Yongjin Yoo

All Publications

• Integrative analyses highlight functional regulatory variants associated with neuropsychiatric diseases. Nature genetics Guo, M. G., Reynolds, D. L., Ang, C. E., Liu, Y., Zhao, Y., Donohue, L. K., Siprashvili, Z., Yang, X., Yoo, Y., Mondal, S., Hong, A., Kain, J., Meservey, L., Fabo, T., Elfaki, I., Kellman, L. N., Abell, N. S., Pershad, Y., Bayat, V., Etminani, P., Holodniy, M., Geschwind, D. H., Montgomery, S. B., Duncan, L. E., Urban, A. E., Altman, R. B., Wernig, M., Khavari, P. A. 2023

  Abstract

  Noncoding variants of presumed regulatory function contribute to the heritability of neuropsychiatric disease. A total of 2,221 noncoding variants connected to risk for ten neuropsychiatric disorders, including autism spectrum disorder, attention deficit hyperactivity disorder, bipolar disorder, borderline personality disorder, major depression, generalized anxiety disorder, panic disorder, post-traumatic stress disorder, obsessive-compulsive disorder and schizophrenia, were studied in developing human neural cells. Integrating epigenomic and transcriptomic data with massively parallel reporter assays identified differentially-active single-nucleotide variants (daSNVs) in specific neural cell types. Expression-gene mapping, network analyses and chromatin looping nominated candidate disease-relevant target genes modulated by these daSNVs. Follow-up integration of daSNV gene editing with clinical cohort analyses suggested that magnesium transport dysfunction may increase neuropsychiatric disease risk and indicated that common genetic pathomechanisms may mediate specific symptoms that are shared across multiple neuropsychiatric diseases.

  View details for DOI 10.1038/s41588-023-01533-5

  View details for PubMedID 37857935

  View details for PubMedCentralID 4112379

• A cell therapy approach to restore microglial Trem2 function in a mouse model of Alzheimer's disease. Cell stem cell Yoo, Y., Neumayer, G., Shibuya, Y., Marc-Daniel Mader, M., Wernig, M. 2023; 30 (8): 1043-1053.e6

  Abstract

  Alzheimer's disease (AD) remains one of the grand challenges facing human society. Much controversy exists around the complex and multifaceted pathogenesis of this prevalent disease. Given strong human genetic evidence, there is little doubt, however, that microglia play an important role in preventing degeneration of neurons. For example, loss of function of the microglial gene Trem2 renders microglia dysfunctional and causes an early-onset neurodegenerative syndrome, and Trem2 variants are among the strongest genetic risk factors for AD. Thus, restoring microglial function represents a rational therapeutic approach. Here, we show that systemic hematopoietic cell transplantation followed by enhancement of microglia replacement restores microglial function in a Trem2 mutant mouse model of AD.

  View details for DOI 10.1016/j.stem.2023.07.006

  View details for PubMedID 37541210

• Augmentation of a neuroprotective myeloid state by hematopoietic cell transplantation. bioRxiv : the preprint server for biology Marc-Daniel Mader, M., Napole, A., Wu, D., Shibuya, Y., Scavetti, A., Foltz, A., Atkins, M., Hahn, O., Yoo, Y., Danziger, R., Tan, C., Wyss-Coray, T., Steinman, L., Wernig, M. 2023

  Abstract

  Multiple sclerosis (MS) is an autoimmune disease associated with inflammatory demyelination in the central nervous system (CNS). Autologous hematopoietic cell transplantation (HCT) is under investigation as a promising therapy for treatment-refractory MS. Here we identify a reactive myeloid state in chronic experimental autoimmune encephalitis (EAE) mice and MS patients that is surprisingly associated with neuroprotection and immune suppression. HCT in EAE mice leads to an enhancement of this myeloid state, as well as clinical improvement, reduction of demyelinated lesions, suppression of cytotoxic T cells, and amelioration of reactive astrogliosis reflected in reduced expression of EAE-associated gene signatures in oligodendrocytes and astrocytes. Further enhancement of myeloid cell incorporation into the CNS following a modified HCT protocol results in an even more consistent therapeutic effect corroborated by additional amplification of HCT-induced transcriptional changes, underlining myeloid-derived beneficial effects in the chronic phase of EAE. Replacement or manipulation of CNS myeloid cells thus represents an intriguing therapeutic direction for inflammatory demyelinating disease.

  View details for DOI 10.1101/2023.03.10.532123

  View details for PubMedID 36945385

  View details for PubMedCentralID PMC10028976

• Treatment of a genetic brain disease by CNS-wide microglia replacement. Science translational medicine Shibuya, Y., Kumar, K. K., Mader, M. M., Yoo, Y., Ayala, L. A., Zhou, M., Mohr, M. A., Neumayer, G., Kumar, I., Yamamoto, R., Marcoux, P., Liou, B., Bennett, F. C., Nakauchi, H., Sun, Y., Chen, X., Heppner, F. L., Wyss-Coray, T., Südhof, T. C., Wernig, M. 2022; 14 (636): eabl9945

  Abstract

  Hematopoietic cell transplantation after myeloablative conditioning has been used to treat various genetic metabolic syndromes but is largely ineffective in diseases affecting the brain presumably due to poor and variable myeloid cell incorporation into the central nervous system. Here, we developed and characterized a near-complete and homogeneous replacement of microglia with bone marrow cells in mice without the need for genetic manipulation of donor or host. The high chimerism resulted from a competitive advantage of scarce donor cells during microglia repopulation rather than enhanced recruitment from the periphery. Hematopoietic stem cells, but not immediate myeloid or monocyte progenitor cells, contained full microglia replacement potency equivalent to whole bone marrow. To explore its therapeutic potential, we applied microglia replacement to a mouse model for Prosaposin deficiency, which is characterized by a progressive neurodegeneration phenotype. We found a reduction of cerebellar neurodegeneration and gliosis in treated brains, improvement of motor and balance impairment, and life span extension even with treatment started in young adulthood. This proof-of-concept study suggests that efficient microglia replacement may have therapeutic efficacy for a variety of neurological diseases.

  View details for DOI 10.1126/scitranslmed.abl9945

  View details for PubMedID 35294256

• Overexpression of Replication-Dependent Histone Signifies a Subset of Dedifferentiated Liposarcoma with Increased Aggressiveness. Cancers Yoo, Y., Park, S., Jo, E. B., Choi, M., Lee, K. W., Hong, D., Lee, S., Lee, C., Lee, Y., Um, J., Park, J. B., Seo, S. W., Choi, Y., Kim, S., Lee, S., Choi, M. 2021; 13 (13)

  Abstract

  Liposarcoma (LPS) is an adult soft tissue malignancy that arises from fat tissue, where well-differentiated (WD) and dedifferentiated (DD) forms are the most common. DDLPS represents the progression of WDLPS into a more aggressive high-grade and metastatic form. Although a few DNA copy-number amplifications are known to be specifically found in WD- or DDLPS, systematic genetic differences that signify subtype determination between WDLPS and DDLPS remain unclear. Here, we profiled the genome and transcriptome of 38 LPS tumors to uncover the genetic signatures of subtype differences. Replication-dependent histone (RD-HIST) mRNAs were highly elevated and their regulation was disrupted in a subset of DDLPS, increasing cellular histone molecule levels, as measured using RNA-seq (the averaged fold change of 53 RD-HIST genes between the DD and WD samples was 10.9) and immunohistochemistry. The change was not observed in normal tissues. Integrated whole-exome sequencing, RNA-seq, and methylation analyses revealed that the overexpressed HMGA2 (the fold change between DD and WD samples was 7.3) was responsible for the increased RD-HIST level, leading to aberrant cell proliferation. Therefore, HMGA2-mediated elevation of RD-HISTs were crucial events in determining the aggressiveness of DDLPS, which may serve as a biomarker for prognosis prediction for liposarcoma patients.

  View details for DOI 10.3390/cancers13133122

  View details for PubMedID 34206586

• Genomic profiling of 553 uncharacterized neurodevelopment patients reveals a high proportion of recessive pathogenic variant carriers in an outbred population. Scientific reports Lee, Y., Park, S., Lee, J. S., Kim, S. Y., Cho, J., Yoo, Y., Lee, S., Yoo, T., Lee, M., Seo, J., Lee, J., Kneissl, J., Lee, J., Jeon, H., Jeon, E. Y., Hong, S. E., Kim, E., Kim, H., Kim, W. J., Kim, J. S., Ko, J. M., Cho, A., Lim, B. C., Kim, W. S., Choi, M., Chae, J. 2020; 10 (1): 1413

  Abstract

  A substantial portion of Mendelian disease patients suffers from genetic variants that are inherited in a recessive manner. A precise understanding of pathogenic recessive variants in a population would assist in pre-screening births of such patients. However, a systematic understanding of the contribution of recessive variants to Mendelian diseases is still lacking. Therefore, genetic diagnosis and variant discovery of 553 undiagnosed Korean patients with complex neurodevelopmental problems (KND for Korean NeuroDevelopmental cohort) were performed using whole exome sequencing of patients and their parents. Disease-causing variants, including newly discovered variants, were identified in 57.5% of the probands of the KND cohort. Among the patients with the previous reported pathogenic variants, 35.1% inherited these variants in a recessive manner. Genes that cause recessive disorders in our cohort tend to be less constrained by loss-of-function variants and were enriched in lipid metabolism and mitochondrial functions. This observation was applied to an estimation that approximately 1 in 17 healthy Korean individuals carry at least one of these pathogenic variants that develop severe neurodevelopmental problems in a recessive manner. Furthermore, the feasibility of these genes for carrier screening was evaluated. Our results will serve as a foundation for recessive variant screening to reduce occurrences of rare Mendelian disease patients. Additionally, our results highlight the utility and necessity of whole exome sequencing-based diagnostics for improving patient care in a country with a centralized medical system.

  View details for DOI 10.1038/s41598-020-58101-8

  View details for PubMedID 31996704

• AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders. Nature communications Salpietro, V., Dixon, C. L., Guo, H., Bello, O. D., Vandrovcova, J., Efthymiou, S., Maroofian, R., Heimer, G., Burglen, L., Valence, S., Torti, E., Hacke, M., Rankin, J., Tariq, H., Colin, E., Procaccio, V., Striano, P., Mankad, K., Lieb, A., Chen, S., Pisani, L., Bettencourt, C., Mannikko, R., Manole, A., Brusco, A., Grosso, E., Ferrero, G. B., Armstrong-Moron, J., Gueden, S., Bar-Yosef, O., Tzadok, M., Monaghan, K. G., Santiago-Sim, T., Person, R. E., Cho, M. T., Willaert, R., Yoo, Y., Chae, J., Quan, Y., Wu, H., Wang, T., Bernier, R. A., Xia, K., Blesson, A., Jain, M., Motazacker, M. M., Jaeger, B., Schneider, A. L., Boysen, K., Muir, A. M., Myers, C. T., Gavrilova, R. H., Gunderson, L., Schultz-Rogers, L., Klee, E. W., Dyment, D., Osmond, M., Parellada, M., Llorente, C., Gonzalez-Penas, J., Carracedo, A., Van Haeringen, A., Ruivenkamp, C., Nava, C., Heron, D., Nardello, R., Iacomino, M., Minetti, C., Skabar, A., Fabretto, A., SYNAPS Study Group, Raspall-Chaure, M., Chez, M., Tsai, A., Fassi, E., Shinawi, M., Constantino, J. N., De Zorzi, R., Fortuna, S., Kok, F., Keren, B., Bonneau, D., Choi, M., Benzeev, B., Zara, F., Mefford, H. C., Scheffer, I. E., Clayton-Smith, J., Macaya, A., Rothman, J. E., Eichler, E. E., Kullmann, D. M., Houlden, H., Hanna, M. G., Bugiardini, E., Hostettler, I., O'Callaghan, B., Khan, A., Cortese, A., O'Connor, E., Yau, W. Y., Bourinaris, T., Kaiyrzhanov, R., Chelban, V., Madej, M., Diana, M. C., Vari, M. S., Pedemonte, M., Bruno, C., Balagura, G., Scala, M., Fiorillo, C., Nobili, L., Malintan, N. T., Zanetti, M. N., Krishnakumar, S. S., Lignani, G., Jepson, J. E., Broda, P., Baldassari, S., Rossi, P., Fruscione, F., Madia, F., Traverso, M., De-Marco, P., Perez-Duenas, B., Munell, F., Kriouile, Y., El-Khorassani, M., Karashova, B., Avdjieva, D., Kathom, H., Tincheva, R., Van-Maldergem, L., Nachbauer, W., Boesch, S., Gagliano, A., Amadori, E., Goraya, J. S., Sultan, T., Kirmani, S., Ibrahim, S., Jan, F., Mine, J., Banu, S., Veggiotti, P., Zuccotti, G. V., Ferrari, M. D., Van Den Maagdenberg, A. M., Verrotti, A., Marseglia, G. L., Savasta, S., Soler, M. A., Scuderi, C., Borgione, E., Chimenz, R., Gitto, E., Dipasquale, V., Sallemi, A., Fusco, M., Cuppari, C., Cutrupi, M. C., Ruggieri, M., Cama, A., Capra, V., Mencacci, N. E., Boles, R., Gupta, N., Kabra, M., Papacostas, S., Zamba-Papanicolaou, E., Dardiotis, E., Maqbool, S., Rana, N., Atawneh, O., Lim, S. Y., Shaikh, F., Koutsis, G., Breza, M., Coviello, D. A., Dauvilliers, Y. A., AlKhawaja, I., AlKhawaja, M., Al-Mutairi, F., Stojkovic, T., Ferrucci, V., Zollo, M., Alkuraya, F. S., Kinali, M., Sherifa, H., Benrhouma, H., Turki, I. B., Tazir, M., Obeid, M., Bakhtadze, S., Saadi, N. W., Zaki, M. S., Triki, C. C., Benfenati, F., Gustincich, S., Kara, M., Belcastro, V., Specchio, N., Capovilla, G., Karimiani, E. G., Salih, A. M., Okubadejo, N. U., Ojo, O. O., Oshinaike, O. O., Oguntunde, O., Wahab, K., Bello, A. H., Abubakar, S., Obiabo, Y., Nwazor, E., Ekenze, O., Williams, U., Iyagba, A., Taiwo, L., Komolafe, M., Senkevich, K., Shashkin, C., Zharkynbekova, N., Koneyev, K., Manizha, G., Isrofilov, M., Guliyeva, U., Salayev, K., Khachatryan, S., Rossi, S., Silvestri, G., Haridy, N., Ramenghi, L. A., Xiromerisiou, G., David, E., Aguennouz, M., Fidani, L., Spanaki, C., Tucci, A. 2019; 10 (1): 3094

  Abstract

  AMPA receptors (AMPARs) are tetrameric ligand-gated channels made up of combinations of GluA1-4 subunits encoded by GRIA1-4 genes. GluA2 has an especially important role because, following post-transcriptional editing at the Q607 site, it renders heteromultimeric AMPARs Ca2+-impermeable, with a linear relationship between current and trans-membrane voltage. Here, we report heterozygous de novo GRIA2 mutations in 28 unrelated patients with intellectual disability (ID) and neurodevelopmental abnormalities including autism spectrum disorder (ASD), Rett syndrome-like features, and seizures or developmental epileptic encephalopathy (DEE). In functional expression studies, mutations lead to a decrease in agonist-evoked current mediated by mutant subunits compared to wild-type channels. When GluA2 subunits are co-expressed with GluA1, most GRIA2 mutations cause a decreased current amplitude and some also affect voltage rectification. Our results show that de-novo variants in GRIA2 can cause neurodevelopmental disorders, complementing evidence that other genetic causes of ID, ASD and DEE also disrupt glutamatergic synaptic transmission.

  View details for DOI 10.1038/s41467-019-10910-w

  View details for PubMedID 31300657

• Heterozygous variants in MYBPC1 are associated with an expanded neuromuscular phenotype beyond arthrogryposis. Human mutation Shashi, V., Geist, J., Lee, Y., Yoo, Y., Shin, U., Schoch, K., Sullivan, J., Stong, N., Smith, E., Jasien, J., Kranz, P., Undiagnosed Diseases Network, Lee, Y., Shin, Y. B., Wright, N. T., Choi, M., Kontrogianni-Konstantopoulos, A., Acosta, M. T., Adams, D. R., Aday, A., Alejandro, M. E., Allard, P., Ashley, E. A., Azamian, M. S., Bacino, C. A., Bademci, G., Baker, E., Balasubramanyam, A., Baldridge, D., Barbouth, D., Batzli, G. F., Beggs, A. H., Bellen, H. J., Bernstein, J. A., Berry, G. T., Bican, A., Bick, D. P., Birch, C. L., Bivona, S., Bonnenmann, C., 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., Carrasquillo, O., Chang, T. C., Chao, H., Clark, G. D., Coakley, T. R., Cobban, L. A., Cogan, J. D., Cole, F. S., Colley, H. A., Cooper, C. M., Cope, H., Craigen, W. J., D'Souza, P., Dasari, S., Davids, M., Davidson, J. M., Dayal, J. G., Dell'Angelica, E. C., Dhar, S. U., Dorrani, N., Dorset, D. C., Douine, E. D., Draper, D. D., Dries, A. M., Duncan, L., Eckstein, D. J., Emrick, L. T., Eng, C. M., Enns, G. M., Esteves, C., Estwick, T., Fernandez, L., Ferreira, C., Fieg, E. L., Fisher, P. G., Fogel, B. L., Forghani, I., Friedman, N. D., Gahl, W. A., Godfrey, R. A., Goldman, A. M., Goldstein, D. B., Gourdine, J. F., Grajewski, A., Groden, C. A., Gropman, A. L., Haendel, M., Hamid, R., Hanchard, N. A., High, F., Holm, I. A., Hom, J., Huang, A., Huang, Y., Isasi, R., Jamal, F., Jiang, Y., Johnston, J. M., Jones, A. L., Karaviti, L., Kelley, E. G., Koeller, D. M., Kohane, I. S., Kohler, J. N., Krakow, D., Krasnewich, D. M., Korrick, S., Koziura, M., Krier, J. B., Kyle, J. E., Lalani, S. R., Lam, B., Lanpher, B. C., Lanza, I. R., Lau, C. C., Lazar, J., LeBlanc, K., Lee, B. H., Lee, H., Levitt, R., Levy, S. E., Lewis, R. A., Lincoln, S. A., Liu, P., Liu, X. Z., Loo, S. K., Loscalzo, J., Maas, R. L., Macnamara, E. F., MacRae, C. A., Maduro, V. V., Majcherska, M. M., Malicdan, M. C., Mamounas, L. A., Manolio, T. A., Markello, T. C., Marom, R., Martin, M. G., Martinez-Agosto, J. A., Marwaha, S., May, T., McCauley, J., McConkie-Rosell, A., McCormack, C. E., McCray, A. T., Merker, J. D., Metz, T. O., Might, M., Morava-Kozicz, E., Moretti, P. M., Morimoto, M., Mulvihill, J. J., Murdock, D. R., Nath, A., Nelson, S. F., Newberry, J. S., Newman, J. H., Nicholas, S. K., Novacic, D., Oglesbee, D., Orengo, J. P., Pak, S., Pallais, J. C., Palmer, C. G., Papp, J. C., Parker, N. H., Pena, L. D., Phillips, J. A., Posey, J. E., Postlethwait, J. H., Potocki, L., Pusey, B. N., Renteria, G., Reuter, C. M., Rives, L., Robertson, A. K., Rodan, L. H., Rosenfeld, J. A., Rowley, R. K., Sacco, R., Sampson, J. B., Samson, S. L., Saporta, M., Schaechter, J., Schedl, T., Schoch, K., Scott, D. A., Shakachite, L., Sharma, P., Shashi, V., Shields, K., Shin, J., Signer, R., Sillari, C. H., Silverman, E. K., Sinsheimer, J. S., Smith, K. S., Solnica-Krezel, L., Spillmann, R. C., Stoler, J. M., Stong, N., Sullivan, J. A., Sweetser, D. A., Tamburro, C. P., Tan, Q. K., Tekin, M., Telischi, F., Thorson, W., Tifft, C. J., Toro, C., Tran, A. A., Urv, T. K., Vogel, T. P., Waggott, D. M., Wahl, C. E., Walley, N. M., Walsh, C. A., Walker, M., Wambach, J., Wan, J., Wang, L., Wangler, M. F., Ward, P. A., Waters, K. M., Webb-Robertson, B. M., Wegner, D., Westerfield, M., Wheeler, M. T., Wise, A. L., Wolfe, L. A., Woods, J. D., Worthey, E. A., Yamamoto, S., Yang, J., Yoon, A. J., Yu, G., Zastrow, D. B., Zhao, C., Zuchner, S. 2019

  Abstract

  Encoding the slow skeletal muscle isoform of myosin binding protein-C, MYBPC1 is associated with autosomal dominant and recessive forms of arthrogryposis. The authors describe a novel association for MYBPC1 in four patients from three independent families with skeletal muscle weakness, myogenic tremors, and hypotonia with gradual clinical improvement. The patients carried one of two de novo heterozygous variants in MYBPC1, with the p.Leu263Arg variant seen in three individuals and the p.Leu259Pro variant in one individual. Both variants are absent from controls, well conserved across vertebrate species, predicted to be damaging, and located in the M-motif. Protein modeling studies suggested that the p.Leu263Arg variant affects the stability of the M-motif, whereas the p.Leu259Pro variant alters its structure. In vitro biochemical and kinetic studies demonstrated that the p.Leu263Arg variant results in decreased binding of the M-motif to myosin, which likely impairs the formation of actomyosin cross-bridges during muscle contraction. Collectively, our data substantiate that damaging variants in MYBPC1 are associated with a new form of an early-onset myopathy with tremor, which is a defining and consistent characteristic in all affected individuals, with no contractures. Recognition of this expanded myopathic phenotype can enable identification of individuals with MYBPC1 variants without arthrogryposis.

  View details for DOI 10.1002/humu.23760

  View details for PubMedID 31264822

• An early seizure variant type of a male Rett syndrome patient with a MECP2 p.Arg133His missense mutation. Molecular genetics & genomic medicine Yoon, J. A., Yoo, Y., Lee, J. S., Kim, Y. M., Shin, Y. B. 2018

  Abstract

  BACKGROUND: The clinical spectrum of Rett syndrome (RTT; Mendelian Inheritance in Man [MIM] #312750) in males is considered to be wider than previously expected. Therefore, the existence of RTT with a normal male karyotype is still controversial. Here, we report the first case of a male patient presenting with an early seizure type of Rett-like phenotypes with a missense variant of MECP2.METHOD: An 8-month-old male was admitted to the pediatric department due to an initial seizure event following aspiration pneumonia and was referred to our clinic for the evaluation of unexplained neuroregression. Genomic DNA was prepared from venous blood by standard procedures and was processed at the Yale Center for Genome Analysis (YCGA) for whole exome sequencing (WES). Processing of sequence data, variant calling, and the identification of de novo mutations were then performed. Direct Sanger sequencing was performed following PCR amplification.RESULT: In this patient with a normal karyotype, WES analysis led to the identification of a novel, de novo missense variant of MECP2 (p.Arg133His) that is not observed in the normal population.CONCLUSION: This rare case of an p.Arg133His hemizygous MECP2 missense mutation could guide future treatment and follow-up plans for RETT-like phenotypes.

  View details for PubMedID 30569584

• Genomic analysis of synchronous intracranial meningiomas with different histological grades JOURNAL OF NEURO-ONCOLOGY Chowdhury, T., Yoo, Y., Seo, Y., Dho, Y., Kim, S., Choi, A., Choi, M., Park, S., Park, C., Lee, S., Lee, J. 2018; 138 (1): 41–48

  Abstract

  Although meningioma is the most common primary tumor of the central nervous system, the mechanism of progression from benign to atypical or anaplastic grade remains elusive. The present case reports the genomic evaluation of two synchronous meningiomas with different histological grades (benign and atypical) in the same patient. Under the assumption that the atypical tumor may have progressed from the benign tumor, the clonal origin of the lesions was investigated to identify genomic events responsible for the oncogenic process of evolution to higher grades in meningioma. A 59 year-old female patient was diagnosed with two synchronous meningiomas with different histological grades, benign and atypical. Whole-exome sequencing (WES) and RNA sequencing (RNA-seq) analysis of both tumors were done. WES analysis showed that each meningioma harbored distinct mutation profiles, and RNA-seq analysis revealed distinct gene expression profiles between the two tumors. The only apparent common genetic abnormality found in both tumors was the loss of heterozygosity of chromosome 22, raising the possibility that this event is the initial step in tumor formation, after which distinct subsequent mutations lead to the evolvement of two separate tumors of different grades. The result provides additional evidence on previous reports suggesting separate, independent mechanism of progression into higher grades in meningioma.

  View details for PubMedID 29423538

• Defining the phenotypic spectrum of SLC6A1 mutations EPILEPSIA Johannesen, K. M., Gardella, E., Linnankivi, T., Courage, C., de Saint Martin, A., Lehesjoki, A., Mignot, C., Afenjar, A., Lesca, G., Abi-Warde, M., Chelly, J., Piton, A., Merritt, J., Rodan, L. H., Tan, W., Bird, L. M., Nespeca, M., Gleeson, J. G., Yoo, Y., Choi, M., Chae, J., Czapansky-Beilman, D., Reichert, S., Pendziwiat, M., Verhoeven, J. S., Schelhaas, H. J., Devinsky, O., Christensen, J., Specchio, N., Trivisano, M., Weber, Y. G., Nava, C., Keren, B., Doummar, D., Schaefer, E., Hopkins, S., Dubbs, H., Shaw, J. E., Pisani, L., Myers, C. T., Tang, S., Tang, S., Pal, D. K., Millichap, J. J., Carvill, G. L., Helbig, K. L., Mecarelli, O., Striano, P., Helbig, I., Rubboli, G., Mefford, H. C., Moller, R. S. 2018; 59 (2): 389–402

  Abstract

  Pathogenic SLC6A1 variants were recently described in patients with myoclonic atonic epilepsy (MAE) and intellectual disability (ID). We set out to define the phenotypic spectrum in a larger cohort of SCL6A1-mutated patients.We collected 24 SLC6A1 probands and 6 affected family members. Four previously published cases were included for further electroclinical description. In total, we reviewed the electroclinical data of 34 subjects.Cognitive development was impaired in 33/34 (97%) subjects; 28/34 had mild to moderate ID, with language impairment being the most common feature. Epilepsy was diagnosed in 31/34 cases with mean onset at 3.7 years. Cognitive assessment before epilepsy onset was available in 24/31 subjects and was normal in 25% (6/24), and consistent with mild ID in 46% (11/24) or moderate ID in 17% (4/24). Two patients had speech delay only, and 1 had severe ID. After epilepsy onset, cognition deteriorated in 46% (11/24) of cases. The most common seizure types were absence, myoclonic, and atonic seizures. Sixteen cases fulfilled the diagnostic criteria for MAE. Seven further patients had different forms of generalized epilepsy and 2 had focal epilepsy. Twenty of 31 patients became seizure-free, with valproic acid being the most effective drug. There was no clear-cut correlation between seizure control and cognitive outcome. Electroencephalography (EEG) findings were available in 27/31 patients showing irregular bursts of diffuse 2.5-3.5 Hz spikes/polyspikes-and-slow waves in 25/31. Two patients developed an EEG pattern resembling electrical status epilepticus during sleep. Ataxia was observed in 7/34 cases. We describe 7 truncating and 18 missense variants, including 4 recurrent variants (Gly232Val, Ala288Val, Val342Met, and Gly362Arg).Most patients carrying pathogenic SLC6A1 variants have an MAE phenotype with language delay and mild/moderate ID before epilepsy onset. However, ID alone or associated with focal epilepsy can also be observed.

  View details for PubMedID 29315614

  View details for PubMedCentralID PMC5912688

• Reply to "a novel mutation in the transmembrane 6 domain of GABBR2 leads to a rett-like phenotype" ANNALS OF NEUROLOGY Yoo, Y., Cho, J., Choi, M. 2018; 83 (2): 439

  View details for PubMedID 29377213

• GABBR2 Mutations Determine Phenotype in Rett Syndrome and Epileptic Encephalopathy ANNALS OF NEUROLOGY Yoo, Y., Jung, J., Lee, Y., Lee, Y., Cho, H., Na, E., Hong, J., Kim, E., Lee, J., Lee, J., Hong, C., Park, S., Wie, J., Miller, K., Shur, N., Clow, C., Ebel, R. S., DeBrosse, S. D., Henderson, L. B., Willaert, R., Castaldi, C., Tikhonova, I., Bilguvar, K., Mane, S., Kim, K., Hwang, Y., Lee, S., So, I., Lim, B., Choi, H., Seong, J., Shin, Y., Jung, H., Chae, J., Choi, M. 2017; 82 (3): 466–78

  Abstract

  Rett syndrome (RTT) and epileptic encephalopathy (EE) are devastating neurodevelopmental disorders with distinct diagnostic criteria. However, highly heterogeneous and overlapping clinical features often allocate patients into the boundary of the two conditions, complicating accurate diagnosis and appropriate medical interventions. Therefore, we investigated the specific molecular mechanism that allows an understanding of the pathogenesis and relationship of these two conditions.We screened novel genetic factors from 34 RTT-like patients without MECP2 mutations, which account for ∼90% of RTT cases, by whole-exome sequencing. The biological function of the discovered variants was assessed in cell culture and Xenopus tropicalis models.We identified a recurring de novo variant in GABAB receptor R2 (GABBR2) that reduces the receptor function, whereas different GABBR2 variants in EE patients possess a more profound effect in reducing receptor activity and are more responsive to agonist rescue in an animal model.GABBR2 is a genetic factor that determines RTT- or EE-like phenotype expression depending on the variant positions. GABBR2-mediated γ-aminobutyric acid signaling is a crucial factor in determining the severity and nature of neurodevelopmental phenotypes. Ann Neurol 2017;82:466-478.

  View details for PubMedID 28856709

• Wiedemann-Steiner Syndrome With 2 Novel KMT2A Mutations. Journal of child neurology Min Ko, J., Cho, J. S., Yoo, Y., Seo, J., Choi, M., Chae, J., Lee, H., Cho, T. 2017; 32 (2): 237–42

  Abstract

  Wiedemann-Steiner syndrome is a rare genetic disorder characterized by short stature, hairy elbows, facial dysmorphism, and developmental delay. It can also be accompanied by musculoskeletal anomalies such as muscular hypotonia and small hands and feet. Mutations in the KMT2A gene have only recently been identified as the cause of Wiedemann-Steiner syndrome; therefore, only 16 patients from 15 families have been described, and new phenotypic features continue to be added. In this report, we describe 2 newly identified patients with Wiedemann-Steiner syndrome who presented with variable severity. One girl exhibited developmental dysplasia of the hip and fibromatosis colli accompanied by other clinical features, including facial dysmorphism, hypertrichosis, patent ductus arteriosus, growth retardation, and borderline intellectual disability. The other patient, a boy, showed severe developmental retardation with automatic self-mutilation, facial dysmorphism, and hypertrichosis at a later age. Exome sequencing analysis of these patients and their parents revealed a de novo nonsense mutation, p.Gln1978*, of KMT2A in the former, and a missense mutation, p.Gly1168Asp, in the latter, which molecularly confirmed the diagnosis of Wiedemann-Steiner syndrome.

  View details for PubMedID 27777327

• GM3 synthase deficiency due to ST3GAL5 variants in two Korean female siblings: Masquerading as Rett syndrome-like phenotype AMERICAN JOURNAL OF MEDICAL GENETICS PART A Lee, J., Yoo, Y., Lim, B., Kim, K., Song, J., Choi, M., Chae, J. 2016; 170 (8): 2200–2205

  Abstract

  There have been a few reports of GM3 synthase deficiency since the disease of the ganglioside biosynthetic pathway was first reported in 2004. It is characterized by infantile-onset epilepsy with severe intellectual disability, blindness, cutaneous dyspigmentation, and choreoathetosis. Here we report the cases of two Korean female siblings with ST3GAL5 variants, who presented with a Rett-like phenotype. They had delayed speech, hand stereotypies with a loss of purposeful hand movements, and choreoathetosis, but no clinical seizures. One of them had microcephaly, while the other had small head circumference less than 10th centile. There were no abnormal laboratory findings with the exception of a high lactate level. MECP2/CDKL5/FOXG1 genetic tests with an array comparative genomic hybridization revealed no molecular defects. Through whole-exome sequencing of the proband, we found compound heterozygous ST3GAL5 variants (p.Gly201Arg and p.Cys195Ser), both of which were novel. The siblings were the same compound heterozygotes and their unaffected parents were heterozygous carriers of each variant. Liquid chromatography-mass spectrometry analysis confirmed a low level of GM3 and its downstream metabolites, indicating GM3 synthase deficiency. These cases expanded the clinical and genetic spectrum of the ultra-rare disease, GM3 synthase deficiency with ST3GAL5 variants. © 2016 Wiley Periodicals, Inc.

  View details for PubMedID 27232954

• SATB2-associated syndrome presenting with Rett-like phenotypes CLINICAL GENETICS Lee, J. S., Yoo, Y., Lim, B. C., Kim, K. J., Choi, M., Chae, J. 2016; 89 (6): 728–32

  Abstract

  The SATB2-associated syndrome (SAS) was proposed recently, after the SATB2 gene was initially discovered to be associated with isolated cleft palate. This syndrome is characterized by intellectual disability with delayed speech development, facial dysmorphism, cleft or high-arched palate, and dentition problems. Here, we describe two novel SATB2 sequence variants in two unrelated patients presenting with Rett-like phenotypes. We performed trio-based whole-exome sequencing in a 17-month-old girl presenting with severe retardation and Rett-like phenotypes, which revealed a de novo missense variant in SATB2 (p.Glu396Gln). Moreover, targeted sequencing of the SATB2 gene was performed in a 2-year-old girl with severe psychomotor retardation, facial hypotonia, and cleft palate who also exhibited some features of Rett syndrome. A nonsense variant in SATB2 was identified in this patient (p.Arg459*). This study expanded the clinical and genetic spectrum of SAS. SATB2 variants should be considered in cases with psychomotor retardation alone or in any cases with Rett-like phenotypes, regardless of the typical features of SAS such as cleft palate.

  View details for DOI 10.1111/cge.12698

  View details for Web of Science ID 000378651300011

  View details for PubMedID 26596517

• Rare cases of congenital arthrogryposis multiplex caused by novel recurrent CHRNG mutations JOURNAL OF HUMAN GENETICS Seo, J., Choi, I., Lee, J., Yoo, Y., Kim, N. D., Choi, M., Ko, J., Shin, Y. 2015; 60 (4): 213–15

  Abstract

  Multiple pterygium syndrome (MPS) is an autosomal recessively inherited condition that becomes evident before birth, with pterygium at multiple joints and akinesia. There are two forms of this syndrome that are differentiated by clinical severity: the milder form, Escobar type (OMIM#265000), and the more severe form, lethal type (OMIM#253290). Mutations in CHRNG, which encode the acetylcholine receptor gamma subunit, cause most cases of MPS. Here, we present three patients from two unrelated families showing multiple joint contractures in both the upper and lower limbs. High-arched palates with malocclusion, short neck and micrognathia were observed in all patients. Peripheral blood karyotypes were normal. Whole-exome sequencing analysis of the patients' genomes led to the discovery of identical missense (p.Pro143Arg) and frameshift deletion variants (p.Pro251fs*45) on CHRNG. These were rare cases of congenital arthrogryposis multiplex related to novel recessive CHRNG variants in two Korean kindred without apparent relatedness.

  View details for PubMedID 25608830

• JAK2, CALR, and MPL mutation spectrum in Japanese patients with myeloproliferative neoplasms HAEMATOLOGICA Shirane, S., Araki, M., Morishita, S., Edahiro, Y., Takei, H., Yoo, Y., Choi, M., Sunami, Y., Hironaka, Y., Noguchi, M., Koike, M., Noda, N., Ohsaka, A., Komatsu, N. 2015; 100 (2): E46–E48

  View details for PubMedID 25398833