptista, J., Person, R. E., Monaghan, K. G., Crunk, A., Keller-Ramey, J., Reich, A., Elloumi, H. Z., Alders, M., Kerkhof, J., McConkey, H., Haghshenas, S., Genomics England Research Consortium, Maroofian, R., Sadikovic, B., Banka, S., Arold, S. T., Barakat, T. S. 2021

  Abstract

  PURPOSE: Pathogenic variants in SETD1B have been associated with a syndromic neurodevelopmental disorder including intellectual disability, language delay, and seizures. To date, clinical features have been described for 11 patients with (likely) pathogenic SETD1B sequence variants. This study aims to further delineate the spectrum of the SETD1B-related syndrome based on characterizing an expanded patient cohort.METHODS: We perform an in-depth clinical characterization of a cohort of 36 unpublished individuals with SETD1B sequence variants, describing their molecular and phenotypic spectrum. Selected variants were functionally tested using in vitro and genome-wide methylation assays.RESULTS: Our data present evidence for a loss-of-function mechanism of SETD1B variants, resulting in a core clinical phenotype of global developmental delay, language delay including regression, intellectual disability, autism and other behavioral issues, and variable epilepsy phenotypes. Developmental delay appeared to precede seizure onset, suggesting SETD1B dysfunction impacts physiological neurodevelopment even in the absence of epileptic activity. Males are significantly overrepresented and more severely affected, and we speculate that sex-linked traits could affect susceptibility to penetrance and the clinical spectrum of SETD1B variants.CONCLUSION: Insights from this extensive cohort will facilitate the counseling regarding the molecular and phenotypic landscape of newly diagnosed patients with the SETD1B-related syndrome.

  View details for DOI 10.1038/s41436-021-01246-2

  View details for PubMedID 34345025

• A novel likely pathogenic heterozygous HECW2 missense variant in a family with variable expressivity of neurodevelopmental delay, hypotonia, and epileptiform EEG patterns AMERICAN JOURNAL OF MEDICAL GENETICS PART A Heide, E., Puk, O., Biskup, S., Krahn, A., Rauf, E., Kreilkamp, B. K., Paulus, W., Focke, N. K. 2021

  Abstract

  Pathogenic variants in HECW2 are extremely rare. So far, only 19 cases have been reported. They were associated with epilepsy, intellectual disability, absent language, hypotonia, and autism. As these cases were all de novo mutations, mostly presenting without identical variants, variable expressivity has never been investigated. Here, we describe the first family with the same novel variant in HECW2. A 19-year old female patient presented with bursts of generalized spike-wave discharges and intellectual disability. We performed next-generation-sequencing, to detect the genetic cause. Next-generation-sequencing revealed a novel likely pathogenic variant in HECW2 (c.3571C>T; p.Arg1191Trp) in the index patient, her mother and brother. They showed some similar phenotypic patterns with intellectual disability, hypotonia and generalized epileptiform patterns. However, the mother was less severely affected and epileptiform patterns were less frequent. The brother presented with additional autistic features. In contrast to previous cases, the speech of all individuals was only mildly impaired. This is the first case report of a family with the same novel likely pathogenic variant in HECW2 and as such provides insight into the phenotypic variability of this mutation. The expressivity of symptoms may be so mild that genetic and EEG analysis are needed to disclose the correct diagnosis.

  View details for DOI 10.1002/ajmg.a.62427

  View details for Web of Science ID 000679309000001

  View details for PubMedID 34327820

• Delineating the genotypic and phenotypic spectrum of HECW2-related neurodevelopmental disorders. Journal of medical genetics Acharya, A., Kavus, H., Dunn, P., Nasir, A., Folk, L., Withrow, K., Wentzensen, I. M., Ruzhnikov, M. R., Fallot, C., Smol, T., Rama, M., Brown, K., Whalen, S., Ziegler, A., Barth, M., Chassevent, A., Smith-Hicks, C., Afenjar, A., Courtin, T., Heide, S., Font-Montgomery, E., Heid, C., Hamm, J. A., Love, D. R., Thabet, F., Misra, V. K., Cunningham, M., Leal, S. M., Jarvela, I., Normand, E. A., Zou, F., Helal, M., Keren, B., Torti, E., Chung, W. K., Schrauwen, I. 2021

  Abstract

  BACKGROUND: Variants in HECW2 have recently been reported to cause a neurodevelopmental disorder with hypotonia, seizures and impaired language; however, only six variants have been reported and the clinical characteristics have only broadly been defined.METHODS: Molecular and clinical data were collected from clinical and research cohorts. Massive parallel sequencing was performed and identified individuals with a HECW2-related neurodevelopmental disorder.RESULTS: We identified 13 novel missense variants in HECW2 in 22 unpublished cases, of which 18 were confirmed to have a de novo variant. In addition, we reviewed the genotypes and phenotypes of previously reported and new cases with HECW2 variants (n=35 cases). All variants identified are missense, and the majority of likely pathogenic and pathogenic variants are located in or near the C-terminal HECT domain (88.2%). We identified several clustered variants and four recurrent variants (p.(Arg1191Gln);p.(Asn1199Lys);p.(Phe1327Ser);p.(Arg1330Trp)). Two variants, (p.(Arg1191Gln);p.(Arg1330Trp)), accounted for 22.9% and 20% of cases, respectively. Clinical characterisation suggests complete penetrance for hypotonia with or without spasticity (100%), developmental delay/intellectual disability (100%) and developmental language disorder (100%). Other common features are behavioural problems (88.9%), vision problems (83.9%), motor coordination/movement (75%) and gastrointestinal issues (70%). Seizures were present in 61.3% of individuals. Genotype-phenotype analysis shows that HECT domain variants are more frequently associated with cortical visual impairment and gastrointestinal issues. Seizures were only observed in individuals with variants in or near the HECT domain.CONCLUSION: We provide a comprehensive review and expansion of the genotypic and phenotypic spectrum of HECW2 disorders, aiding future molecular and clinical diagnosis and management.

  View details for DOI 10.1136/jmedgenet-2021-107871

  View details for PubMedID 34321324

• Variants in PRKAR1B cause a neurodevelopmental disorder with autism spectrum disorder, apraxia, and insensitivity to pain GENETICS IN MEDICINE Marbach, F., Stoyanov, G., Erger, F., Stratakis, C. A., Settas, N., London, E., Rosenfeld, J. A., Torti, E., Haldeman-Englert, C., Sklirou, E., Kessler, E., Ceulemans, S., Nelson, S. F., Martinez-Agosto, J. A., Palmer, C. S., Signer, R. H., Acosta, M. T., Adam, M., Adams, D. R., Agrawal, P. B., Alejandro, M. E., Alvey, J., Amendola, L., Andrews, A., Ashley, E. A., Azamian, M. S., Bacino, C. A., Bademci, G., Baker, E., Balasubramanyam, A., Baldridge, D., Bale, J., Bamshad, M., Barbouth, D., Bayrak-Toydemir, P., Beck, A., Beggs, A. H., Behrens, E., Bejerano, G., Bennett, J., Berg-Rood, B., Bernstein, J. A., Berry, G. T., Bican, A., Bivona, S., Blue, E., Bohnsack, J., Bonnenmann, C., Bonner, D., Botto, L., Boyd, B., Briere, L. C., Brokamp, E., Brown, G., Burke, E. A., Burrage, L. C., Butte, M. J., Byers, P., Byrd, W. E., Carey, J., Carrasquillo, O., Chang, T., Chanprasert, S., Chao, H., Clark, G. D., Coakley, T. R., Cobban, L. A., Cogan, J. D., Coggins, M., Cole, F., Colley, H. A., Cooper, C. M., Cope, H., Craigen, W. J., Crouse, A. B., Cunningham, M., D'Souza, P., Dai, H., Dasari, S., Davis, J., Daya, J. G., Deardorff, M., Dell'Angelica, E. C., Dhar, S. U., Dipple, K., Doherty, D., Dorrani, N., Doss, A. L., Douine, E. D., Draper, D. D., Duncan, L., Earl, D., Eckstein, D. J., Emrick, L. T., Eng, C. M., Esteves, C., Falk, M., Fernandez, L., Ferreira, C., Fieg, E. L., Findley, L. C., Fisher, P. G., Fogel, B. L., Forghani, I., Fresard, L., Gahl, W. A., Glass, I., Gochuico, B., Godfrey, R. A., Golden-Grant, K., Goldman, A. M., Goldrich, M. P., Goldstein, D. B., Grajewski, A., Groden, C. A., Gutierrez, I., Hahn, S., Hamid, R., Hanchard, N. A., Hassey, K., Hayes, N., High, F., Hing, A., Hisama, F. M., Holm, I. A., Hom, J., Horike-Pyne, M., Huang, A., Huang, Y., Huryn, L., Isasi, R., Jamal, F., Jarvik, G. P., Jarvik, J., Jayadev, S., Karaviti, L., Kennedy, J., Kiley, D., Kohane, I. S., Kohler, J. N., Korrick, S., Kozuira, M., Krakow, D., Krasnewich, D. M., Kravets, E., Krier, J. B., LaMoure, G. L., Lalani, S. R., Lam, B., Lam, C., Lanpher, B. C., Lanza, I. R., Latham, L., LeBlanc, K., Lee, B. H., Lee, H., Levitt, R., Lewis, R. A., Lincoln, S. A., Liu, P., Liu, X., Longo, N., Loo, S. K., Loscalzo, J., Maas, R. L., MacDowall, J., MacRae, C. A., Macnamara, E. F., Maduro, V. V., Majcherska, M. M., Mak, B. C., Malicdan, M. V., Mamounas, L. A., Manolio, T. A., Mao, R., Maravilla, K., Markello, T. C., Marom, R., Marth, G., Martin, B. A., Martin, M. G., Martinez-Agosto, J. A., Marwaha, S., McCauley, J., McConkie-Rosell, A., McCormack, C. E., McCray, A. T., McGee, E., Mefford, H., Merritt, J., Might, M., Mirzaa, G., Morava, E., Moretti, P. M., Moretti, P., Mosbrook-Davis, D., Mulvihill, J. J., Murdock, D. R., Nagy, A., Nakano-Okuno, M., Nath, A., Nelson, S. F., Newman, J. H., Nicholas, S. K., Nickerson, D., Nieves-Rodriguez, S., Novacic, D., Oglesbee, D., Orengo, J. P., Pace, L., Pak, S., Pallais, J., Palmer, C. S., Papp, J. C., Parker, N. H., Phillips, J. A., Posey, J. E., Potocki, L., Power, B., Pusey, B. N., Quinlan, A., Raja, A. N., Rao, D. A., Raskind, W., Renteria, G., Reuter, C. M., Rives, L., Robertson, A. K., Rodan, L. H., Rosenfeld, J. A., Rosenwasser, N., Rossignol, F., Ruzhnikov, M., Sacco, R., Sampson, J. B., Samson, S. L., Saporta, M., Schaechter, J., Schedl, T., Schoch, K., Scott, C., Scott, D. A., Shashi, V., Shin, J., Signer, R. H., Silverman, E. K., Sinsheimer, J. S., Sisco, K., Smith, E. C., Smith, K. S., Solem, E., Solnica-Krezel, L., Ben Solomon, Spillmann, R. C., Stoler, J. M., Sullivan, J. A., Sullivan, K., Sun, A., Sutton, S., Sweetser, D. A., Sybert, V., Tabor, H. K., Tan, A. M., Tan, Q., Tekin, M., Telischi, F., Thorson, W., Thurm, A., Tifft, C. J., Toro, C., Tran, A. A., Tucker, B. M., Urv, T. K., Vanderver, A., Velinder, M., Viskochil, D., Vogel, T. P., Wahl, C. E., Walker, M., Wallace, S., Walley, N. M., Walsh, C. A., Wambach, J., Wan, J., Wang, L., Wangler, M. F., Ward, P. A., Wegner, D., Wener, M., Wenger, T., Perry, K., Westerfield, M., Wheeler, M. T., Whitlock, J., Wolfe, L. A., Woods, J. D., Yamamoto, S., Yang, J., Yousef, M., Zastrow, D. B., Zein, W., Zhao, C., Zuchner, S., Andrews, M. V., Grange, D. K., Willaert, R., Person, R., Telegrafi, A., Sievers, A., Laugsch, M., Theiss, S., Cheng, Y., Lichtarge, O., Katsonis, P., Stocco, A., Schaaf, C. P., Undiagnosed Diseases Network 2021

  Abstract

  We characterize the clinical and molecular phenotypes of six unrelated individuals with intellectual disability and autism spectrum disorder who carry heterozygous missense variants of the PRKAR1B gene, which encodes the R1β subunit of the cyclic AMP-dependent protein kinase A (PKA).Variants of PRKAR1B were identified by single- or trio-exome analysis. We contacted the families and physicians of the six individuals to collect phenotypic information, performed in vitro analyses of the identified PRKAR1B-variants, and investigated PRKAR1B expression during embryonic development.Recent studies of large patient cohorts with neurodevelopmental disorders found significant enrichment of de novo missense variants in PRKAR1B. In our cohort, de novo origin of the PRKAR1B variants could be confirmed in five of six individuals, and four carried the same heterozygous de novo variant c.1003C>T (p.Arg335Trp; NM_001164760). Global developmental delay, autism spectrum disorder, and apraxia/dyspraxia have been reported in all six, and reduced pain sensitivity was found in three individuals carrying the c.1003C>T variant. PRKAR1B expression in the brain was demonstrated during human embryonal development. Additionally, in vitro analyses revealed altered basal PKA activity in cells transfected with variant-harboring PRKAR1B expression constructs.Our study provides strong evidence for a PRKAR1B-related neurodevelopmental disorder.

  View details for DOI 10.1038/s41436-021-01152-7

  View details for Web of Science ID 000638059400001

  View details for PubMedID 33833410

• The yield of thorough record review in the Undiagnosed Diseases Network Findley, L., Rosenfeld, J., Spillman, R., Cope, H., Schoch, K., Briere, L., Bernstein, J., Hom, J., Ruzhnikov, M., Kravets, E., Botto, L., Bentley, A., Newman, J., Becan, A., Mak, B., Martinez-Agosto, J., Palmer, C., Nelson, S., Parker, N., Martin, M., Fogel, B., Butte, M. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2021: S187

  View details for Web of Science ID 000639219800290

• Early Signs and Symptoms of Leukodystrophies: A Case-Based Guide. Pediatrics in review Ruzhnikov, M. R., Brimble, E., Hickey, R. E., Leukodystrophy Care Network 2021; 42 (3): 133–46

  View details for DOI 10.1542/pir.2019-0184

  View details for PubMedID 33648992

• Commonalities across computational workflows for uncovering explanatory variants in undiagnosed cases. Genetics in medicine : official journal of the American College of Medical Genetics Kobren, S. N., Baldridge, D., Velinder, M., Krier, J. B., LeBlanc, K., Esteves, C., Pusey, B. N., Zuchner, S., Blue, E., Lee, H., Huang, A., Bastarache, L., Bican, A., Cogan, J., Marwaha, S., Alkelai, A., Murdock, D. R., Liu, P., Wegner, D. J., Paul, A. J., Undiagnosed Diseases Network, Sunyaev, S. R., Kohane, I. S., Acosta, M. T., Adam, M., Adams, D. R., Agrawal, P. B., Alejandro, M. E., Alvey, J., Amendola, L., Andrews, A., Ashley, E. A., Azamian, M. S., Bacino, C. A., Bademci, G., Baker, E., Balasubramanyam, A., Baldridge, D., Bale, J., Bamshad, M., Barbouth, D., Bayrak-Toydemir, P., Beck, A., Beggs, A. H., Behrens, E., Bejerano, G., Bennett, J., Berg-Rood, B., Bernstein, J. A., Berry, G. T., Bican, A., Bivona, S., Blue, E., Bohnsack, J., Bonnenmann, C., Bonner, D., Botto, L., Boyd, B., Briere, L. C., Brokamp, E., Brown, G., Burke, E. A., Burrage, L. C., Butte, M. J., Byers, P., Byrd, W. E., Carey, J., Carrasquillo, O., Chang, T. C., Chanprasert, S., Chao, H., Clark, G. D., Coakley, T. R., Cobban, L. A., Cogan, J. D., Coggins, M., Cole, F. S., Colley, H. A., Cooper, C. M., Cope, H., Craigen, W. J., Crouse, A. B., Cunningham, M., D'Souza, P., Dai, H., Dasari, S., Davis, J., Daya, J. G., Deardorff, M., Dell'Angelica, E. C., Dhar, S. U., Dipple, K., Doherty, D., Dorrani, N., Doss, A. L., Douine, E. D., Draper, D. D., Duncan, L., Earl, D., Eckstein, D. J., Emrick, L. T., Eng, C. M., Esteves, C., Falk, M., Fernandez, L., Ferreira, C., Fieg, E. L., Findley, L. C., Fisher, P. G., Fogel, B. L., Forghani, I., Fresard, L., Gahl, W. A., Glass, I., Gochuico, B., Godfrey, R. A., Golden-Grant, K., Goldman, A. M., Goldrich, M. P., Goldstein, D. B., Grajewski, A., Groden, C. A., Gutierrez, I., Hahn, S., Hamid, R., Hanchard, N. A., Hassey, K., Hayes, N., High, F., Hing, A., Hisama, F. M., Holm, I. A., Hom, J., Horike-Pyne, M., Huang, A., Huang, Y., Huryn, L., Isasi, R., Jamal, F., Jarvik, G. P., Jarvik, J., Jayadev, S., Karaviti, L., Kennedy, J., Kiley, D., Kohane, I. S., Kohler, J. N., Korrick, S., Kozuira, M., Krakow, D., Krasnewich, D. M., Kravets, E., Krier, J. B., LaMoure, G. L., Lalani, S. R., Lam, B., Lam, C., Lanpher, B. C., Lanza, I. R., Latham, L., LeBlanc, K., Lee, B. H., Lee, H., Levitt, R., Lewis, R. A., Lincoln, S. A., Liu, P., Liu, X. Z., Longo, N., Loo, S. K., Loscalzo, J., Maas, R. L., MacDowall, J., MacRae, C. A., Macnamara, E. F., Maduro, V. V., Majcherska, M. M., Mak, B. C., Malicdan, M. C., Mamounas, L. A., Manolio, T. A., Mao, R., Maravilla, K., Markello, T. C., Marom, R., Marth, G., Martin, B. A., Martin, M. G., Martinez-Agosto, J. A., Marwaha, S., McCauley, J., McConkie-Rosell, A., McCormack, C. E., McCray, A. T., McGee, E., Mefford, H., Merritt, J. L., Might, M., Mirzaa, G., Morava, E., Moretti, P. M., Moretti, P., Mosbrook-Davis, D., Mulvihill, J. J., Murdock, D. R., Nagy, A., Nakano-Okuno, M., Nath, A., Nelson, S. F., Newman, J. H., Nicholas, S. K., Nickerson, D., Nieves-Rodriguez, S., Novacic, D., Oglesbee, D., Orengo, J. P., Pace, L., Pak, S., Pallais, J. C., Palmer, C. G., Papp, J. C., Parker, N. H., Phillips, J. A., Posey, J. E., Potocki, L., Power, B., Pusey, B. N., Quinlan, A., Raja, A. N., Rao, D. A., Raskind, W., Renteria, G., Reuter, C. M., Rives, L., Robertson, A. K., Rodan, L. H., Rosenfeld, J. A., Rosenwasser, N., Rossignol, F., Ruzhnikov, M., Sacco, R., Sampson, J. B., Samson, S. L., Saporta, M., Schaechter, J., Schedl, T., Schoch, K., Scott, C. R., Scott, D. A., Shashi, V., Shin, J., Signer, R. H., Silverman, E. K., Sinsheimer, J. S., Sisco, K., Smith, E. C., Smith, K. S., Solem, E., Solnica-Krezel, L., Ben Solomon, S., Spillmann, R. C., Stoler, J. M., Sullivan, J. A., Sullivan, K., Sun, A., Sutton, S., Sweetser, D. A., Sybert, V., Tabor, H. K., Tan, A. L., Tan, Q. K., Tekin, M., Telischi, F., Thorson, W., Thurm, A., Tifft, C. J., Toro, C., Tran, A. A., Tucker, B. M., Urv, T. K., Vanderver, A., Velinder, M., Viskochil, D., Vogel, T. P., Wahl, C. E., Walker, M., Wallace, S., Walley, N. M., Walsh, C. A., Wambach, J., Wan, J., Wang, L., Wangler, M. F., Ward, P. A., Wegner, D., Wener, M., Wenger, T., Perry, K. W., Westerfield, M., Wheeler, M. T., Whitlock, J., Wolfe, L. A., Woods, J. D., Yamamoto, S., Yang, J., Yousef, M., Zastrow, D. B., Zein, W., Zhao, C., Zuchner, S. 2021

  Abstract

  PURPOSE: Genomic sequencing has become an increasingly powerful and relevant tool to be leveraged for the discovery of genetic aberrations underlying rare, Mendelian conditions. Although the computational tools incorporated into diagnostic workflows for this task are continually evolving and improving, we nevertheless sought to investigate commonalities across sequencing processing workflows to reveal consensus and standard practice tools and highlight exploratory analyses where technical and theoretical method improvements would be most impactful.METHODS: We collected details regarding the computational approaches used by a genetic testing laboratory and 11 clinical research sites in the United States participating in the Undiagnosed Diseases Network via meetings with bioinformaticians, online survey forms, and analyses of internal protocols.RESULTS: We found that tools for processing genomic sequencing data can be grouped into four distinct categories. Whereas well-established practices exist for initial variant calling and quality control steps, there is substantial divergence across sites in later stages for variant prioritization and multimodal data integration, demonstrating a diversity of approaches for solving the most mysterious undiagnosed cases.CONCLUSION: The largest differences across diagnostic workflows suggest that advances in structural variant detection, noncoding variant interpretation, and integration of additional biomedical data may be especially promising for solving chronically undiagnosed cases.

  View details for DOI 10.1038/s41436-020-01084-8

  View details for PubMedID 33580225

• Aicardi-Goutières syndrome may present with positive newborn screen for X-linked adrenoleukodystrophy. American journal of medical genetics. Part A Tise, C. G., Morales, J. A., Lee, A. S., Velez-Bartolomei, F. n., Floyd, B. J., Levy, R. J., Cusmano-Ozog, K. P., Feigenbaum, A. S., Ruzhnikov, M. R., Lee, C. U., Enns, G. M. 2021

  Abstract

  We report three unrelated probands, two male and one female, diagnosed with Aicardi-Goutières syndrome (AGS) after screening positive on California newborn screening (CA NBS) for X-linked adrenoleukodystrophy (X-ALD) due to elevated C26:0 lysophosphatidylcholine (C26:0-LPC). Follow-up evaluation was notable for elevated C26:0, C26:1, and C26:0/C22:0 ratio, and normal red blood cell plasmalogens levels in all three probands. Diagnoses were confirmed by molecular sequencing prior to 12 months of age after clinical evaluation was inconsistent with X-ALD or suggestive of AGS. For at least one proband, the early diagnosis of AGS enabled candidacy for enrollment into a therapeutic clinical trial. This report demonstrates the importance of including AGS on the differential diagnosis for individuals who screen positive for X-ALD, particularly infants with abnormal neurological features, as this age of onset would be highly unusual for X-ALD. While AGS is not included on the Recommended Universal Screening Panel, affected individuals can be identified early through state NBS programs so long as providers are aware of a broader differential that includes AGS. This report is timely, as state NBS algorithms for X-ALD are actively being established, implemented, and refined.

  View details for DOI 10.1002/ajmg.a.62160

  View details for PubMedID 33683010

• PROSPECTIVE STUDY OF EPILEPSY IN NGLY1 DEFICIENCY Levy, R. J., Frater, C. H., Galentine, W. B., Ruzhnikov, M. R. BMJ PUBLISHING GROUP. 2021: 103

  View details for DOI 10.1136/jim-2021-WRMC

  View details for Web of Science ID 000608729100019

• Identification of protein quality control regulators using a Drosophila model of TPI deficiency. Neurobiology of disease Hrizo, S. L., Eicher, S. L., Myers, T. D., McGrath, I. n., Wodrich, A. P., Venkatesh, H. n., Manjooran, D. n., Swoger, S. n., Gagnon, K. n., Bruskin, M. n., Lebedev, M. V., Zheng, S. n., Vitantonio, A. n., Kim, S. n., Lamb, Z. J., Vogt, A. n., Ruzhnikov, M. R., Palladino, M. J. 2021: 105299

  Abstract

  Triosephosphate isomerase (TPI) deficiency (Df) is a rare recessive metabolic disorder that manifests as hemolytic anemia, locomotor impairment, and progressive neurodegeneration. Research suggests that TPI Df mutations, including the "common" TPIE104Dmutation, results in reduced TPI protein stability that appears to underlie disease pathogenesis. Drosophila with the recessive TPIsugarkill allele (a.k.a. sgk or M80T) exhibit progressive locomotor impairment, neuromuscular impairment and reduced longevity, modeling the human disorder. TPIsugarkill produces a functional protein that is degraded by the proteasome. Molecular chaperones, such as Hsp70 and Hsp90, have been shown to contribute to the regulation of TPIsugarkill degradation. In addition, stabilizing the mutant protein through chaperone modulation results in improved TPI deficiency phenotypes. To identify additional regulators of TPIsugarkill degradation, we performed a genome-wide RNAi screen that targeted known and predicted quality control proteins in the cell to identify novel factors that modulate TPIsugarkill turnover. Of the 430 proteins screened, 25 regulators of TPIsugarkill were identified. Interestingly, 10 proteins identified were novel, previously undescribed Drosophila proteins. Proteins involved in co-translational protein quality control and ribosome function were also isolated in the screen, suggesting that TPIsugarkill may undergo co-translational selection for polyubiquitination and proteasomal degradation as a nascent polypeptide. The proteins identified in this study may reveal novel pathways for the degradation of a functional, cytosolic protein by the ubiquitin proteasome system and define therapeutic pathways for TPI Df and other biomedically important diseases.

  View details for DOI 10.1016/j.nbd.2021.105299

  View details for PubMedID 33600953

• Use of electronic medical record templates improves quality of care for patients with infantile spasms HEALTH INFORMATION MANAGEMENT JOURNAL Santoro, J. D., Sandoval Karamian, A. G., Ruzhnikov, M., Brimble, E., Chadwick, W., Wusthoff, C. J. 2021; 50 (1-2): 47–54

  View details for DOI 10.1177/1833358318794501

  View details for Web of Science ID 000599908600007

• Metabolic Disorders Presenting with Seizures in the Neonatal Period. Seminars in neurology Brimble, E., Ruzhnikov, M. R. 2020

  Abstract

  Metabolic disorders represent rare but often treatable causes of seizures and epilepsy of neonatal onset. As seizures are relatively common in the neonatal period, systemic clues to a specific diagnosis may be lacking or shrouded by acute illness. An important role of the consulting pediatric neurologist is to identify neonates with a possible metabolic or otherwise genetic diagnosis. In this review, the authors describe presenting signs and symptoms, a diagnostic framework, and disorder-specific treatment options for inborn errors of metabolism that may present in the neonatal period. Specific attention is given to the neurologic aspects of each condition, including the electroclinical phenotype and findings on brain imaging. As expedited diagnosis and prompt initiation of available therapies have been demonstrated to result in improved epilepsy and developmental outcomes, this work acts as a framework to guide evaluation when an inherited metabolic disorder is suspected. In addition to informing treatment, a definitive diagnosis allows for appropriate counseling regarding prognosis, any associated screening or preventive measures, and family planning.

  View details for DOI 10.1055/s-0040-1705119

  View details for PubMedID 32185789

• Expanding the Molecular and Clinical Phenotypes of FUT8-CDG. Journal of inherited metabolic disease Ng, B. G., Dastsooz, H., Silawi, M., Habibzadeh, P., Jahan, S. B., Fard, M. A., Halliday, B. J., Raymond, K., Ruzhnikov, M. R., Tabatabaei, Z., Taghipour-Sheshdeh, A., Brimble, E., Robertson, S. P., Faghihi, M. A., Freeze, H. H. 2020

  Abstract

  Pathogenic variants in the Golgi localized alpha 1,6 fucosyltransferase, FUT8, cause a rare inherited metabolic disorder known as FUT8-CDG. To date, only three affected individuals have been reported presenting with a constellation of symptoms including intrauterine growth restriction, severe delays in growth and development, other neurological impairments, significantly shortened limbs, respiratory complications and shortened lifespan. Here we report an additional four unrelated affected individuals homozygous for novel pathogenic variants in FUT8. Analysis of serum N-glycans revealed a complete lack of core fucosylation, an important diagnostic biomarker of FUT8-CDG. Our data expands both the molecular and clinical phenotypes of FUT8-CDG and highlights the importance of identifying a reliable biomarker for confirming potentially pathogenic variants. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/jimd.12221

  View details for PubMedID 32049367

• De novo EIF2AK1 and EIF2AK2 Variants Are Associated with Developmental Delay, Leukoencephalopathy, and Neurologic Decompensation. American journal of human genetics Mao, D. n., Reuter, C. M., Ruzhnikov, M. R., Beck, A. E., Farrow, E. G., Emrick, L. T., Rosenfeld, J. A., Mackenzie, K. M., Robak, L. n., Wheeler, M. T., Burrage, L. C., Jain, M. n., Liu, P. n., Calame, D. n., Küry, S. n., Sillesen, M. n., Schmitz-Abe, K. n., Tonduti, D. n., Spaccini, L. n., Iascone, M. n., Genetti, C. A., Koenig, M. K., Graf, M. n., Tran, A. n., Alejandro, M. n., Lee, B. H., Thiffault, I. n., Agrawal, P. B., Bernstein, J. A., Bellen, H. J., Chao, H. T. 2020

  Abstract

  EIF2AK1 and EIF2AK2 encode members of the eukaryotic translation initiation factor 2 alpha kinase (EIF2AK) family that inhibits protein synthesis in response to physiologic stress conditions. EIF2AK2 is also involved in innate immune response and the regulation of signal transduction, apoptosis, cell proliferation, and differentiation. Despite these findings, human disorders associated with deleterious variants in EIF2AK1 and EIF2AK2 have not been reported. Here, we describe the identification of nine unrelated individuals with heterozygous de novo missense variants in EIF2AK1 (1/9) or EIF2AK2 (8/9). Features seen in these nine individuals include white matter alterations (9/9), developmental delay (9/9), impaired language (9/9), cognitive impairment (8/9), ataxia (6/9), dysarthria in probands with verbal ability (6/9), hypotonia (7/9), hypertonia (6/9), and involuntary movements (3/9). Individuals with EIF2AK2 variants also exhibit neurological regression in the setting of febrile illness or infection. We use mammalian cell lines and proband-derived fibroblasts to further confirm the pathogenicity of variants in these genes and found reduced kinase activity. EIF2AKs phosphorylate eukaryotic translation initiation factor 2 subunit 1 (EIF2S1, also known as EIF2α), which then inhibits EIF2B activity. Deleterious variants in genes encoding EIF2B proteins cause childhood ataxia with central nervous system hypomyelination/vanishing white matter (CACH/VWM), a leukodystrophy characterized by neurologic regression in the setting of febrile illness and other stressors. Our findings indicate that EIF2AK2 missense variants cause a neurodevelopmental syndrome that may share phenotypic and pathogenic mechanisms with CACH/VWM.

  View details for DOI 10.1016/j.ajhg.2020.02.016

  View details for PubMedID 32197074

• MONOZYGOTIC TWINS DISCORDANT FOR CRANIAL DYSINNERVATION DISORDER: EVIDENCE OF VASCULAR DISRUPTION Tise, C. G., DeFilippo, C., Ruzhnikov, M. R., Stevenson, D. BMJ PUBLISHING GROUP. 2020: A147

  View details for DOI 10.1136/jim-2019-WMRC.339

  View details for Web of Science ID 000507513300339

• TANGO2 DEFICIENCY: A CASE SERIES HIGHLIGHTING INTRAFAMILIAL VARIABILITY AND REVIEW OF THE LITERATURE Schymick, J., Bonner, D., Leahy, P., Cowan, T., Ruzhnikov, M., Kohler, J., McCormack, C., Fernandez, L., Matalon, D., Yarlagadda, V., Fisher, P., Ashley, E., Wheeler, M., Enns, G., Bernstein, J., Lee, C. BMJ PUBLISHING GROUP. 2020: A116

  View details for DOI 10.1136/jim-2019-WMRC.268

  View details for Web of Science ID 000507513300269

• Clinical sites of the Undiagnosed Diseases Network: unique contributions to genomic medicine and science. Genetics in medicine : official journal of the American College of Medical Genetics Schoch, K. n., Esteves, C. n., Bican, A. n., Spillmann, R. n., Cope, H. n., McConkie-Rosell, A. n., Walley, N. n., Fernandez, L. n., Kohler, J. N., Bonner, D. n., Reuter, C. n., Stong, N. n., Mulvihill, J. J., Novacic, D. n., Wolfe, L. n., Abdelbaki, A. n., Toro, C. n., Tifft, C. n., Malicdan, M. n., Gahl, W. n., Liu, P. n., Newman, J. n., Goldstein, D. B., Hom, J. n., Sampson, J. n., Wheeler, M. T., Cogan, J. n., Bernstein, J. A., Adams, D. R., McCray, A. T., Shashi, V. n. 2020

  Abstract

  The NIH Undiagnosed Diseases Network (UDN) evaluates participants with disorders that have defied diagnosis, applying personalized clinical and genomic evaluations and innovative research. The clinical sites of the UDN are essential to advancing the UDN mission; this study assesses their contributions relative to standard clinical practices.We analyzed retrospective data from four UDN clinical sites, from July 2015 to September 2019, for diagnoses, new disease gene discoveries and the underlying investigative methods.Of 791 evaluated individuals, 231 received 240 diagnoses and 17 new disease-gene associations were recognized. Straightforward diagnoses on UDN exome and genome sequencing occurred in 35% (84/240). We considered these tractable in standard clinical practice, although genome sequencing is not yet widely available clinically. The majority (156/240, 65%) required additional UDN-driven investigations, including 90 diagnoses that occurred after prior nondiagnostic exome sequencing and 45 diagnoses (19%) that were nongenetic. The UDN-driven investigations included complementary/supplementary phenotyping, innovative analyses of genomic variants, and collaborative science for functional assays and animal modeling.Investigations driven by the clinical sites identified diagnostic and research paradigms that surpass standard diagnostic processes. The new diagnoses, disease gene discoveries, and delineation of novel disorders represent a model for genomic medicine and science.

  View details for DOI 10.1038/s41436-020-00984-z

  View details for PubMedID 33093671

• MRI Surveillance of Boys with X-linked Adrenoleukodystrophy Identified by Newborn Screening: Meta-analysis and Consensus Guidelines. Journal of inherited metabolic disease Mallack, E. J., Turk, B. R., Yan, H. n., Price, C. n., Mlis, M. D., Moser, A. B., Becker, C. n., Hollandsworth, K. n., Adang, L. n., Vanderver, A. n., Van Haren, K. n., Ruzhnikov, M. n., Kurtzberg, J. n., Maegawa, G. n., Orchard, P. J., Lund, T. C., Raymond, G. V., Regelmann, M. n., Orsini, J. J., Seeger, E. n., Kemp, S. n., Eichler, F. n., Fatemi, A. n. 2020

  Abstract

  Among boys with X-Linked adrenoleukodystrophy, a subset will develop childhood cerebral adrenoleukodystrophy (CCALD). CCALD is typically lethal without hematopoietic stem cell transplant before or soon after symptom onset. We sought to establish evidence-based guidelines detailing the neuroimaging surveillance of boys with neurologically asymptomatic adrenoleukodystrophy.To establish the most frequent age and diagnostic neuroimaging modality for CCALD, we completed a meta-analysis of relevant studies published between January 1, 1970 and September 10, 2019. We used the consensus development conference method to incorporate the resulting data into guidelines to inform the timing and techniques for neuroimaging surveillance. Final guideline agreement was defined as >80% consensus.One hundred twenty-three studies met inclusion criteria yielding 1,285 patients. The overall mean age of CCALD diagnosis is 7.91 years old. The median age of CCALD diagnosis calculated from individual patient data is 7.0 years old (IQR: 6.0 - 9.5, n = 349). Ninety percent of patients were diagnosed between 3 and 12. Conventional MRI was most frequently reported, comprised most often of T2-weighted and contrast-enhanced T1-weighted MRI. The expert panel achieved 95.7% consensus on the following surveillance parameters: (1) Obtain an MRI between 12 and 18 months old. (2) Obtain a second MRI 1 year after baseline. (3) Between 3 and 12 years old, obtain a contrast-enhanced MRI every 6 months. (4) After 12 years, obtain an annual MRI.Boys with adrenoleukodystrophy identified early in life should be monitored with serial brain MRIs during the period of highest risk for conversion to CCALD. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/jimd.12356

  View details for PubMedID 33373467

• De Novo EIF2AK1 and EIF2AK2 Variants are Associated with Developmental Delay, Movement Disorders, Cerebellar Ataxia, Leukoencephalopathy, and Neurologic Decompensation Chao, H., Mao, D., Reuter, C., Ruzhnikov, M., Beck, A., Farrow, E., Emrick, L., Mackenzie, K., Robak, L., Wheeler, M., Calame, D., Thiffault, Agarwal, P., Bernstein, J., Bellen, H. WILEY. 2019: S167

  View details for Web of Science ID 000502868300277

• LOCALIZING NEUROLOGIC FEATURES AT PRESENTATION OF VLCAD DEFICIENCY Leahy, P., Matalon, D., Ruzhnikov, M., Cowan, T., Enns, G. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2019: 282

  View details for Web of Science ID 000483451500104

• Extracutaneous manifestations in phacomatosis cesioflammea and cesiomarmorata: Case series and literature review AMERICAN JOURNAL OF MEDICAL GENETICS PART A Kumar, A., Zastrow, D. B., Kravets, E. J., Beleford, D., Ruzhnikov, M. Z., Grove, M. E., Dries, A. M., Kohler, J. N., Waggott, D. M., Yang, Y., Huang, Y., Mackenzie, K. M., Eng, C. M., Fisher, P. G., Ashley, E. A., Teng, J. M., Stevenson, D. A., Shieh, J. T., Wheeler, M. T., Bernstein, J. A., Adams, D. R., Aday, A., Alejandro, M. E., Allard, P., Azamian, M. S., Bacino, C. A., Baker, E., Balasubramanyam, A., Barseghyan, H., Batzli, G. F., Beggs, A. H., Behnam, B., Bellen, H. J., Bican, A., Bick, D. P., Birch, C. L., Bonner, D., Boone, B. E., Bostwick, B. L., Briere, L. C., Brokamp, E., Brown, D. M., Brush, M., Burke, E. A., Burrage, L. C., Butte, M. J., Chen, S., Clark, G. D., Coakley, T. R., Cogan, J. D., Colley, H. A., Cooper, C. M., Cope, H., Craigen, W. J., D'Souza, P., Davids, M., Davidson, J. M., Dayal, J. G., Dell'Angelica, E. C., Dhar, S. U., Dipple, K. M., Donnell-Fink, L. A., Dorrani, N., Dorset, D. C., Douine, E. D., Draper, D. D., Eckstein, D. J., Emrick, L. T., Enns, G. M., Eskin, A., Esteves, C., Estwick, T., Fairbrother, L., Fernandez, L., Ferreira, C., Fieg, E. L., Fogel, B. L., Friedman, N. D., Gahl, W. A., Glanton, E., Godfrey, R. A., Goldman, A. M., Goldstein, D. B., Gould, S. E., Gourdine, J. F., Groden, C. A., Gropman, A. L., Haendel, M., Hamid, R., Hanchard, N. A., High, F., Holm, I. A., Hom, J., Howerton, E. M., Jamal, F., Jiang, Y., Johnston, J. M., Jones, A. L., Karaviti, L., Koeller, D. M., Kohane, I. S., Krasnewich, D. M., Korrick, S., Koziura, M., Krier, J. B., Kyle, J. E., Lalani, S. R., Lau, C., Lazar, J., LeBlanc, K., Lee, B. H., Lee, H., Levy, S. E., Lewis, R. A., Lincoln, S. A., Loo, S. K., Loscalzo, J., Maas, R. L., Macnamara, E. F., MacRae, C. A., Maduro, V. V., Majcherska, M. M., Malicdan, M., Mamounas, L. A., Manolio, T. A., Markello, T. C., Marom, R., Martin, M. G., Martinez-Agosto, J. A., Marwaha, S., May, T., McConkie-Rosell, A., McCormack, C. E., McCray, A. T., Merker, J. D., Metz, T. O., Might, M., Moretti, P. M., Morimoto, M., Mulvihill, J. J., Murdock, D. R., Murphy, J. L., Muzny, D. M., Nehrebecky, M. E., Nelson, S. F., Newberry, J., Newman, J. H., Nicholas, S. K., Novacic, D., Orange, J. S., Orengo, J. P., Pallais, J., Palmer, C. S., Papp, J. C., Parker, N. H., Pena, L. M., Phillips, J. A., Posey, J. E., Postlethwait, J. H., Potocki, L., Pusey, B. N., Reuter, C. M., Rives, L., Robertson, A. K., Rodan, L. H., Rosenfeld, J. A., Sampson, J. B., Samson, S. L., Schoch, K., Scott, D. A., Shakachite, L., Sharma, P., Shashi, V., Signer, R., Silverman, E. K., Sinsheimer, J. S., Smith, K. S., Spillmann, R. C., Staler, J. M., Stong, N., Sullivan, J. A., Sweetser, D. A., Tan, Q., Tifft, C. J., Toro, C., Tran, A. A., Urv, T. K., Vilain, E., Vogel, T. P., Wahl, C. E., Walley, N. M., Walsh, C. A., Walker, M., Wan, J., Wangler, M. F., Ward, P. A., Waters, K. M., Webb-Robertson, B. M., Westerfield, M., Wise, A. L., Wolfe, L. A., Worthey, E. A., Yamamoto, S., Yang, J., Yoon, A. J., Yu, G., Zhao, C., Zheng, A., Undiagnosed Dis Network 2019; 179 (6): 966–77

  View details for DOI 10.1002/ajmg.a.61134

  View details for Web of Science ID 000468322800015

• Consensus Guidelines: MRI surveillance of Children with Presymptomatic Adrenoleukodystrophy Turk, B., Mallack, E., Adang, L., Becker, C., Eichler, F., Van Haren, K., Hollandsworth, K., Kurtzberg, J., Kwon, J., Lund, T., Maegawa, G., Moser, A., Orchard, P., Orsini, J., Rauner, B., Raymond, G., Regelman, M., Ruzhnikov, M., Salzman, A., Vanderver, A., Seeger, E., Fatemi, S. LIPPINCOTT WILLIAMS & WILKINS. 2019

  View details for Web of Science ID 000475965904217

• De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder AMERICAN JOURNAL OF HUMAN GENETICS Calpena, E., Hervieu, A., Kaserer, T., Swagemakers, S. A., Goos, J. C., Popoola, O., Ortiz-Ruiz, M., Barbaro-Dieber, T., Bownass, L., Brilstra, E. H., Brimble, E., Foulds, N., Grebe, T. A., Harder, A. E., Lees, M. M., Monaghan, K. G., Newbury-Ecob, R. A., Ong, K., Osio, D., Santos, F., Ruzhnikov, M. Z., Telegrafi, A., van Binsbergen, E., van Dooren, M. F., van der Spek, P. J., Blagg, J., Twigg, S. F., Mathijssen, I. J., Clarke, P. A., Wilkie, A. M., Deciphering Dev Disorders Study 2019; 104 (4): 709–20

  View details for DOI 10.1016/j.ajhg.2019.02.006

  View details for Web of Science ID 000463474700011

• Extracutaneous manifestations in phacomatosis cesioflammea and cesiomarmorata: Case series and literature review. American journal of medical genetics. Part A Kumar, A., Zastrow, D. B., Kravets, E. J., Beleford, D., Ruzhnikov, M. R., Grove, M. E., Dries, A. M., Kohler, J. N., Waggott, D. M., Yang, Y., Huang, Y., Undiagnosed Diseases Network, Mackenzie, K. M., Eng, C. M., Fisher, P. G., Ashley, E. A., Teng, J. M., Stevenson, D. A., Shieh, J. T., Wheeler, M. T., Bernstein, J. A. 2019

  Abstract

  Phacomatosis pigmentovascularis (PPV) comprises a family of rare conditions that feature vascular abnormalities and melanocytic lesions that can be solely cutaneous or multisystem in nature. Recently published work has demonstrated that both vascular and melanocytic abnormalities in PPV of the cesioflammea and cesiomarmorata subtypes can result from identical somatic mosaic activating mutations in the genes GNAQ and GNA11. Here, we present three new cases of PPV with features of the cesioflammea and/or cesiomarmorata subtypes and mosaic mutations in GNAQ or GNA11. To better understand the risk of potentially occult complications faced by such patients we additionally reviewed 176 cases published in the literature. We report the frequency of clinical findings, their patterns of co-occurrence as well as published recommendations for surveillance after diagnosis. Features assessed include: capillary malformation; dermal and ocular melanocytosis; glaucoma; limb asymmetry; venous malformations; and central nervous system (CNS) anomalies, such as ventriculomegaly and calcifications. We found that ocular findings are common in patients with phacomatosis cesioflammea and cesiomarmorata. Facial vascular involvement correlates with a higher risk of seizures (p=.0066). Our genetic results confirm the role of mosaic somatic mutations in GNAQ and GNA11 in phacomatosis cesioflammea and cesiomarmorata. Their clinical and molecular findings place these conditions on a clinical spectrum encompassing other GNAQ and GNA11 related disorders and inform recommendations for their management.

  View details for PubMedID 30920161

• De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder. American journal of human genetics Calpena, E., Hervieu, A., Kaserer, T., Swagemakers, S. M., Goos, J. A., Popoola, O., Ortiz-Ruiz, M. J., Barbaro-Dieber, T., Bownass, L., Brilstra, E. H., Brimble, E., Foulds, N., Grebe, T. A., Harder, A. V., Lees, M. M., Monaghan, K. G., Newbury-Ecob, R. A., Ong, K., Osio, D., Reynoso Santos, F. J., Ruzhnikov, M. R., Telegrafi, A., van Binsbergen, E., van Dooren, M. F., Deciphering Developmental Disorders Study, van der Spek, P. J., Blagg, J., Twigg, S. R., Mathijssen, I. M., Clarke, P. A., Wilkie, A. O. 2019

  Abstract

  The Mediator is an evolutionarily conserved, multi-subunit complex that regulates multiple steps of transcription. Mediator activity is regulated by the reversible association of a four-subunit module comprising CDK8 or CDK19 kinases, together with cyclin C, MED12 or MED12L, and MED13 or MED13L. Mutations in MED12, MED13, and MED13L were previously identified in syndromic developmental disorders with overlapping phenotypes. Here, we report CDK8 mutations (located at 13q12.13) that cause a phenotypically related disorder. Using whole-exome or whole-genome sequencing, and by international collaboration, we identified eight different heterozygous missense CDK8 substitutions, including 10 shown to have arisen de novo, in 12 unrelated subjects; a recurrent mutation, c.185C>T (p.Ser62Leu), was present in five individuals. All predicted substitutions localize to the ATP-binding pocket of the kinase domain. Affected individuals have overlapping phenotypes characterized by hypotonia, mild to moderate intellectual disability, behavioral disorders, and variable facial dysmorphism. Congenital heart disease occurred in six subjects; additional features present in multiple individuals included agenesis of the corpus callosum, ano-rectal malformations, seizures, and hearing or visual impairments. To evaluate the functional impact of the mutations, we measured phosphorylation at STAT1-Ser727, a known CDK8 substrate, in a CDK8 and CDK19 CRISPR double-knockout cell line transfected with wild-type (WT) or mutant CDK8 constructs. These experiments demonstrated a reduction in STAT1 phosphorylation by all mutants, in most cases to a similar extent as in a kinase-dead control. We conclude that missense mutations in CDK8 cause a developmental disorder that has phenotypic similarity to syndromes associated with mutations in other subunits of the Mediator kinase module, indicating probable overlap in pathogenic mechanisms.

  View details for PubMedID 30905399

• LOCALIZING NEUROLOGIC FEATURES AT PRESENTATION OF VLCAD DEFICIENCY Leahy, P., Matalon, D., Ruzhnikov, M., Cowan, T., Enns, G. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2019: 311

  View details for Web of Science ID 000463310000117

• De Novo Mutations Affecting the Catalytic C alpha Subunit of PP2A, PPP2CA, Cause Syndromic Intellectual Disability Resembling Other PP2A-Related Neurodevelopmental Disorders AMERICAN JOURNAL OF HUMAN GENETICS Reynhout, S., Jansen, S., Haesen, D., van Belle, S., de Munnik, S. A., Bongers, E. F., Schieving, J. H., Marcelis, C., Amiel, J., Rio, M., Mclaughlin, H., Ladda, R., Sell, S., Kriek, M., Peeters-Scholte, C. D., Terhal, P. A., van Gassen, K. L., Verbeek, N., Henry, S., Schwoerer, J., Malik, S., Revencu, N., Ferreira, C. R., Macnamara, E., Braakman, H. H., Brimble, E., Ruznikov, M. Z., Wagner, M., Harrer, P., Wieczorek, D., Kuechler, A., Tziperman, B., Barel, O., de Vries, B. A., Gordon, C. T., Janssens, V., Vissers, L. M. 2019; 104 (1): 139–56

  Abstract

  Type 2A protein phosphatases (PP2As) are highly expressed in the brain and regulate neuronal signaling by catalyzing phospho-Ser/Thr dephosphorylations in diverse substrates. PP2A holoenzymes comprise catalytic C-, scaffolding A-, and regulatory B-type subunits, which determine substrate specificity and physiological function. Interestingly, de novo mutations in genes encoding A- and B-type subunits have recently been implicated in intellectual disability (ID) and developmental delay (DD). We now report 16 individuals with mild to profound ID and DD and a de novo mutation in PPP2CA, encoding the catalytic Cα subunit. Other frequently observed features were severe language delay (71%), hypotonia (69%), epilepsy (63%), and brain abnormalities such as ventriculomegaly and a small corpus callosum (67%). Behavioral problems, including autism spectrum disorders, were reported in 47% of individuals, and three individuals had a congenital heart defect. PPP2CA de novo mutations included a partial gene deletion, a frameshift, three nonsense mutations, a single amino acid duplication, a recurrent mutation, and eight non-recurrent missense mutations. Functional studies showed complete PP2A dysfunction in four individuals with seemingly milder ID, hinting at haploinsufficiency. Ten other individuals showed mutation-specific biochemical distortions, including poor expression, altered binding to the A subunit and specific B-type subunits, and impaired phosphatase activity and C-terminal methylation. Four were suspected to have a dominant-negative mechanism, which correlated with severe ID. Two missense variants affecting the same residue largely behaved as wild-type in our functional assays. Overall, we found that pathogenic PPP2CA variants impair PP2A-B56(δ) functionality, suggesting that PP2A-related neurodevelopmental disorders constitute functionally converging ID syndromes.

  View details for PubMedID 30595372

• Perinatal distress in 1p36 deletion syndrome can mimic hypoxic ischemic encephalopathy. American journal of medical genetics. Part A Carter, L. B., Battaglia, A. n., Cherry, A. n., Manning, M. A., Ruzhnikov, M. R., Bird, L. M., Dowsett, L. n., Graham, J. M., Alkuraya, F. S., Hashem, M. n., Dinulos, M. B., Vallee, S. n., Adam, M. P., Glass, I. n., Beck, A. E., Stevens, C. A., Zackai, E. n., McDougall, C. n., Keena, B. n., Peron, A. n., Vignoli, A. n., Seaver, L. H., Slavin, T. P., Hudgins, L. n. 2019

  Abstract

  1p36 deletion syndrome is a well-described condition with a recognizable phenotype, including cognitive impairment, seizures, and structural brain anomalies such as periventricular leukomalacia (PVL). In a large series of these individuals by Battaglia et al., "birth history was notable in 50% of the cases for varying degrees of perinatal distress." Given the potential for perinatal distress, seizures and PVL, we questioned if this disorder has clinical overlap with hypoxic ischemic encephalopathy (HIE). We reviewed the medical records of 69 individuals with 1p36 deletion to clarify the perinatal phenotype of this disorder and determine if there is evidence of perinatal distress and/or hypoxic injury. Our data provides evidence that these babies have signs of perinatal distress. The majority (59% term; 75% preterm) needed resuscitation and approximately 18% had cardiac arrest. Most had abnormal brain imaging (84% term; 73% preterm) with abnormal white matter findings in over half of patients. PVL or suggestion of "hypoxic insult" was present in 18% of term and 45% of preterm patients. In conclusion, individuals with 1p36 deletion have evidence of perinatal distress, white matter changes, and seizures, which can mimic HIE but are likely related to their underlying chromosome disorder.

  View details for DOI 10.1002/ajmg.a.61266

  View details for PubMedID 31207089

• A case report of a suspected dual diagnosis: 22q11.2 deletion syndrome and X-linked chondrodysplasia punctata CLINICAL DYSMORPHOLOGY Brimble, E., Pacione, M., Farrelly, E., Stevenson, D. A., Ruzhnikov, M. Z. 2018; 27 (4): 151–53

  View details for DOI 10.1097/MCD.0000000000000231

  View details for Web of Science ID 000445749500011

  View details for PubMedID 29912012

• Infantile Spasms of Unknown Cause: Predictors of Outcome and Genotype-Phenotype Correlation PEDIATRIC NEUROLOGY Yuskaitis, C. J., Ruzhnikov, M. Z., Howell, K. B., Allen, I., Kapur, K., Dlugos, D. J., Scheffer, I. E., Poduri, A., Sherr, E. H., EPGP Investigators 2018; 87: 48–56

  View details for DOI 10.1016/j.pediatrneurol.2018.04.012

  View details for Web of Science ID 000454972400011

• Use of electronic medical record templates improves quality of care for patients with infantile spasms. Health information management : journal of the Health Information Management Association of Australia Santoro, J. D., Sandoval, A., Ruzhnikov, M., Brimble, E., Chadwick, W., Wusthoff, C. J. 2018: 1833358318794501

  Abstract

  BACKGROUND: Infantile spasms (IS) is a neurologic disorder of childhood where time to treatment may affect long-term outcomes. Due to the clinical complexity of IS, care can be delayed.OBJECTIVE: To determine if the use of electronic medical record templates (EMRTs) improved care quality in patients treated for IS.METHOD: Records of patients newly diagnosed with IS were retrospectively reviewed both before and after creation of an EMRT for the workup and treatment of IS. Quality of care measures reviewed included delays in treatment plan, medication administration, obtaining neurodiagnostic studies and discharge. The need for repeat neurodiagnostic studies was also assessed. Resident physicians were surveyed regarding template ease of use and functionality.RESULTS: Of 17 patients with IS, 7 received template-based care and 10 did not. Patients in the non-template group had more delays in treatment ( p = 0.010), delay in medication administration ( p = 0.10), delay in diagnostic studies ( p = 0.01) and delay in discharge ( p = 0.39). Neurodiagnostic studies needed to be repeated in 5 out of 10 patients in the non-template group and none of the 7 patients in the template group ( p = 0.04). Surveyed resident physicians reported improved coordination in care, avoidance of delays in discharge and improved ability to predict side effects of treatment with template use.CONCLUSION: In a single centre, the use of protocolised EMRTs decreased treatment delays and the need for repeated invasive procedures in patients with newly diagnosed IS and was reported as easy to use by resident physicians.IMPLICATIONS: The use of protocolised EMRTs may improve the quality of patient care in IS and other rare diseases.

  View details for PubMedID 30124080

• Infantile Spasms of Unknown Cause: Predictors of Outcome and Genotype-Phenotype Correlation. Pediatric neurology Yuskaitis, C. J., Ruzhnikov, M. R., Howell, K. B., Allen, I. E., Kapur, K., Dlugos, D. J., Scheffer, I. E., Poduri, A., Sherr, E. H. 2018

  Abstract

  BACKGROUND: No large-scale studies have specifically evaluated the outcomes of infantile spasms (IS) of unknown cause, previously known as cryptogenic or idiopathic. The Epilepsy Phenome/Genome Project aimed to characterize IS of unknown cause by phenotype and genotype analysis.METHODS: We undertook a retrospective multicenter observational cohort of 133 individuals within the Epilepsy Phenome/Genome Project database met criteria for IS of unknown cause with at least six months of follow-up data. Clinical medical records, imaging, and electroencephalography were examined.RESULTS: Normal development occurred in only 15% of IS of unknown cause. The majority (85%) had clinically documented developmental delay (15% mild, 20% moderate, and 50% severe) at last assessment (median 2.7 years; interquartile interval 1.71-6.25 years). Predictors of positive developmental outcomes included no delay prior to IS (P < 0.001), older age of IS onset (median six months old), and resolution of IS after initial treatment (P < 0.001). Additional seizures after IS occurred in 67%, with predictors being seizures prior to IS (P = 0.018), earlier age of IS onset (median five months old), and refractory IS (P = 0.008). On a research basis, whole exome sequencing identified 15% with de novo variants in known epilepsy genes. Individuals with a genetic finding were more likely to have poor developmental outcomes (P = 0.035).CONCLUSIONS: The current study highlights the predominately unfavorable developmental outcomes and that subsequent seizures are common in children with IS of unknown cause. Ongoing genetic evaluation of IS of seemingly unknown cause is likely to yield a diagnosis and provide valuable prognostic information.

  View details for PubMedID 30174244

• Clinical Transcriptome Sequencing Confirms Activation of a Cryptic Splice Site in Suspected <it><bold>SYNGAP1</it></bold>-Related Disorder MOLECULAR SYNDROMOLOGY Brimble, E., Lee-Messer, C., Nagy, P. L., Propst, J., Ruzhnikov, M. Z. 2018; 9 (6): 295–99

  View details for DOI 10.1159/000492706

  View details for Web of Science ID 000456045700004

• Variable clinical course of identical twin neonates with Alström syndrome presenting coincidentally with dilated cardiomyopathy. American journal of medical genetics. Part A Hollander, S. A., Alsaleh, N., Ruzhnikov, M., Jensen, K., Rosenthal, D. N., Stevenson, D. A., Manning, M. 2017; 173 (6): 1687-1689

  Abstract

  Alström Syndrome (AS) is a rare autosomal recessive disorder caused by mutations in the ALMS1 gene. We report monozygotic twin infants who presented concurrently with symptoms of congestive heart failure (CHF) due to dilated cardiomyopathy (DCM). Following their initial presentation, one twin improved both echocardiographically and functionally while the other twin showed a progressive decline in ventricular function and worsening CHF symptoms requiring multiple hospitalizations and augmentation of heart failure therapy. Concordant findings of nystagmus, vision loss, and developmental delay were noted in both twins. Additional discordant findings included obesity and signs of insulin resistance in one twin. Genetic testing on one sibling confirmed AS. These twins underscore the importance of considering AS in any child presenting with DCM, particularly in infancy, and highlights that, even in monozygotic twins, the clinical course of AS is variable with regard to both the cardiac and non-cardiac manifestations of the disease.

  View details for DOI 10.1002/ajmg.a.38200

  View details for PubMedID 28407410

• DIAGNOSTIC OUTCOMES AND RELATIVE COST OF CLINICAL WHOLE EXOME SEQUENCING Ruzhnikov, M. R., Alsadah, A., Mendelsohn, B., Alhariri, A., Cilio, M. R., Wu, Y., Marco, E. J., Hsiao, E., Sullivan, J., Shieh, J., Slavotinek, A., Sherr, E. H. LIPPINCOTT WILLIAMS & WILKINS. 2016: 247

  View details for DOI 10.1136/jim-d-15-00013.260

  View details for Web of Science ID 000368699600269

• De novo mutations in KIF1A cause progressive encephalopathy and brain atrophy. Annals of clinical and translational neurology Esmaeeli Nieh, S. n., Madou, M. R., Sirajuddin, M. n., Fregeau, B. n., McKnight, D. n., Lexa, K. n., Strober, J. n., Spaeth, C. n., Hallinan, B. E., Smaoui, N. n., Pappas, J. G., Burrow, T. A., McDonald, M. T., Latibashvili, M. n., Leshinsky-Silver, E. n., Lev, D. n., Blumkin, L. n., Vale, R. D., Barkovich, A. J., Sherr, E. H. 2015; 2 (6): 623–35

  Abstract

  To determine the cause and course of a novel syndrome with progressive encephalopathy and brain atrophy in children.Clinical whole-exome sequencing was performed for global developmental delay and intellectual disability; some patients also had spastic paraparesis and evidence of clinical regression. Six patients were identified with de novo missense mutations in the kinesin gene KIF1A. The predicted functional disruption of these mutations was assessed in silico to compare the calculated conformational flexibility and estimated efficiency of ATP binding to kinesin motor domains of wild-type (WT) versus mutant alleles. Additionally, an in vitro microtubule gliding assay was performed to assess the effects of de novo dominant, inherited recessive, and polymorphic variants on KIF1A motor function.All six subjects had severe developmental delay, hypotonia, and varying degrees of hyperreflexia and spastic paraparesis. Microcephaly, cortical visual impairment, optic neuropathy, peripheral neuropathy, ataxia, epilepsy, and movement disorders were also observed. All six patients had a degenerative neurologic course with progressive cerebral and cerebellar atrophy seen on sequential magnetic resonance imaging scans. Computational modeling of mutant protein structures when compared to WT kinesin showed substantial differences in conformational flexibility and ATP-binding efficiency. The de novo KIF1A mutants were nonmotile in the microtubule gliding assay.De novo mutations in KIF1A cause a degenerative neurologic syndrome with brain atrophy. Computational and in vitro assays differentiate the severity of dominant de novo heterozygous versus inherited recessive KIF1A mutations. The profound effect de novo mutations have on axonal transport is likely related to the cause of progressive neurologic impairment in these patients.

  View details for DOI 10.1002/acn3.198

  View details for PubMedID 26125038

  View details for PubMedCentralID PMC4479523

• Hallucinogens Causing Seizures? A Case Report of the Synthetic Amphetamine 2,5-Dimethoxy-4-Chloroamphetamine NEUROHOSPITALIST Burish, M. J., Thoren, K. L., Madou, M., Toossi, S., Shah, M. 2015; 5 (1): 32-34

  Abstract

  Although traditional hallucinogenic drugs such as marijuana and lysergic acid diethylamide (LSD) are not typically associated with seizures, newer synthetic hallucinogenic drugs can provoke seizures. Here, we report the unexpected consequences of taking a street-bought hallucinogenic drug thought to be LSD. Our patient presented with hallucinations and agitation progressing to status epilepticus with a urine toxicology screen positive only for cannabinoids and opioids. Using liquid chromatography high-resolution mass spectrometry, an additional drug was found: an amphetamine-derived phenylethylamine called 2,5-dimethoxy-4-chloroamphetamine. We bring this to the attention of the neurologic community as there are a growing number of hallucinogenic street drugs that are negative on standard urine toxicology and cause effects that are unexpected for both the patient and the neurologist, including seizures.

  View details for DOI 10.1177/1941874414528939

  View details for Web of Science ID 000457808800008

  View details for PubMedID 25553227

  View details for PubMedCentralID PMC4272348

• De novo mutations in epileptic encephalopathies. Nature Allen, A. S., Berkovic, S. F., Cossette, P. n., Delanty, N. n., Dlugos, D. n., Eichler, E. E., Epstein, M. P., Glauser, T. n., Goldstein, D. B., Han, Y. n., Heinzen, E. L., Hitomi, Y. n., Howell, K. B., Johnson, M. R., Kuzniecky, R. n., Lowenstein, D. H., Lu, Y. F., Madou, M. R., Marson, A. G., Mefford, H. C., Esmaeeli Nieh, S. n., O'Brien, T. J., Ottman, R. n., Petrovski, S. n., Poduri, A. n., Ruzzo, E. K., Scheffer, I. E., Sherr, E. H., Yuskaitis, C. J., Abou-Khalil, B. n., Alldredge, B. K., Bautista, J. F., Berkovic, S. F., Boro, A. n., Cascino, G. D., Consalvo, D. n., Crumrine, P. n., Devinsky, O. n., Dlugos, D. n., Epstein, M. P., Fiol, M. n., Fountain, N. B., French, J. n., Friedman, D. n., Geller, E. B., Glauser, T. n., Glynn, S. n., Haut, S. R., Hayward, J. n., Helmers, S. L., Joshi, S. n., Kanner, A. n., Kirsch, H. E., Knowlton, R. C., Kossoff, E. H., Kuperman, R. n., Kuzniecky, R. n., Lowenstein, D. H., McGuire, S. M., Motika, P. V., Novotny, E. J., Ottman, R. n., Paolicchi, J. M., Parent, J. M., Park, K. n., Poduri, A. n., Scheffer, I. E., Shellhaas, R. A., Sherr, E. H., Shih, J. J., Singh, R. n., Sirven, J. n., Smith, M. C., Sullivan, J. n., Lin Thio, L. n., Venkat, A. n., Vining, E. P., Von Allmen, G. K., Weisenberg, J. L., Widdess-Walsh, P. n., Winawer, M. R. 2013; 501 (7466): 217–21

  Abstract

  Epileptic encephalopathies are a devastating group of severe childhood epilepsy disorders for which the cause is often unknown. Here we report a screen for de novo mutations in patients with two classical epileptic encephalopathies: infantile spasms (n = 149) and Lennox-Gastaut syndrome (n = 115). We sequenced the exomes of 264 probands, and their parents, and confirmed 329 de novo mutations. A likelihood analysis showed a significant excess of de novo mutations in the ∼4,000 genes that are the most intolerant to functional genetic variation in the human population (P = 2.9 × 10(-3)). Among these are GABRB3, with de novo mutations in four patients, and ALG13, with the same de novo mutation in two patients; both genes show clear statistical evidence of association with epileptic encephalopathy. Given the relevant site-specific mutation rates, the probabilities of these outcomes occurring by chance are P = 4.1 × 10(-10) and P = 7.8 × 10(-12), respectively. Other genes with de novo mutations in this cohort include CACNA1A, CHD2, FLNA, GABRA1, GRIN1, GRIN2B, HNRNPU, IQSEC2, MTOR and NEDD4L. Finally, we show that the de novo mutations observed are enriched in specific gene sets including genes regulated by the fragile X protein (P < 10(-8)), as has been reported previously for autism spectrum disorders.

  View details for DOI 10.1038/nature12439

  View details for PubMedID 23934111

  View details for PubMedCentralID PMC3773011

• Outcomes analysis after routine removal of implants in healthy pediatric patients JOURNAL OF PEDIATRIC ORTHOPAEDICS-PART B Chu, A., Madou, M. Z., Sala, D. A., Chorney, G. S., Feldman, D. S. 2009; 18 (6): 381-387

  Abstract

  Routine removal of nonspinal, orthopedic implants from pediatric patients is a debated practice. The purpose of this study was to compare preremoval and postremoval outcome measures in children. Twenty-five patients, mean age 11.6 years, completed a pain scale and the Pediatric Outcomes Data Collection Instrument (PODCI). Many patients scored in the normal range of the PODCI before and after removal. Higher postoperative PODCI scores were found in patients without preoperative pain, and in patients with upper extremity versus lower extremity implants. In summary, routine removal of implants in children was carried out without complications and with some functional benefits.

  View details for DOI 10.1097/BPB.0b013e32832d5da2

  View details for Web of Science ID 000270765400021

  View details for PubMedID 19623086

• First-Episode Psychosis in an Adolescent with Seizure Disorder and Tetralogy of Fallot JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY Hulvershorn, L. A., Madou, M. Z., Weis, J., Coffey, B. 2009; 19 (3): 307-311

  View details for DOI 10.1089/cap.2009.19302

  View details for Web of Science ID 000266915800012

  View details for PubMedID 19519268