Elizabeth Spiteri

All Publications

• Advancing access to genome sequencing for rare genetic disorders: recent progress and call to action. NPJ genomic medicine Jobanputra, V., Schroeder, B., Rehm, H. L., Shen, W., Spiteri, E., Nakouzi, G., Taylor, S., Marshall, C. R., Meng, L., Kingsmore, S. F., Ellsworth, K., Ashley, E., Taft, R. J. 2024; 9 (1): 23

  View details for DOI 10.1038/s41525-024-00410-2

  View details for PubMedID 38538605

  View details for PubMedCentralID 8322922

• Evidence review and considerations for use of first line genome sequencing to diagnose rare genetic disorders. NPJ genomic medicine Wigby, K. M., Brockman, D., Costain, G., Hale, C., Taylor, S. L., Belmont, J., Bick, D., Dimmock, D., Fernbach, S., Greally, J., Jobanputra, V., Kulkarni, S., Spiteri, E., Taft, R. J. 2024; 9 (1): 15

  Abstract

  Early use of genome sequencing (GS) in the diagnostic odyssey can reduce suffering and improve care, but questions remain about which patient populations are most amenable to GS as a first-line diagnostic test. To address this, the Medical Genome Initiative conducted a literature review to identify appropriate clinical indications for GS. Studies published from January 2011 to August 2022 that reported on the diagnostic yield (DY) or clinical utility of GS were included. An exploratory meta-analysis using a random effects model evaluated DY based on cohort size and diagnosed cases per cohort. Seventy-one studies met inclusion criteria, comprising over 13,000 patients who received GS in one of the following settings: hospitalized pediatric patients, pediatric outpatients, adult outpatients, or mixed. GS was the first-line test in 38% (27/71). The unweighted mean DY of first-line GS was 45% (12-73%), 33% (6-86%) in cohorts with prior genetic testing, and 33% (9-60%) in exome-negative cohorts. Clinical utility was reported in 81% of first-line GS studies in hospitalized pediatric patients. Changes in management varied by cohort and underlying molecular diagnosis (24-100%). To develop evidence-informed points to consider, the quality of all 71 studies was assessed using modified American College of Radiology (ACR) criteria, with five core points to consider developed, including recommendations for use of GS in the N/PICU, in lieu of sequential testing and when disorders with substantial allelic heterogeneity are suspected. Future large and controlled studies in the pediatric and adult populations may support further refinement of these recommendations.

  View details for DOI 10.1038/s41525-024-00396-x

  View details for PubMedID 38409289

• Section E6.7-6.12 of the American College of Medical Genetics and Genomics (ACMG) Technical Laboratory Standards: Cytogenomic studies of acquired chromosomal abnormalities in solid tumors. Genetics in medicine : official journal of the American College of Medical Genetics Church, A. J., Akkari, Y., Deeb, K., Kolhe, R., Lin, F., Spiteri, E., Wolff, D. J., Shao, L. 2024: 101070

  Abstract

  Clinical cytogenomic studies of solid tumor samples are critical to the diagnosis, prognostication, and treatment selection for cancer patients. An overview of current cytogenomic techniques for solid tumor analysis is provided, including standards for sample preparation, clinical and technical considerations, and documentation of results. With the evolving technologies and their application in solid tumor analysis, these standards now include sequencing technology and optical genome mapping, in addition to the conventional cytogenomic methods, such as G-banded chromosome analysis, fluorescence in situ hybridization, and chromosomal microarray analysis. This updated Section E6.7-6.12 supersedes the previous Section E6.5-6.8 in Section E: Clinical Cytogenetics of the American College of Medical Genetics and Genomics Standards for Clinical Genetics Laboratories.

  View details for DOI 10.1016/j.gim.2024.101070

  View details for PubMedID 38376505

• The clinical, molecular, and prognostic features of the 2022 WHO and ICC classification systems for myelodysplastic neoplasms. Leukemia research Khanna, V., Lu, R., Kumar, J., Molina, A., Stehr, H., Spiteri, E., Spinner, M., Silva, O., Fernandez-Pol, S., Tan, B., Greenberg, P. L. 2023; 136: 107433

  Abstract

  Myelodysplastic neoplasms (MDS) are clonal disorders of bone marrow failure exhibiting a variable risk of progression to acute myeloid leukemia. MDS exhibit certain prognostic genetic or cytogenetic abnormalities, an observation that has led to both the pathologic reclassification of MDS in the 2022 World Health Organization (WHO) and International Consensus Classification (ICC) systems, as well as to an updated prognostic schema, the Molecular International Prognostic Scoring System (IPSS-M). This single-institution study characterized the molecular patterns and clinical outcomes associated with the 2022 WHO and ICC classification schemas to assess their clinical utility. Strikingly, with the exception of one individual, all 210 patients in our cohort were classified into analogous categories by the two pathologic/diagnostic schemas. Most patients (70%) were classified morphologically while the remaining 30% had genetically classified disease by both criteria. Prognostic risk, as assessed by the IPSS-M score was highest in patients with MDS with biallelic/multi-hit TP53 mutations and lowest in pts with MDS-SF3B1. Median leukemia-free survival (LFS) was shortest for those with MDS with biallelic/multi-hit TP53 (0.7 years) and longest for those with MDS with low blasts (LFS not reached). These data demonstrate the clear ability of the 2022 WHO and ICC classifications to organize MDS patients into distinct prognostic risk groups and further show that both classification systems share more similarities than differences. Incorporation of the IPSS-M and IPSS-R features provide additive prognostic and survival components to both the WHO and ICC classifications, which together enhance their utility for evaluating and treating MDS patients.

  View details for DOI 10.1016/j.leukres.2023.107433

  View details for PubMedID 38154193

• Two epilepsy-associated variants in KCNA2 (KV1.2) at position H310 oppositely affect channel functional expression. The Journal of physiology Minguez-Vinas, T., Prakash, V., Wang, K., Lindstrom, S. H., Pozzi, S., Scott, S. A., Spiteri, E., Stevenson, D. A., Ashley, E. A., Gunnarsson, C., Pantazis, A. 2023

  Abstract

  Two KCNA2 variants (p.H310Y and p.H310R) were discovered in paediatric patients with epilepsy and developmental delay. KCNA2 encodes KV 1.2-channel subunits, which regulate neuronal excitability. Both gain and loss of KV 1.2 function cause epilepsy, precluding the prediction of variant effects; and while H310 is conserved throughout the KV -channel superfamily, it is largely understudied. We investigated both variants in heterologously expressed, human KV 1.2 channels by immunocytochemistry, electrophysiology and voltage-clamp fluorometry. Despite affecting the same channel, at the same position, and being associated with severe neurological disease, the two variants had diametrically opposite effects on KV 1.2 functional expression. The p.H310Y variant produced 'dual gain of function', increasing both cell-surface trafficking and activity, delaying channel closure. We found that the latter is due to the formation of a hydrogen bond that stabilizes the active state of the voltage-sensor domain. Additionally, H310Y abolished 'ball and chain' inactivation of KV 1.2 by KV beta1 subunits, enhancing gain of function. In contrast, p.H310R caused 'dual loss of function', diminishing surface levels by multiple impediments to trafficking and inhibiting voltage-dependent channel opening. We discuss the implications for KV -channel biogenesis and function, an emergent hotspot for disease-associated variants, and mechanisms of epileptogenesis. KEY POINTS: KCNA2 encodes the subunits of KV 1.2 voltage-activated, K+ -selective ion channels, which regulate electrical signalling in neurons. We characterize two KCNA2 variants from patients with developmental delay and epilepsy. Both variants affect position H310, highly conserved in KV channels. The p.H310Y variant caused 'dual gain of function', increasing both KV 1.2-channel activity and the number of KV 1.2 subunits on the cell surface. H310Y abolished 'ball and chain' (N-type) inactivation of KV 1.2 by KV beta1 subunits, enhancing the gain-of-function phenotype. The p.H310R variant caused 'dual loss of function', diminishing the presence of KV 1.2 subunits on the cell surface and inhibiting voltage-dependent channel opening. As H310Y stabilizes the voltage-sensor active conformation and abolishes N-type inactivation, it can serve as an investigative tool for functional and pharmacological studies.

  View details for DOI 10.1113/JP285052

  View details for PubMedID 37883018

• The landscape of reported VUS in multi-gene panel and genomic testing: Time for a change. Genetics in medicine : official journal of the American College of Medical Genetics Rehm, H. L., Alaimo, J. T., Aradhya, S., Bayrak-Toydemir, P., Best, H., Brandon, R., Buchan, J. G., Chao, E. C., Chen, E., Clifford, J., Cohen, A. S., Conlin, L. K., Das, S., Davis, K. W., Gaudio, D. D., Del Viso, F., DiVincenzo, C., Eisenberg, M., Guidugli, L., Hammer, M. B., Harrison, S. M., Hatchell, K. E., Dyer, L. H., Hoang, L. U., Holt, J. M., Jobanputra, V., Karbassi, I. D., Kearney, H. M., Kelly, M. A., Kelly, J. M., Kluge, M. L., Komala, T., Kruszka, P., Lau, L., Lebo, M. S., Marshall, C. R., McKnight, D., McWalter, K., Meng, Y., Nagan, N., Neckelmann, C. S., Neerman, N., Niu, Z., Paolillo, V. K., Paolucci, S. A., Perry, D., Pesaran, T., Radtke, K., Rasmussen, K. J., Retterer, K., Saunders, C. J., Spiteri, E., Stanley, C., Szuto, A., Taft, R. J., Thiffault, I., Thomas, B. C., Thomas-Wilson, A., Thorpe, E., Tidwell, T. J., Towne, M. C., Zouk, H. 2023: 100947

  Abstract

  Variants of uncertain significance (VUS) are a common result of diagnostic genetic testing and can be difficult to manage with potential misinterpretation and downstream costs, including time investment by clinicians. We investigated the rate of VUS reported on diagnostic testing via multi-gene panels (MGPs) and exome and genome sequencing (ES/GS) to measure the magnitude of uncertain results and explore ways to reduce their potentially detrimental impact.Rates of inconclusive results due to VUS were collected from over 1.5 million sequencing test results from 19 clinical laboratories in North America from 2020 - 2021.We found a lower rate of inconclusive test results due to VUSs from ES/GS (22.5%) compared to MGPs (32.6%; p<0.0001). For MGPs, the rate of inconclusive results correlated with panel size. The use of trios reduced inconclusive rates (18.9% vs 27.6%; p<0.001) whereas the use of GS compared to ES had no impact (22.2% vs 22.6%; p=ns).The high rate of VUS observed in diagnostic MGP testing warrants examining current variant reporting practices. We propose several approaches to reduce reported VUS rates, while directing clinician resources towards important VUS follow-up.

  View details for DOI 10.1016/j.gim.2023.100947

  View details for PubMedID 37534744

• Accurate Detection of Clinically Actionable Copy Number Variants in Diverse Hematological Neoplasms By Routine Targeted Sequencing: A Comparative Performance Study Mosquera, A., Hosoya, H., Jin, M. C., Esfahani, M., Schroers-Martin, J., Sworder, B., Liu, C., Spiteri, E., Natkunam, Y., Zehnder, J. L., Stehr, H., Kurtz, D. M., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2022: 10712-10713

  View details for DOI 10.1182/blood-2022-167900

  View details for Web of Science ID 000893230303319

• Deconvoluting complex correlates of COVID-19 severity with a multi-omic pandemic tracking strategy. Nature communications Parikh, V. N., Ioannidis, A. G., Jimenez-Morales, D., Gorzynski, J. E., De Jong, H. N., Liu, X., Roque, J., Cepeda-Espinoza, V. P., Osoegawa, K., Hughes, C., Sutton, S. C., Youlton, N., Joshi, R., Amar, D., Tanigawa, Y., Russo, D., Wong, J., Lauzon, J. T., Edelson, J., Mas Montserrat, D., Kwon, Y., Rubinacci, S., Delaneau, O., Cappello, L., Kim, J., Shoura, M. J., Raja, A. N., Watson, N., Hammond, N., Spiteri, E., Mallempati, K. C., Montero-Martín, G., Christle, J., Kim, J., Kirillova, A., Seo, K., Huang, Y., Zhao, C., Moreno-Grau, S., Hershman, S. G., Dalton, K. P., Zhen, J., Kamm, J., Bhatt, K. D., Isakova, A., Morri, M., Ranganath, T., Blish, C. A., Rogers, A. J., Nadeau, K., Yang, S., Blomkalns, A., O'Hara, R., Neff, N. F., DeBoever, C., Szalma, S., Wheeler, M. T., Gates, C. M., Farh, K., Schroth, G. P., Febbo, P., deSouza, F., Cornejo, O. E., Fernandez-Vina, M., Kistler, A., Palacios, J. A., Pinsky, B. A., Bustamante, C. D., Rivas, M. A., Ashley, E. A. 2022; 13 (1): 5107

  Abstract

  The SARS-CoV-2 pandemic has differentially impacted populations across race and ethnicity. A multi-omic approach represents a powerful tool to examine risk across multi-ancestry genomes. We leverage a pandemic tracking strategy in which we sequence viral and host genomes and transcriptomes from nasopharyngeal swabs of 1049 individuals (736 SARS-CoV-2 positive and 313 SARS-CoV-2 negative) and integrate them with digital phenotypes from electronic health records from a diverse catchment area in Northern California. Genome-wide association disaggregated by admixture mapping reveals novel COVID-19-severity-associated regions containing previously reported markers of neurologic, pulmonary and viral disease susceptibility. Phylodynamic tracking of consensus viral genomes reveals no association with disease severity or inferred ancestry. Summary data from multiomic investigation reveals metagenomic and HLA associations with severe COVID-19. The wealth of data available from residual nasopharyngeal swabs in combination with clinical data abstracted automatically at scale highlights a powerful strategy for pandemic tracking, and reveals distinct epidemiologic, genetic, and biological associations for those at the highest risk.

  View details for DOI 10.1038/s41467-022-32397-8

  View details for PubMedID 36042219

• Loss-of-function variants in SRRM2 cause a neurodevelopmental disorder. Genetics in medicine : official journal of the American College of Medical Genetics Cuinat, S., Nizon, M., Isidor, B., Stegmann, A., van Jaarsveld, R. H., van Gassen, K. L., van der Smagt, J. J., Volker-Touw, C. M., Holwerda, S. J., Terhal, P. A., Schuhmann, S., Vasileiou, G., Khalifa, M., Nugud, A. A., Yasaei, H., Ousager, L. B., Brasch-Andersen, C., Deb, W., Besnard, T., Simon, M. E., Amsterdam, K. H., Verbeek, N. E., Matalon, D., Dykzeul, N., White, S., Spiteri, E., Devriendt, K., Boogaerts, A., Willemsen, M., Brunner, H. G., Sinnema, M., De Vries, B. B., Gerkes, E. H., Pfundt, R., Izumi, K., Krantz, I. D., Xu, Z. L., Murrell, J. R., Valenzuela, I., Cusco, I., Rovira-Moreno, E., Yang, Y., Bizaoui, V., Patat, O., Faivre, L., Tran-Mau-Them, F., Vitobello, A., Denommé-Pichon, A. S., Philippe, C., Bezieau, S., Cogné, B. 2022

  Abstract

  SRRM2 encodes the SRm300 protein, a splicing factor of the SR-related protein family characterized by its serine- and arginine-enriched domains. It promotes interactions between messenger RNA and the spliceosome catalytic machinery. This gene, predicted to be highly intolerant to loss of function (LoF) and very conserved through evolution, has not been previously reported in constitutive human disease.Among the 1000 probands studied with developmental delay and intellectual disability in our database, we found 2 patients with de novo LoF variants in SRRM2. Additional families were identified through GeneMatcher.Here, we report on 22 patients with LoF variants in SRRM2 and provide a description of the phenotype. Molecular analysis identified 12 frameshift variants, 8 nonsense variants, and 2 microdeletions of 66 kb and 270 kb. The patients presented with a mild developmental delay, predominant speech delay, autistic or attention-deficit/hyperactivity disorder features, overfriendliness, generalized hypotonia, overweight, and dysmorphic facial features. Intellectual disability was variable and mild when present.We established SRRM2 as a gene responsible for a rare neurodevelopmental disease.

  View details for DOI 10.1016/j.gim.2022.04.011

  View details for PubMedID 35567594

• Best practices for the interpretation and reporting of clinical whole genome sequencing. NPJ genomic medicine Austin-Tse, C. A., Jobanputra, V., Perry, D. L., Bick, D., Taft, R. J., Venner, E., Gibbs, R. A., Young, T., Barnett, S., Belmont, J. W., Boczek, N., Chowdhury, S., Ellsworth, K. A., Guha, S., Kulkarni, S., Marcou, C., Meng, L., Murdock, D. R., Rehman, A. U., Spiteri, E., Thomas-Wilson, A., Kearney, H. M., Rehm, H. L. 2022; 7 (1): 27

  Abstract

  Whole genome sequencing (WGS) shows promise as a first-tier diagnostic test for patients with rare genetic disorders. However, standards addressing the definition and deployment practice of a best-in-class test are lacking. To address these gaps, the Medical Genome Initiative, a consortium of leading health care and research organizations in the US and Canada, was formed to expand access to high quality clinical WGS by convening experts and publishing best practices. Here, we present best practice recommendations for the interpretation and reporting of clinical diagnostic WGS, including discussion of challenges and emerging approaches that will be critical to harness the full potential of this comprehensive test.

  View details for DOI 10.1038/s41525-022-00295-z

  View details for PubMedID 35395838

• 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

• Comparison of the Transcriptomic Signatures in Pediatric and Adult CML. Cancers Youn, M., Smith, S. M., Lee, A. G., Chae, H., Spiteri, E., Erdmann, J., Galperin, I., Jones, L. M., Donato, M., Abidi, P., Bittencourt, H., Lacayo, N., Dahl, G., Aftandilian, C., Davis, K. L., Matthews, J. A., Kornblau, S. M., Huang, M., Sumarsono, N., Redell, M. S., Fu, C. H., Chen, I., Alonzo, T. A., Eklund, E., Gotlib, J., Khatri, P., Sweet-Cordero, E. A., Hijiya, N., Sakamoto, K. M. 1800; 13 (24)

  Abstract

  Children with chronic myeloid leukemia (CML) tend to present with higher white blood counts and larger spleens than adults with CML, suggesting that the biology of pediatric and adult CML may differ. To investigate whether pediatric and adult CML have unique molecular characteristics, we studied the transcriptomic signature of pediatric and adult CML CD34+ cells and healthy pediatric and adult CD34+ control cells. Using high-throughput RNA sequencing, we found 567 genes (207 up- and 360 downregulated) differentially expressed in pediatric CML CD34+ cells compared to pediatric healthy CD34+ cells. Directly comparing pediatric and adult CML CD34+ cells, 398 genes (258 up- and 140 downregulated), including many in the Rho pathway, were differentially expressed in pediatric CML CD34+ cells. Using RT-qPCR to verify differentially expressed genes, VAV2 and ARHGAP27 were significantly upregulated in adult CML CD34+ cells compared to pediatric CML CD34+ cells. NCF1, CYBB, and S100A8 were upregulated in adult CML CD34+ cells but not in pediatric CML CD34+ cells, compared to healthy controls. In contrast, DLC1 was significantly upregulated in pediatric CML CD34+ cells but not in adult CML CD34+ cells, compared to healthy controls. These results demonstrate unique molecular characteristics of pediatric CML, such as dysregulation of the Rho pathway, which may contribute to clinical differences between pediatric and adult patients.

  View details for DOI 10.3390/cancers13246263

  View details for PubMedID 34944883

• Identification of a pathogenic TUBB1 variant in a Chinese family with congenital macrothrombocytopenia through whole genome sequencing. Platelets Hou, Y. n., Shao, L. n., Zhou, H. n., Liu, Y. n., Fisk, D. G., Spiteri, E. n., Zehnder, J. L., Peng, J. n., Zhang, B. M., Hou, M. n. 2021: 1–5

  Abstract

  Congenital macrothrombocytopenia is a genetically heterogeneous group of rare disorders. We herein report a large Chinese family presented with phenotypic variability involving thrombocytopenia and/or giant platelets. Whole genome sequencing (WGS) of the proband and one of his affected brothers identified a potentially pathogenic c.952 C > T heterozygous variant in the TUBB1 gene. This p.R318W β1-tubulin variant was also identified in three additional siblings and five members of the next generation. These findings were consistent with an autosomal dominant inheritance with incomplete penetrance. Moreover, impaired platelet agglutination in response to ristocetin was detected in the patient's brother. Half of the family members harboring the p.R318W mutation displayed significantly decreased external release of p-selectin by stimulated platelets. The p.R318W β1-tubulin mutation was identified for the first time in a Chinese family with congenital macrothrombocytopenia using WGS as an unbiased sequencing approach. Affected individuals within the family demonstrated impaired platelet aggregation and/or release functions.

  View details for DOI 10.1080/09537104.2020.1869714

  View details for PubMedID 33400601

• Biallelic UBE4A loss-of-function variants cause intellectual disability and global developmental delay. Genetics in medicine : official journal of the American College of Medical Genetics Melo, U. S., Bonner, D. n., Kent Lloyd, K. C., Moshiri, A. n., Willis, B. n., Lanoue, L. n., Bower, L. n., Leonard, B. C., Martins, D. J., Gomes, F. n., de Souza Leite, F. n., Oliveira, D. n., Kitajima, J. P., Monteiro, F. P., Zatz, M. n., Menck, C. F., Wheeler, M. T., Bernstein, J. A., Dumas, K. n., Spiteri, E. n., Di Donato, N. n., Jahn, A. n., Hashem, M. n., Alsaif, H. S., Chedrawi, A. n., Alkuraya, F. S., Kok, F. n., Byers, H. M. 2021

  Abstract

  To identify novel genes associated with intellectual disability (ID) in four unrelated families.Here, through exome sequencing and international collaboration, we report eight individuals from four unrelated families of diverse geographic origin with biallelic loss-of-function variants in UBE4A.Eight evaluated individuals presented with syndromic intellectual disability and global developmental delay. Other clinical features included hypotonia, short stature, seizures, and behavior disorder. Characteristic features were appreciated in some individuals but not all; in some cases, features became more apparent with age. We demonstrated that UBE4A loss-of-function variants reduced RNA expression and protein levels in clinical samples. Mice generated to mimic patient-specific Ube4a loss-of-function variant exhibited muscular and neurological/behavioral abnormalities, some of which are suggestive of the clinical abnormalities seen in the affected individuals.These data indicate that biallelic loss-of-function variants in UBE4A cause a novel intellectual disability syndrome, suggesting that UBE4A enzyme activity is required for normal development and neurological function.

  View details for DOI 10.1038/s41436-020-01047-z

  View details for PubMedID 33420346