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1. Diagnostic utility of DNA methylation analysis in genetically unsolved pediatric epilepsies and CHD2 episignature refinement

Author

Christy W. LaFlamme, Cassandra Rastin, Soham Sengupta, Helen E. Pennington, Sophie J. Russ-Hall, Amy L. Schneider, Emily S. Bonkowski, Edith P. Almanza Fuerte, Talia J. Allan, Miranda Perez-Galey Zalusky, Joy Goffena, Sophia B. Gibson, Denis M. Nyaga, Nico Lieffering, Malavika Hebbar, Emily V. Walker, Daniel Darnell, Scott R. Olsen, Pandurang Kolekar, Mohamed Nadhir Djekidel, Wojciech Rosikiewicz, Haley McConkey, Jennifer Kerkhof, Michael A. Levy, Raissa Relator, Dorit Lev, Tally Lerman-Sagie, Kristen L. Park, Marielle Alders, Gerarda Cappuccio, Nicolas Chatron, Leigh Demain, David Genevieve, Gaetan Lesca, Tony Roscioli, Damien Sanlaville, Matthew L. Tedder, Sachin Gupta, Elizabeth A. Jones, Monika Weisz-Hubshman, Shamika Ketkar, Hongzheng Dai, Kim C. Worley, Jill A. Rosenfeld, Hsiao-Tuan Chao, Undiagnosed Diseases Network, Geoffrey Neale, Gemma L. Carvill, University of Washington Center for Rare Disease Research, Zhaoming Wang, Samuel F. Berkovic, Lynette G. Sadleir, Danny E. Miller, Ingrid E. Scheffer, Bekim Sadikovic, and Heather C. Mefford

Subjects
Science
Abstract

Abstract Sequence-based genetic testing identifies causative variants in ~ 50% of individuals with developmental and epileptic encephalopathies (DEEs). Aberrant changes in DNA methylation are implicated in various neurodevelopmental disorders but remain unstudied in DEEs. We interrogate the diagnostic utility of genome-wide DNA methylation array analysis on peripheral blood samples from 582 individuals with genetically unsolved DEEs. We identify rare differentially methylated regions (DMRs) and explanatory episignatures to uncover causative and candidate genetic etiologies in 12 individuals. Using long-read sequencing, we identify DNA variants underlying rare DMRs, including one balanced translocation, three CG-rich repeat expansions, and four copy number variants. We also identify pathogenic variants associated with episignatures. Finally, we refine the CHD2 episignature using an 850 K methylation array and bisulfite sequencing to investigate potential insights into CHD2 pathophysiology. Our study demonstrates the diagnostic yield of genome-wide DNA methylation analysis to identify causal and candidate variants as 2% (12/582) for unsolved DEE cases.

Published
2024
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2. Variants in the WDR44 WD40-repeat domain cause a spectrum of ciliopathy by impairing ciliogenesis initiation

Author

Andrea Accogli, Saurabh Shakya, Taewoo Yang, Christine Insinna, Soo Yeon Kim, David Bell, Kirill R. Butov, Mariasavina Severino, Marcello Niceta, Marcello Scala, Hyun Sik Lee, Taekyeong Yoo, Jimmy Stauffer, Huijie Zhao, Chiara Fiorillo, Marina Pedemonte, Maria C. Diana, Simona Baldassari, Viktoria Zakharova, Anna Shcherbina, Yulia Rodina, Christina Fagerberg, Laura Sønderberg Roos, Jolanta Wierzba, Artur Dobosz, Amanda Gerard, Lorraine Potocki, Jill A. Rosenfeld, Seema R. Lalani, Tiana M. Scott, Daryl Scott, Mahshid S. Azamian, Raymond Louie, Hannah W. Moore, Neena L. Champaigne, Grace Hollingsworth, Annalaura Torella, Vincenzo Nigro, Rafal Ploski, Vincenzo Salpietro, Federico Zara, Simone Pizzi, Giovanni Chillemi, Marzia Ognibene, Erin Cooney, Jenny Do, Anders Linnemann, Martin J. Larsen, Suzanne Specht, Kylie J. Walters, Hee-Jung Choi, Murim Choi, Marco Tartaglia, Phillippe Youkharibache, Jong-Hee Chae, Valeria Capra, Sung-Gyoo Park, and Christopher J. Westlake

Subjects
Science
Abstract

Abstract WDR44 prevents ciliogenesis initiation by regulating RAB11-dependent vesicle trafficking. Here, we describe male patients with missense and nonsense variants within the WD40 repeats (WDR) of WDR44, an X-linked gene product, who display ciliopathy-related developmental phenotypes that we can model in zebrafish. The patient phenotypic spectrum includes developmental delay/intellectual disability, hypotonia, distinct craniofacial features and variable presence of brain, renal, cardiac and musculoskeletal abnormalities. We demonstrate that WDR44 variants associated with more severe disease impair ciliogenesis initiation and ciliary signaling. Because WDR44 negatively regulates ciliogenesis, it was surprising that pathogenic missense variants showed reduced abundance, which we link to misfolding of WDR autonomous repeats and degradation by the proteasome. We discover that disease severity correlates with increased RAB11 binding, which we propose drives ciliogenesis initiation dysregulation. Finally, we discover interdomain interactions between the WDR and NH2-terminal region that contains the RAB11 binding domain (RBD) and show patient variants disrupt this association. This study provides new insights into WDR44 WDR structure and characterizes a new syndrome that could result from impaired ciliogenesis.

Published
2024
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3. Integrative analysis of transcriptome dynamics during human craniofacial development identifies candidate disease genes

Author

Tara N. Yankee, Sungryong Oh, Emma Wentworth Winchester, Andrea Wilderman, Kelsey Robinson, Tia Gordon, Jill A. Rosenfeld, Jennifer VanOudenhove, Daryl A. Scott, Elizabeth J. Leslie, and Justin Cotney

Subjects
Science
Abstract

Abstract Craniofacial disorders arise in early pregnancy and are one of the most common congenital defects. To fully understand how craniofacial disorders arise, it is essential to characterize gene expression during the patterning of the craniofacial region. To address this, we performed bulk and single-cell RNA-seq on human craniofacial tissue from 4-8 weeks post conception. Comparisons to dozens of other human tissues revealed 239 genes most strongly expressed during craniofacial development. Craniofacial-biased developmental enhancers were enriched +/− 400 kb surrounding these craniofacial-biased genes. Gene co-expression analysis revealed that regulatory hubs are enriched for known disease causing genes and are resistant to mutation in the normal healthy population. Combining transcriptomic and epigenomic data we identified 539 genes likely to contribute to craniofacial disorders. While most have not been previously implicated in craniofacial disorders, we demonstrate this set of genes has increased levels of de novo mutations in orofacial clefting patients warranting further study.

Published
2023
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4. De novo variants in CACNA1E found in patients with intellectual disability, developmental regression and social cognition deficit but no seizures

Author

Beryl Royer-Bertrand, Marine Jequier Gygax, Katarina Cisarova, Jill A. Rosenfeld, Jennifer A. Bassetti, Oana Moldovan, Emily O’Heir, Lindsay C. Burrage, Jake Allen, Lisa T. Emrick, Emma Eastman, Camille Kumps, Safdar Abbas, Geraldine Van Winckel, Undiagnosed Diseases Network, Nadia Chabane, Elaine H. Zackai, Sebastien Lebon, Beth Keena, Elizabeth J. Bhoj, Muhammad Umair, Dong Li, Kirsten A. Donald, and Andrea Superti-Furga

Subjects
Autism spectrum disorder, CACNA1E, Developmental regression, Epilepsy, Exome sequencing, Global developmental delay, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Background De novo variants in the voltage-gated calcium channel subunit α1 E gene (CACNA1E) have been described as causative of epileptic encephalopathy with contractures, macrocephaly and dyskinesias. Methods Following the observation of an index patient with developmental delay and autism spectrum disorder (ASD) without seizures who had a de novo deleterious CACNA1E variant, we screened GeneMatcher for other individuals with CACNA1E variants and neurodevelopmental phenotypes without epilepsy. The spectrum of pathogenic CACNA1E variants was compared to the mutational landscape of variants in the gnomAD control population database. Results We identified seven unrelated individuals with intellectual disability, developmental regression and ASD-like behavioral profile, and notably without epilepsy, who had de novo heterozygous putatively pathogenic variants in CACNA1E. Age of onset of clinical manifestation, presence or absence of regression and degree of severity were variable, and no clear-cut genotype–phenotype association could be recognized. The analysis of disease-associated variants and their comparison to benign variants from the control population allowed for the identification of regions in the CACNA1E protein that seem to be intolerant to substitutions and thus more likely to harbor pathogenic variants. As in a few reported cases with CACNA1E variants and epilepsy, one patient showed a positive clinical behavioral response to topiramate, a specific calcium channel modulator. Limitations The significance of our study is limited by the absence of functional experiments of the effect of identified variants, the small sample size and the lack of systematic ASD assessment in all participants. Moreover, topiramate was given to one patient only and for a short period of time. Conclusions Our results indicate that CACNA1E variants may result in neurodevelopmental disorders without epilepsy and expand the mutational and phenotypic spectrum of this gene. CACNA1E deserves to be included in gene panels for non-specific developmental disorders, including ASD, and not limited to patients with seizures, to improve diagnostic recognition and explore the possible efficacy of topiramate.

Published
2021
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5. Determining the Likelihood of Disease Pathogenicity Among Incidentally Identified Genetic Variants in Rare Dilated Cardiomyopathy‐Associated Genes

Author

Qixin Yang, Amy M. Berkman, Jordan E. Ezekian, Michael Rosamilia, Jill A. Rosenfeld, Pengfei Liu, and Andrew P. Landstrom

Subjects
dilated cardiomyopathy, exome sequencing, genetics, incidental finding, secondary finding, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Background As utilization of clinical exome sequencing (ES) has expanded, criteria for evaluating the diagnostic weight of incidentally identified variants are critical to guide clinicians and researchers. This is particularly important in genes associated with dilated cardiomyopathy (DCM), which can cause heart failure and sudden death. We sought to compare the frequency and distribution of incidentally identified variants in DCM‐associated genes between a clinical referral cohort with those in control and known case cohorts to determine the likelihood of pathogenicity among those undergoing genetic testing for non‐DCM indications. Methods and Results A total of 39 rare, non‐TTN DCM‐associated genes were identified and evaluated from a clinical ES testing referral cohort (n=14 005, Baylor Genetic Laboratories) and compared with a DCM case cohort (n=9442) as well as a control cohort of population variants (n=141 456) derived from the gnomAD database. Variant frequencies in each cohort were compared. Signal‐to‐noise ratios were calculated comparing the DCM and ES cohort with the gnomAD cohort. The likely pathogenic/pathogenic variant yield in the DCM cohort (8.2%) was significantly higher than in the ES cohort (1.9%). Based on signal‐to‐noise and correlation analysis, incidental variants found in FLNC, RBM20, MYH6, DSP, ABCC9, JPH2, and NEXN had the greatest chance of being DCM‐associated. Conclusions The distribution of pathogenic variants between the ES cohort and the DCM case cohort was gene specific, and variants found in the ES cohort were similar to variants found in the control cohort. Incidentally identified variants in specific genes are more associated with DCM than others.

Published
2022
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6. Molecular characterisation of rare loss-of-function NPAS3 and NPAS4 variants identified in individuals with neurodevelopmental disorders

Author

Joseph J. Rossi, Jill A. Rosenfeld, Katie M. Chan, Haley Streff, Victoria Nankivell, Daniel J. Peet, Murray L. Whitelaw, and David C. Bersten

Subjects
Medicine, Science
Abstract

Abstract Aberrations in the excitatory/inhibitory balance within the brain have been associated with both intellectual disability (ID) and schizophrenia (SZ). The bHLH-PAS transcription factors NPAS3 and NPAS4 have been implicated in controlling the excitatory/inhibitory balance, and targeted disruption of either gene in mice results in a phenotype resembling ID and SZ. However, there are few human variants in NPAS3 and none in NPAS4 that have been associated with schizophrenia or neurodevelopmental disorders. From a clinical exome sequencing database we identified three NPAS3 variants and four NPAS4 variants that could potentially disrupt protein function in individuals with either developmental delay or ID. The transcriptional activity of the variants when partnered with either ARNT or ARNT2 was assessed by reporter gene activity and it was found that variants which truncated the NPAS3/4 protein resulted in a complete loss of transcriptional activity. The ability of loss-of-function variants to heterodimerise with neuronally enriched partner protein ARNT2 was then determined by co-immunoprecipitation experiments. It was determined that the mechanism for the observed loss of function was the inability of the truncated NPAS3/4 protein to heterodimerise with ARNT2. This further establishes NPAS3 and NPAS4 as candidate neurodevelopmental disorder genes.

Published
2021
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7. Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders

Author

Tianyun Wang, Kendra Hoekzema, Davide Vecchio, Huidan Wu, Arvis Sulovari, Bradley P. Coe, Madelyn A. Gillentine, Amy B. Wilfert, Luis A. Perez-Jurado, Malin Kvarnung, Yoeri Sleyp, Rachel K. Earl, Jill A. Rosenfeld, Madeleine R. Geisheker, Lin Han, Bing Du, Chris Barnett, Elizabeth Thompson, Marie Shaw, Renee Carroll, Kathryn Friend, Rachael Catford, Elizabeth E. Palmer, Xiaobing Zou, Jianjun Ou, Honghui Li, Hui Guo, Jennifer Gerdts, Emanuela Avola, Giuseppe Calabrese, Maurizio Elia, Donatella Greco, Anna Lindstrand, Ann Nordgren, Britt-Marie Anderlid, Geert Vandeweyer, Anke Van Dijck, Nathalie Van der Aa, Brooke McKenna, Miroslava Hancarova, Sarka Bendova, Marketa Havlovicova, Giovanni Malerba, Bernardo Dalla Bernardina, Pierandrea Muglia, Arie van Haeringen, Mariette J. V. Hoffer, Barbara Franke, Gerarda Cappuccio, Martin Delatycki, Paul J. Lockhart, Melanie A. Manning, Pengfei Liu, Ingrid E. Scheffer, Nicola Brunetti-Pierri, Nanda Rommelse, David G. Amaral, Gijs W. E. Santen, Elisabetta Trabetti, Zdeněk Sedláček, Jacob J. Michaelson, Karen Pierce, Eric Courchesne, R. Frank Kooy, The SPARK Consortium, Magnus Nordenskjöld, Corrado Romano, Hilde Peeters, Raphael A. Bernier, Jozef Gecz, Kun Xia, and Evan E. Eichler

Subjects
Science
Abstract

For many neurodevelopmental disorder (NDD) risk genes, the significance for mutational burden is unestablished. Here, the authors sequence 125 candidate NDD genes in over 16,000 NDD cases; case-control mutational burden analysis identifies 48 genes with a significant burden of severe ultra-rare mutations.

Published
2020
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8. Biallelic GRM7 variants cause epilepsy, microcephaly, and cerebral atrophy

Author

Dana Marafi, Tadahiro Mitani, Sedat Isikay, Jozef Hertecant, Mohammed Almannai, Kandamurugu Manickam, Rami Abou Jamra, Ayman W. El‐Hattab, Jaishen Rajah, Jawid M. Fatih, Haowei Du, Ender Karaca, Yavuz Bayram, Jaya Punetha, Jill A. Rosenfeld, Shalini N. Jhangiani, Eric Boerwinkle, Zeynep C. Akdemir, Serkan Erdin, Jill V. Hunter, Richard A. Gibbs, Davut Pehlivan, Jennifer E. Posey, and James R. Lupski

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Objective Defects in ion channels and neurotransmitter receptors are implicated in developmental and epileptic encephalopathy (DEE). Metabotropic glutamate receptor 7 (mGluR7), encoded by GRM7, is a presynaptic G‐protein‐coupled glutamate receptor critical for synaptic transmission. We previously proposed GRM7 as a candidate disease gene in two families with neurodevelopmental disorders (NDDs). One additional family has been published since. Here, we describe three additional families with GRM7 biallelic variants and deeply characterize the associated clinical neurological and electrophysiological phenotype and molecular data in 11 affected individuals from six unrelated families. Methods Exome sequencing and family‐based rare variant analyses on a cohort of 220 consanguineous families with NDDs revealed three families with GRM7 biallelic variants; three additional families were identified through literature search and collaboration with a clinical molecular laboratory. Results We compared the observed clinical features and variants of 11 affected individuals from the six unrelated families. Identified novel deleterious variants included two homozygous missense variants (c.2671G>A:p.Glu891Lys and c.1973G>A:p.Arg685Gln) and one homozygous stop‐gain variant (c.1975C>T:p.Arg659Ter). Developmental delay, neonatal‐ or infantile‐onset epilepsy, and microcephaly were universal. Three individuals had hypothalamic–pituitary–axis dysfunction without pituitary structural abnormality. Neuroimaging showed cerebral atrophy and hypomyelination in a majority of cases. Two siblings demonstrated progressive loss of myelination by 2 years in both and an acquired microcephaly pattern in one. Five individuals died in early or late childhood. Conclusion Detailed clinical characterization of 11 individuals from six unrelated families demonstrates that rare biallelic GRM7 pathogenic variants can cause DEEs, microcephaly, hypomyelination, and cerebral atrophy.

Published
2020
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9. Novel pathogenic variants and quantitative phenotypic analyses of Robinow syndrome: WNT signaling perturbation and phenotypic variability

Author

Chaofan Zhang, Angad Jolly, Brian J. Shayota, Juliana F. Mazzeu, Haowei Du, Moez Dawood, Patricia Celestino Soper, Ariadne Ramalho de Lima, Bárbara Merfort Ferreira, Zeynep Coban-Akdemir, Janson White, Deborah Shears, Fraser Robert Thomson, Sarah Louise Douglas, Andrew Wainwright, Kathryn Bailey, Paul Wordsworth, Mike Oldridge, Tracy Lester, Alistair D. Calder, Katja Dumic, Siddharth Banka, Dian Donnai, Shalini N. Jhangiani, Lorraine Potocki, Wendy K. Chung, Sara Mora, Hope Northrup, Myla Ashfaq, Jill A. Rosenfeld, Kati Mason, Lynda C. Pollack, Allyn McConkie-Rosell, Wei Kelly, Marie McDonald, Natalie S. Hauser, Peter Leahy, Cynthia M. Powell, Raquel Boy, Rachel Sayuri Honjo, Fernando Kok, Lucia R. Martelli, Vicente Odone Filho, Genomics England Research Consortium, Donna M. Muzny, Richard A. Gibbs, Jennifer E. Posey, Pengfei Liu, James R. Lupski, V. Reid Sutton, and Claudia M.B. Carvalho

Subjects
genotype-phenotype correlation, skeletal dysplasia, HPO terms, quantitative phenotyping cluster heatmap, molecular diagnosis, traits and OMIM clinical synopsis, Genetics, QH426-470
Abstract

Summary: Robinow syndrome (RS) is a genetically heterogeneous disorder with six genes that converge on the WNT/planar cell polarity (PCP) signaling pathway implicated (DVL1, DVL3, FZD2, NXN, ROR2, and WNT5A). RS is characterized by skeletal dysplasia and distinctive facial and physical characteristics. To further explore the genetic heterogeneity, paralog contribution, and phenotypic variability of RS, we investigated a cohort of 22 individuals clinically diagnosed with RS from 18 unrelated families. Pathogenic or likely pathogenic variants in genes associated with RS or RS phenocopies were identified in all 22 individuals, including the first variant to be reported in DVL2. We retrospectively collected medical records of 16 individuals from this cohort and extracted clinical descriptions from 52 previously published cases. We performed Human Phenotype Ontology (HPO) based quantitative phenotypic analyses to dissect allele-specific phenotypic differences. Individuals with FZD2 variants clustered into two groups with demonstrable phenotypic differences between those with missense and truncating alleles. Probands with biallelic NXN variants clustered together with the majority of probands carrying DVL1, DVL2, and DVL3 variants, demonstrating no phenotypic distinction between the NXN-autosomal recessive and dominant forms of RS. While phenotypically similar diseases on the RS differential matched through HPO analysis, clustering using phenotype similarity score placed RS-associated phenotypes in a unique cluster containing WNT5A, FZD2, and ROR2 apart from non-RS-associated paralogs. Through human phenotype analyses of this RS cohort and OMIM clinical synopses of Mendelian disease, this study begins to tease apart specific biologic roles for non-canonical WNT-pathway proteins.

Published
2022
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10. AHDC1 missense mutations in Xia-Gibbs syndrome

Author

Michael M. Khayat, Jianhong Hu, Yunyun Jiang, He Li, Varuna Chander, Moez Dawood, Adam W. Hansen, Shoudong Li, Jennifer Friedman, Laura Cross, Emilia K. Bijlsma, Claudia A.L. Ruivenkamp, Francis H. Sansbury, Jeffrey W. Innis, Jessica Omark O’Shea, Qingchang Meng, Jill A. Rosenfeld, Kirsty McWalter, Michael F. Wangler, James R. Lupski, Jennifer E. Posey, David Murdock, and Richard A. Gibbs

Subjects
AHDC1, Xia-Gibbs syndrome, missense mutation, de novo mutation, Genetics, QH426-470
Abstract

Summary: Xia-Gibbs syndrome (XGS; MIM: 615829) is a phenotypically heterogeneous neurodevelopmental disorder (NDD) caused by newly arising mutations in the AT-Hook DNA-Binding Motif-Containing 1 (AHDC1) gene that are predicted to lead to truncated AHDC1 protein synthesis. More than 270 individuals have been diagnosed with XGS worldwide. Despite the absence of an independent assay for AHDC1 protein function to corroborate potential functional consequences of rare variant genetic findings, there are also reports of individuals with XGS-like trait manifestations who have de novo missense AHDC1 mutations and who have been provided a molecular diagnosis of the disorder. To investigate a potential contribution of missense mutations to XGS, we mapped the missense mutations from 10 such individuals to the AHDC1 conserved protein domain structure and detailed the observed phenotypes. Five newly identified individuals were ascertained from a local XGS Registry, and an additional five were taken from external reports or databases, including one publication. Where clinical data were available, individuals with missense mutations all displayed phenotypes consistent with those observed in individuals with AHDC1 truncating mutations, including delayed motor milestones, intellectual disability (ID), hypotonia, and speech delay. A subset of the 10 reported missense mutations cluster in two regions of the AHDC1 protein with known conserved domains, likely representing functional motifs. Variants outside the clustered regions score lower for computational prediction of their likely damaging effects. Overall, de novo missense variants in AHDC1 are likely diagnostic of XGS when in silico analysis of their position relative to conserved regions is considered together with disease trait manifestations.

Published
2021
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11. Saturation mutagenesis defines novel mouse models of severe spine deformity

Author

Jonathan J. Rios, Kristin Denton, Hao Yu, Kandamurugu Manickam, Shannon Garner, Jamie Russell, Sara Ludwig, Jill A. Rosenfeld, Pengfei Liu, Jake Munch, Daniel J. Sucato, Bruce Beutler, and Carol A. Wise

Subjects
enu, n-ethyl-n-nitrosourea, scoliosis, kyphosis, Medicine, Pathology, RB1-214
Abstract

Embryonic formation and patterning of the vertebrate spinal column requires coordination of many molecular cues. After birth, the integrity of the spine is impacted by developmental abnormalities of the skeletal, muscular and nervous systems, which may result in deformities, such as kyphosis and scoliosis. We sought to identify novel genetic mouse models of severe spine deformity by implementing in vivo skeletal radiography as part of a high-throughput saturation mutagenesis screen. We report selected examples of genetic mouse models following radiographic screening of 54,497 mice from 1275 pedigrees. An estimated 30.44% of autosomal genes harbored predicted damaging alleles examined twice or more in the homozygous state. Of the 1275 pedigrees screened, 7.4% presented with severe spine deformity developing in multiple mice, and of these, meiotic mapping implicated N-ethyl-N-nitrosourea alleles in 21% of pedigrees. Our study provides proof of concept that saturation mutagenesis is capable of discovering novel mouse models of human disease, including conditions with skeletal, neural and neuromuscular pathologies. Furthermore, we report a mouse model of skeletal disease, including severe spine deformity, caused by recessive mutation in Scube3. By integrating results with a human clinical exome database, we identified a patient with undiagnosed skeletal disease who harbored recessive mutations in SCUBE3, and we demonstrated that disease-associated mutations are associated with reduced transactivation of Smad signaling in vitro. All radiographic results and mouse models are made publicly available through the Mutagenetix online database with the goal of advancing understanding of spine development and discovering novel mouse models of human disease.

Published
2021
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12. Disruptive mutations in TANC2 define a neurodevelopmental syndrome associated with psychiatric disorders

Author

Hui Guo, Elisa Bettella, Paul C. Marcogliese, Rongjuan Zhao, Jonathan C. Andrews, Tomasz J. Nowakowski, Madelyn A. Gillentine, Kendra Hoekzema, Tianyun Wang, Huidan Wu, Sharayu Jangam, Cenying Liu, Hailun Ni, Marjolein H. Willemsen, Bregje W. van Bon, Tuula Rinne, Servi J. C. Stevens, Tjitske Kleefstra, Han G. Brunner, Helger G. Yntema, Min Long, Wenjing Zhao, Zhengmao Hu, Cindy Colson, Nicolas Richard, Charles E. Schwartz, Corrado Romano, Lucia Castiglia, Maria Bottitta, Shweta U. Dhar, Deanna J. Erwin, Lisa Emrick, Boris Keren, Alexandra Afenjar, Baosheng Zhu, Bing Bai, Pawel Stankiewicz, Kristin Herman, University of Washington Center for Mendelian Genomics, Saadet Mercimek-Andrews, Jane Juusola, Amy B. Wilfert, Rami Abou Jamra, Benjamin Büttner, Heather C. Mefford, Alison M. Muir, Ingrid E. Scheffer, Brigid M. Regan, Stephen Malone, Jozef Gecz, Jan Cobben, Marjan M. Weiss, Quinten Waisfisz, Emilia K. Bijlsma, Mariëtte J. V. Hoffer, Claudia A. L. Ruivenkamp, Stefano Sartori, Fan Xia, Jill A. Rosenfeld, Raphael A. Bernier, Michael F. Wangler, Shinya Yamamoto, Kun Xia, Alexander P. A. Stegmann, Hugo J. Bellen, Alessandra Murgia, and Evan E. Eichler

Subjects
Science
Abstract

Neurodevelopmental disorders (NDDs) are a heterogeneous group of diseases for which the genetic basis is still unknown in more than half of the cases. Here, the authors report a NDD associated with disruptive variants in the TANC2 gene and show that rols, the TANC2 homolog in flies, is required for synapse growth and function.

Published
2019
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13. Disruption of PHF21A causes syndromic intellectual disability with craniofacial anomalies, epilepsy, hypotonia, and neurobehavioral problems including autism

Author

Hyung-Goo Kim, Jill A. Rosenfeld, Daryl A. Scott, Gerard Bénédicte, Jonathan D. Labonne, Jason Brown, Marianne McGuire, Sonal Mahida, Sakkubai Naidu, Jacqueline Gutierrez, Gaetan Lesca, Vincent des Portes, Ange-Line Bruel, Arthur Sorlin, Fan Xia, Yline Capri, Eric Muller, Dianalee McKnight, Erin Torti, Franz Rüschendorf, Oliver Hummel, Zeyaul Islam, Prasanna R. Kolatkar, Lawrence C. Layman, Duchwan Ryu, Il-Keun Kong, Suneeta Madan-Khetarpal, and Cheol-Hee Kim

Subjects
PHF21A, BHC80, Intellectual disability (ID), Autism spectrum disorder (ASD), Neurodevelopmental disorders, Potocki-Shaffer syndrome (PSS), Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Background PHF21A has been associated with intellectual disability and craniofacial anomalies based on its deletion in the Potocki-Shaffer syndrome region at 11p11.2 and its disruption in three patients with balanced translocations. In addition, three patients with de novo truncating mutations in PHF21A were reported recently. Here, we analyze genomic data from seven unrelated individuals with mutations in PHF21A and provide detailed clinical descriptions, further expanding the phenotype associated with PHF21A haploinsufficiency. Methods Diagnostic trio whole exome sequencing, Sanger sequencing, use of GeneMatcher, targeted gene panel sequencing, and MiSeq sequencing techniques were used to identify and confirm variants. RT-qPCR was used to measure the normal expression pattern of PHF21A in multiple human tissues including 13 different brain tissues. Protein-DNA modeling was performed to substantiate the pathogenicity of the missense mutation. Results We have identified seven heterozygous coding mutations, among which six are de novo (not maternal in one). Mutations include four frameshifts, one nonsense mutation in two patients, and one heterozygous missense mutation in the AT Hook domain, predicted to be deleterious and likely to cause loss of PHF21A function. We also found a new C-terminal domain composed of an intrinsically disordered region. This domain is truncated in six patients and thus likely to play an important role in the function of PHF21A, suggesting that haploinsufficiency is the likely underlying mechanism in the phenotype of seven patients. Our results extend the phenotypic spectrum of PHF21A mutations by adding autism spectrum disorder, epilepsy, hypotonia, and neurobehavioral problems. Furthermore, PHF21A is highly expressed in the human fetal brain, which is consistent with the neurodevelopmental phenotype. Conclusion Deleterious nonsense, frameshift, and missense mutations disrupting the AT Hook domain and/or an intrinsically disordered region in PHF21A were found to be associated with autism spectrum disorder, epilepsy, hypotonia, neurobehavioral problems, tapering fingers, clinodactyly, and syndactyly, in addition to intellectual disability and craniofacial anomalies. This suggests that PHF21A is involved in autism spectrum disorder and intellectual disability, and its haploinsufficiency causes a diverse neurological phenotype.

Published
2019
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14. De novo and inherited TCF20 pathogenic variants are associated with intellectual disability, dysmorphic features, hypotonia, and neurological impairments with similarities to Smith–Magenis syndrome

Author

Francesco Vetrini, Shane McKee, Jill A. Rosenfeld, Mohnish Suri, Andrea M. Lewis, Kimberly Margaret Nugent, Elizabeth Roeder, Rebecca O. Littlejohn, Sue Holder, Wenmiao Zhu, Joseph T. Alaimo, Brett Graham, Jill M. Harris, James B. Gibson, Matthew Pastore, Kim L. McBride, Makanko Komara, Lihadh Al-Gazali, Aisha Al Shamsi, Elizabeth A. Fanning, Klaas J. Wierenga, Daryl A. Scott, Ziva Ben-Neriah, Vardiella Meiner, Hanoch Cassuto, Orly Elpeleg, J. Lloyd Holder, Lindsay C. Burrage, Laurie H. Seaver, Lionel Van Maldergem, Sonal Mahida, Janet S. Soul, Margaret Marlatt, Ludmila Matyakhina, Julie Vogt, June-Anne Gold, Soo-Mi Park, Vinod Varghese, Anne K. Lampe, Ajith Kumar, Melissa Lees, Muriel Holder-Espinasse, Vivienne McConnell, Birgitta Bernhard, Ed Blair, Victoria Harrison, The DDD study, Donna M. Muzny, Richard A. Gibbs, Sarah H. Elsea, Jennifer E. Posey, Weimin Bi, Seema Lalani, Fan Xia, Yaping Yang, Christine M. Eng, James R. Lupski, and Pengfei Liu

Subjects
TCF20, 22q13, Neurodevelopmental disorders, Smith–Magenis syndrome, Haploinsufficiency, Loss-of-function variants, Medicine, Genetics, QH426-470
Abstract

Abstract Background Neurodevelopmental disorders are genetically and phenotypically heterogeneous encompassing developmental delay (DD), intellectual disability (ID), autism spectrum disorders (ASDs), structural brain abnormalities, and neurological manifestations with variants in a large number of genes (hundreds) associated. To date, a few de novo mutations potentially disrupting TCF20 function in patients with ID, ASD, and hypotonia have been reported. TCF20 encodes a transcriptional co-regulator structurally related to RAI1, the dosage-sensitive gene responsible for Smith–Magenis syndrome (deletion/haploinsufficiency) and Potocki–Lupski syndrome (duplication/triplosensitivity). Methods Genome-wide analyses by exome sequencing (ES) and chromosomal microarray analysis (CMA) identified individuals with heterozygous, likely damaging, loss-of-function alleles in TCF20. We implemented further molecular and clinical analyses to determine the inheritance of the pathogenic variant alleles and studied the spectrum of phenotypes. Results We report 25 unique inactivating single nucleotide variants/indels (1 missense, 1 canonical splice-site variant, 18 frameshift, and 5 nonsense) and 4 deletions of TCF20. The pathogenic variants were detected in 32 patients and 4 affected parents from 31 unrelated families. Among cases with available parental samples, the variants were de novo in 20 instances and inherited from 4 symptomatic parents in 5, including in one set of monozygotic twins. Two pathogenic loss-of-function variants were recurrent in unrelated families. Patients presented with a phenotype characterized by developmental delay, intellectual disability, hypotonia, variable dysmorphic features, movement disorders, and sleep disturbances. Conclusions TCF20 pathogenic variants are associated with a novel syndrome manifesting clinical characteristics similar to those observed in Smith–Magenis syndrome. Together with previously described cases, the clinical entity of TCF20-associated neurodevelopmental disorders (TAND) emerges from a genotype-driven perspective.

Published
2019
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15. Germline mutation in POLR2A: a heterogeneous, multi-systemic developmental disorder characterized by transcriptional dysregulation

Author

Adam W. Hansen, Payal Arora, Michael M. Khayat, Leah J. Smith, Andrea M. Lewis, Linda Z. Rossetti, Joy Jayaseelan, Ingrid Cristian, Devon Haynes, Stephanie DiTroia, Naomi Meeks, Mauricio R. Delgado, Jill A. Rosenfeld, Lynn Pais, Susan M. White, Qingchang Meng, Davut Pehlivan, Pengfei Liu, Marie-Claude Gingras, Michael F. Wangler, Donna M. Muzny, James R. Lupski, Craig D. Kaplan, and Richard A. Gibbs

Subjects
POLR2A, Pol II, RNA polymerase II, Mendelian disease, developmental disorder, phenotypic expansion, Genetics, QH426-470
Abstract

Summary: De novo germline variation in POLR2A was recently reported to associate with a neurodevelopmental disorder. We report twelve individuals harboring putatively pathogenic de novo or inherited variants in POLR2A, detail their phenotypes, and map all known variants to the domain structure of POLR2A and crystal structure of RNA polymerase II. Affected individuals were ascertained from a local data lake, pediatric genetics clinic, and an online community of families of affected individuals. These include six affected by de novo missense variants (including one previously reported individual), four clinical laboratory samples affected by missense variation with unknown inheritance—with yeast functional assays further supporting altered function—one affected by a de novo in-frame deletion, and one affected by a C-terminal frameshift variant inherited from a largely asymptomatic mother. Recurrently observed phenotypes include ataxia, joint hypermobility, short stature, skin abnormalities, congenital cardiac abnormalities, immune system abnormalities, hip dysplasia, and short Achilles tendons. We report a significantly higher occurrence of epilepsy (8/12, 66.7%) than previously reported (3/15, 20%) (p value = 0.014196; chi-square test) and a lower occurrence of hypotonia (8/12, 66.7%) than previously reported (14/15, 93.3%) (p value = 0.076309). POLR2A-related developmental disorders likely represent a spectrum of related, multi-systemic developmental disorders, driven by distinct mechanisms, converging at a single locus.

Published
2021
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16. Missense variants in CTNNB1 can be associated with vitreoretinopathy—Seven new cases of CTNNB1‐associated neurodevelopmental disorder including a previously unreported retinal phenotype

Author

Linda Z. Rossetti, Mir Reza Bekheirnia, Andrea M. Lewis, Heather C. Mefford, Katie Golden‐Grant, Kristina Tarczy‐Hornoch, Lauren C. Briere, David A. Sweetser, Melissa A. Walker, Elijah Kravets, David A. Stevenson, Georgette Bruenner, Jessica Sebastian, Julia Knapo, Jill A. Rosenfeld, Paul C. Marcogliese, Undiagnosed Diseases Network, and Michael F. Wangler

Subjects
CTNNB1, developmental delay, familial exudative vitreoretinopathy, neurodevelopmental disorder with spastic diplegia and visual defects, visual defects, Genetics, QH426-470
Abstract

Abstract Background CTNNB1 (MIM 116806) encodes beta‐catenin, an adherens junction protein that supports the integrity between layers of epithelial tissue and mediates intercellular signaling. Recently, various heterozygous germline variants in CTNNB1 have been associated with human disease, including neurodevelopmental disorder with spastic diplegia and visual defects (MIM 615075) as well as isolated familial exudative vitreoretinopathy without developmental delays or other organ system involvement (MIM 617572). From over 40 previously reported patients with CTNNB1‐related neurodevelopmental disorder, many have had ocular anomalies including strabismus, hyperopia, and astigmatism. More recently, multiple reports indicate that these abnormalities are associated with the presence of vitreoretinopathy. Methods We gathered a cohort of three patients with CTNNB1‐related neurodevelopmental disorder, recruited from both our own clinic and referred from outside providers. We then searched for a clinical database comprised of over 12,000 exome sequencing studies to identify and recruit four additional patients. Results Here, we report seven new cases of CTNNB1‐related neurodevelopmental disorder, all harboring de novo variants, six of which were previously unreported. All patients but one presented with a spectrum of ocular abnormalities and one patient, who was found to carry a missense variant in CTNNB1, had notable vitreoretinopathy. Conclusions Our findings suggest ophthalmologic screening should be performed in all patients with CTNNB1 variants.

Published
2021
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17. Missed diagnoses: Clinically relevant lessons learned through medical mysteries solved by the Undiagnosed Diseases Network

Author

Heidi Cope, Rebecca Spillmann, Jill A. Rosenfeld, Elly Brokamp, Rebecca Signer, Kelly Schoch, Emily Glanton, Jennifer A. Sullivan, Ellen Macnamara, Sharyn Lincoln, Katie Golden‐Grant, Undiagnosed Diseases Network, James P. Orengo, Gary Clark, Lindsay C. Burrage, Jennifer E. Posey, Jaya Punetha, Amy Robertson, Joy Cogan, John A. Phillips III, Julian Martinez‐Agosto, and Vandana Shashi

Subjects
exome sequencing, genome sequencing, phenotyping, targeted genetic testing, variant interpretation, Genetics, QH426-470
Abstract

Abstract Background Resources within the Undiagnosed Diseases Network (UDN), such as genome sequencing (GS) and model organisms aid in diagnosis and identification of new disease genes, but are currently difficult to access by clinical providers. While these resources do contribute to diagnoses in many cases, they are not always necessary to reach diagnostic resolution. The UDN experience has been that participants can also receive diagnoses through the thoughtful and customized application of approaches and resources that are readily available in clinical settings. Methods The UDN Genetic Counseling and Testing Working Group collected case vignettes that illustrated how clinically available methods resulted in diagnoses. The case vignettes were classified into three themes; phenotypic considerations, selection of genetic testing, and evaluating exome/GS variants and data. Results We present 12 participants that illustrate how clinical practices such as phenotype‐driven genomic investigations, consideration of variable expressivity, selecting the relevant tissue of interest for testing, utilizing updated testing platforms, and recognition of alternate transcript nomenclature resulted in diagnoses. Conclusion These examples demonstrate that when a diagnosis is elusive, an iterative patient‐specific approach utilizing assessment options available to clinical providers may solve a portion of cases. However, this does require increased provider time commitment, a particular challenge in the current practice of genomics.

Published
2020
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18. The transcription factor Maz is essential for normal eye development

Author

Olga Medina-Martinez, Meade Haller, Jill A. Rosenfeld, Marisol A. O'Neill, Dolores J. Lamb, and Milan Jamrich

Subjects
maz, sfrp2, wnt pathway, eye, cnv 16p11.2, Medicine, Pathology, RB1-214
Abstract

Wnt/β-catenin signaling has an essential role in eye development. Faulty regulation of this pathway results in ocular malformations, owing to defects in cell-fate determination and differentiation. Herein, we show that disruption of Maz, the gene encoding Myc-associated zinc-finger transcription factor, produces developmental eye defects in mice and humans. Expression of key genes involved in the Wnt cascade, Sfrp2, Wnt2b and Fzd4, was significantly increased in mice with targeted inactivation of Maz, resulting in abnormal peripheral eye formation with reduced proliferation of the progenitor cells in the region. Paradoxically, the Wnt reporter TCF-Lef1 displayed a significant downregulation in Maz-deficient eyes. Molecular analysis indicates that Maz is necessary for the activation of the Wnt/β-catenin pathway and participates in the network controlling ciliary margin patterning. Copy-number variations and single-nucleotide variants of MAZ were identified in humans that result in abnormal ocular development. The data support MAZ as a key contributor to the eye comorbidities associated with chromosome 16p11.2 copy-number variants and as a transcriptional regulator of ocular development.

Published
2020
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19. Characterization of the renal phenotype in RMND1‐related mitochondrial disease

Author

Brian J. Shayota, Nhon T. Le, Nasim Bekheirnia, Jill A. Rosenfeld, Amy C. Goldstein, Michael Moritz, Dennis W. Bartholomew, Matthew T. Pastore, Fan Xia, Christine Eng, Yaping Yang, Dolores J. Lamb, Fernando Scaglia, Michael C. Braun, and Mir Reza Bekheirnia

Subjects
chronic kidney disease, Mitochondrial disease, renal transplantation, RMND1, Genetics, QH426-470
Abstract

Abstract Background The nuclear encoded gene RMND1 (Required for Meiotic Nuclear Division 1 homolog) has recently been linked to RMND1‐related mitochondrial disease (RRMD). This autosomal recessive condition characteristically presents with an infantile‐onset multisystem disease characterized by severe hypotonia, global developmental delay, failure to thrive, sensorineural hearing loss, and lactic acidosis. Renal disease, however, appears to be one of the more prominent features of RRMD, affecting patients at significantly higher numbers compared to other mitochondrial diseases. We report the clinical, histological, and molecular findings of four RRMD patients across three academic institutions with a focus on the renal manifestations. Methods Four patients were identified for the purpose of this study, all of whom had molecular confirmation at the time of inclusion, which included the common pathogenic variant c.713A>G (p.N238S) as well as the three rare variants: c.485delC (p.P162fs), c.533C>T (p.T178M), and c.1317 + 1G>C splice donor variant. Medical history and laboratory findings were collected from the medical records and medical providers. Results In this study, all four patients developed renal disease characterized as tubulopathy (3/4), renal tubular acidosis (2/4), interstitial nephritis (1/4), and/or end‐stage renal disease (4/4) necessitating renal transplantation (2/4). Histological evaluation of renal biopsy specimens revealed generalized tubular atrophy and on electron microscopy, abundant mitochondria with pleomorphism and abnormal cristae. Conclusion Our experience with RRMD demonstrates a specific pattern of renal disease manifestations and clinical course. Patients are unlikely to respond to traditional chronic kidney disease (CKD) treatments, making early diagnosis and consideration of renal transplantation paramount to the management of RRMD.

Published
2019
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20. Identification of novel candidate disease genes from de novo exonic copy number variants

Author

Tomasz Gambin, Bo Yuan, Weimin Bi, Pengfei Liu, Jill A. Rosenfeld, Zeynep Coban-Akdemir, Amber N. Pursley, Sandesh C. S. Nagamani, Ronit Marom, Sailaja Golla, Lauren Dengle, Heather G. Petrie, Reuben Matalon, Lisa Emrick, Monica B. Proud, Diane Treadwell-Deering, Hsiao-Tuan Chao, Hannele Koillinen, Chester Brown, Nora Urraca, Roya Mostafavi, Saunder Bernes, Elizabeth R. Roeder, Kimberly M. Nugent, Patricia I. Bader, Gary Bellus, Michael Cummings, Hope Northrup, Myla Ashfaq, Rachel Westman, Robert Wildin, Anita E. Beck, LaDonna Immken, Lindsay Elton, Shaun Varghese, Edward Buchanan, Laurence Faivre, Mathilde Lefebvre, Christian P. Schaaf, Magdalena Walkiewicz, Yaping Yang, Sung-Hae L. Kang, Seema R. Lalani, Carlos A. Bacino, Arthur L. Beaudet, Amy M. Breman, Janice L. Smith, Sau Wai Cheung, James R. Lupski, Ankita Patel, Chad A. Shaw, and Paweł Stankiewicz

Subjects
Exon targeted array CGH, Intragenic copy number variants, CNVs, de novo variants, Medicine, Genetics, QH426-470
Abstract

Abstract Background Exon-targeted microarrays can detect small (

Published
2017
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21. Phenotypic and molecular characterisation of CDK13-related congenital heart defects, dysmorphic facial features and intellectual developmental disorders

Author

Bret L. Bostwick, Scott McLean, Jennifer E. Posey, Haley E. Streff, Karen W. Gripp, Alyssa Blesson, Nina Powell-Hamilton, Jessica Tusi, David A. Stevenson, Ellyn Farrelly, Louanne Hudgins, Yaping Yang, Fan Xia, Xia Wang, Pengfei Liu, Magdalena Walkiewicz, Marianne McGuire, Dorothy K. Grange, Marisa V. Andrews, Marybeth Hummel, Suneeta Madan-Khetarpal, Elena Infante, Zeynep Coban-Akdemir, Karol Miszalski-Jamka, John L. Jefferies, Members of the Undiagnosed Diseases Network, Jill A. Rosenfeld, Lisa Emrick, Kimberly M. Nugent, James R. Lupski, John W. Belmont, Brendan Lee, and Seema R. Lalani

Subjects
CDK13, CHDFIDD, De novo variant, Neurodevelopmental disorders, Agenesis of the corpus callosum, Hypertelorism, Medicine, Genetics, QH426-470
Abstract

Abstract Background De novo missense variants in CDK13 have been described as the cause of syndromic congenital heart defects in seven individuals ascertained from a large congenital cardiovascular malformations cohort. We aimed to further define the phenotypic and molecular spectrum of this newly described disorder. Methods To minimise ascertainment bias, we recruited nine additional individuals with CDK13 pathogenic variants from clinical and research exome laboratory sequencing cohorts. Each individual underwent dysmorphology exam and comprehensive medical history review. Results We demonstrate greater than expected phenotypic heterogeneity, including 33% (3/9) of individuals without structural heart disease on echocardiogram. There was a high penetrance for a unique constellation of facial dysmorphism and global developmental delay, as well as less frequently seen renal and sacral anomalies. Two individuals had novel CDK13 variants (p.Asn842Asp, p.Lys734Glu), while the remaining seven unrelated individuals had a recurrent, previously published p.Asn842Ser variant. Summary of all variants published to date demonstrates apparent restriction of pathogenic variants to the protein kinase domain with clustering in the ATP and magnesium binding sites. Conclusions Here we provide detailed phenotypic and molecular characterisation of individuals with pathogenic variants in CDK13 and propose management guidelines based upon the estimated prevalence of anomalies identified.

Published
2017
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22. Incidentally identified genetic variants in arrhythmogenic right ventricular cardiomyopathy‐associated genes among children undergoing exome sequencing reflect healthy population variation

Author

Andrew T. Headrick, Jill A. Rosenfeld, Yaping Yang, Hari Tunuguntla, Hugh D. Allen, Daniel J. Penny, Jeffrey J. Kim, and Andrew P. Landstrom

Subjects
arrhythmogenic right ventricular cardiomyopathy, genetic testing, genetics, incidental finding, secondary finding, variant of undetermined significance, Genetics, QH426-470
Abstract

Abstract Background With expanding use of clinical whole exome sequencing (WES), genetic variants of uncertain significance are increasingly identified. As pathologic mutations in genes associated with arrhythmogenic right ventricular cardiomyopathy (ARVC) carry a risk of sudden death, determining the diagnostic relevance of incidentally identified variants associated with these genes is critical. Methods WES variants from a large, predominantly pediatric cohort (N = 7,066 probands) were obtained for nine ARVC‐associated genes (Baylor Miraca). For comparison, a control cohort was derived from the gnomAD database and an ARVC case cohort (N = 1,379 probands) was established from ARVC cases in the literature. Topologic mapping was performed and signal‐to‐noise analysis was conducted normalizing WES, or case variants, against control variant frequencies. Retrospective chart review was performed of WES cases evaluated clinically (Texas Children's Hospital). Results Incidentally identified variants occurred in 14% of WES referrals and localized to genes which were rare among ARVC cases yet similar to controls. Amino acid‐level signal‐to‐noise analysis of cases demonstrated “pathologic hotspots” localizing to critical domains of PKP2 and DSG2 while WES variants did not. PKP2 ARM7 and ARM8 domains and DSG2 N‐terminal cadherin‐repeat domains demonstrated high pathogenicity while normalized WES variant frequency was low. Review of clinical data available on WES referrals demonstrated none with evidence of ARVC among variant‐positive individuals. Conclusions Incidentally identified variants are common among pediatric WES testing with gene frequencies similar to “background” variants. Incidentally identified variants are unlikely to be pathologic.

Published
2019
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23. MIPEP recessive variants cause a syndrome of left ventricular non-compaction, hypotonia, and infantile death

Author

Mohammad K. Eldomery, Zeynep C. Akdemir, F.-Nora Vögtle, Wu-Lin Charng, Patrycja Mulica, Jill A. Rosenfeld, Tomasz Gambin, Shen Gu, Lindsay C. Burrage, Aisha Al Shamsi, Samantha Penney, Shalini N. Jhangiani, Holly H. Zimmerman, Donna M. Muzny, Xia Wang, Jia Tang, Ravi Medikonda, Prasanna V. Ramachandran, Lee-Jun Wong, Eric Boerwinkle, Richard A. Gibbs, Christine M. Eng, Seema R. Lalani, Jozef Hertecant, Richard J. Rodenburg, Omar A. Abdul-Rahman, Yaping Yang, Fan Xia, Meng C. Wang, James R. Lupski, Chris Meisinger, and V. Reid Sutton

Subjects
Respiratory Chain Complex, Whole Exome Sequencing, Oct1 Protein, Whole Exome Sequencing Data, Oct1 Activity, Medicine, Genetics, QH426-470
Abstract

Abstract Background Mitochondrial presequence proteases perform fundamental functions as they process about 70 % of all mitochondrial preproteins that are encoded in the nucleus and imported posttranslationally. The mitochondrial intermediate presequence protease MIP/Oct1, which carries out precursor processing, has not yet been established to have a role in human disease. Methods Whole exome sequencing was performed on four unrelated probands with left ventricular non-compaction (LVNC), developmental delay (DD), seizures, and severe hypotonia. Proposed pathogenic variants were confirmed by Sanger sequencing or array comparative genomic hybridization. Functional analysis of the identified MIP variants was performed using the model organism Saccharomyces cerevisiae as the protein and its functions are highly conserved from yeast to human. Results Biallelic single nucleotide variants (SNVs) or copy number variants (CNVs) in MIPEP, which encodes MIP, were present in all four probands, three of whom had infantile/childhood death. Two patients had compound heterozygous SNVs (p.L582R/p.L71Q and p.E602*/p.L306F) and one patient from a consanguineous family had a homozygous SNV (p.K343E). The fourth patient, identified through the GeneMatcher tool, a part of the Matchmaker Exchange Project, was found to have inherited a paternal SNV (p.H512D) and a maternal CNV (1.4-Mb deletion of 13q12.12) that includes MIPEP. All amino acids affected in the patients’ missense variants are highly conserved from yeast to human and therefore S. cerevisiae was employed for functional analysis (for p.L71Q, p.L306F, and p.K343E). The mutations p.L339F (human p.L306F) and p.K376E (human p.K343E) resulted in a severe decrease of Oct1 protease activity and accumulation of non-processed Oct1 substrates and consequently impaired viability under respiratory growth conditions. The p.L83Q (human p.L71Q) failed to localize to the mitochondria. Conclusions Our findings reveal for the first time the role of the mitochondrial intermediate peptidase in human disease. Loss of MIP function results in a syndrome which consists of LVNC, DD, seizures, hypotonia, and cataracts. Our approach highlights the power of data exchange and the importance of an interrelationship between clinical and research efforts for disease gene discovery.

Published
2016
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24. Author Correction: Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders

Author

Tianyun Wang, Kendra Hoekzema, Davide Vecchio, Huidan Wu, Arvis Sulovari, Bradley P. Coe, Madelyn A. Gillentine, Amy B. Wilfert, Luis A. Perez-Jurado, Malin Kvarnung, Yoeri Sleyp, Rachel K. Earl, Jill A. Rosenfeld, Madeleine R. Geisheker, Lin Han, Bing Du, Chris Barnett, Elizabeth Thompson, Marie Shaw, Renee Carroll, Kathryn Friend, Rachael Catford, Elizabeth E. Palmer, Xiaobing Zou, Jianjun Ou, Honghui Li, Hui Guo, Jennifer Gerdts, Emanuela Avola, Giuseppe Calabrese, Maurizio Elia, Donatella Greco, Anna Lindstrand, Ann Nordgren, Britt-Marie Anderlid, Geert Vandeweyer, Anke Van Dijck, Nathalie Van der Aa, Brooke McKenna, Miroslava Hancarova, Sarka Bendova, Marketa Havlovicova, Giovanni Malerba, Bernardo Dalla Bernardina, Pierandrea Muglia, Arie van Haeringen, Mariette J. V. Hoffer, Barbara Franke, Gerarda Cappuccio, Martin Delatycki, Paul J. Lockhart, Melanie A. Manning, Pengfei Liu, Ingrid E. Scheffer, Nicola Brunetti-Pierri, Nanda Rommelse, David G. Amaral, Gijs W. E. Santen, Elisabetta Trabetti, Zdeněk Sedláček, Jacob J. Michaelson, Karen Pierce, Eric Courchesne, R. Frank Kooy, The SPARK Consortium, Magnus Nordenskjöld, Corrado Romano, Hilde Peeters, Raphael A. Bernier, Jozef Gecz, Kun Xia, and Evan E. Eichler

Subjects
Science
Abstract

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Published
2020
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25. Correction to: De novo and inherited TCF20 pathogenic variants are associated with intellectual disability, dysmorphic features, hypotonia, and neurological impairments with similarities to Smith–Magenis syndrome

Author

Francesco Vetrini, Shane McKee, Jill A. Rosenfeld, Mohnish Suri, Andrea M. Lewis, Kimberly Margaret Nugent, Elizabeth Roeder, Rebecca O. Littlejohn, Sue Holder, Wenmiao Zhu, Joseph T. Alaimo, Brett Graham, Jill M. Harris, James B. Gibson, Matthew Pastore, Kim L. McBride, Makanko Komara, Lihadh Al-Gazali, Aisha Al Shamsi, Elizabeth A. Fanning, Klaas J. Wierenga, Daryl A. Scott, Ziva Ben-Neriah, Vardiella Meiner, Hanoch Cassuto, Orly Elpeleg, J. Lloyd Holder Jr, Lindsay C. Burrage, Laurie H. Seaver, Lionel Van Maldergem, Sonal Mahida, Janet S. Soul, Margaret Marlatt, Ludmila Matyakhina, Julie Vogt, June-Anne Gold, Soo-Mi Park, Vinod Varghese, Anne K. Lampe, Ajith Kumar, Melissa Lees, Muriel Holder-Espinasse, Vivienne McConnell, Birgitta Bernhard, Ed Blair, Victoria Harrison, The DDD study, Donna M. Muzny, Richard A. Gibbs, Sarah H. Elsea, Jennifer E. Posey, Weimin Bi, Seema Lalani, Fan Xia, Yaping Yang, Christine M. Eng, James R. Lupski, and Pengfei Liu

Subjects
Medicine, Genetics, QH426-470
Abstract

It was highlighted that the original article [1] contained a typographical error in the Results section. Subject 17 was incorrectly cited as Subject 1. This Correction article shows the revised statement. The original article has been updated.

Published
2019
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26. Genetic studies in Drosophila and humans support a model for the concerted function of CISD2, PPT1 and CLN3 in disease

Author

Melanie A. Jones, Sami Amr, Aerial Ferebee, Phung Huynh, Jill A. Rosenfeld, Michael F. Miles, Andrew G. Davies, Christopher A. Korey, John M. Warrick, Rita Shiang, Sarah H. Elsea, Santhosh Girirajan, and Mike Grotewiel

Subjects
RNA interference, Neurodegeneration, Genetic modifiers, Wolfram syndrome, Copy number variants, Lysosomal storage disease, Gene network, Science, Biology (General), QH301-705.5
Abstract

Wolfram syndrome (WFS) is a progressive neurodegenerative disease characterized by diabetes insipidus, diabetes mellitus, optic atrophy, and deafness. WFS1 and WFS2 are caused by recessive mutations in the genes Wolfram Syndrome 1 (WFS1) and CDGSH iron sulfur domain 2 (CISD2), respectively. To explore the function of CISD2, we performed genetic studies in flies with altered expression of its Drosophila orthologue, cisd2. Surprisingly, flies with strong ubiquitous RNAi-mediated knockdown of cisd2 had no obvious signs of altered life span, stress resistance, locomotor behavior or several other phenotypes. We subsequently found in a targeted genetic screen, however, that altered function of cisd2 modified the effects of overexpressing the fly orthologues of two lysosomal storage disease genes, palmitoyl-protein thioesterase 1 (PPT1 in humans, Ppt1 in flies) and ceroid-lipofuscinosis, neuronal 3 (CLN3 in humans, cln3 in flies), on eye morphology in flies. We also found that cln3 modified the effects of overexpressing Ppt1 in the eye and that overexpression of cln3 interacted with a loss of function mutation in cisd2 to disrupt locomotor ability in flies. Follow-up multi-species bioinformatic analyses suggested that a gene network centered on CISD2, PPT1 and CLN3 might impact disease through altered carbohydrate metabolism, protein folding and endopeptidase activity. Human genetic studies indicated that copy number variants (duplications and deletions) including CLN3, and possibly another gene in the CISD2/PPT1/CLN3 network, are over-represented in individuals with developmental delay. Our studies indicate that cisd2, Ppt1 and cln3 function in concert in flies, suggesting that CISD2, PPT1 and CLN3 might also function coordinately in humans. Further, our studies raise the possibility that WFS2 and some lysosomal storage disorders might be influenced by common mechanisms and that the underlying genes might have previously unappreciated effects on developmental delay.

Published
2014
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27. Bi-allelic TTI1 variants cause an autosomal-recessive neurodevelopmental disorder with microcephaly

Author

Margaux Serey-Gaut, Marisol Cortes, Periklis Makrythanasis, Mohnish Suri, Alexander M.R. Taylor, Jennifer A. Sullivan, Ayat N. Asleh, Jaba Mitra, Mohamad A. Dar, Amy McNamara, Vandana Shashi, Sarah Dugan, Xiaofei Song, Jill A. Rosenfeld, Christelle Cabrol, Justyna Iwaszkiewicz, Vincent Zoete, Davut Pehlivan, Zeynep Coban Akdemir, Elizabeth R. Roeder, Rebecca Okashah Littlejohn, Harpreet K. Dibra, Philip J. Byrd, Grant S. Stewart, Bilgen B. Geckinli, Jennifer Posey, Rachel Westman, Chelsy Jungbluth, Jacqueline Eason, Rani Sachdev, Carey-Anne Evans, Gabrielle Lemire, Grace E. VanNoy, Anne O’Donnell-Luria, Frédéric Tran Mau-Them, Aurélien Juven, Juliette Piard, Cheng Yee Nixon, Ying Zhu, Taekjip Ha, Michael F. Buckley, Christel Thauvin, George K. Essien Umanah, Lionel Van Maldergem, James R. Lupski, Tony Roscioli, Valina L. Dawson, Ted M. Dawson, and Stylianos E. Antonarakis

Subjects
Genetics, Genetics (clinical)
Published
2023

28. Bi-allelic SNAPC4 variants dysregulate global alternative splicing and lead to neuroregression and progressive spastic paraparesis

Author

F. Graeme Frost, Marie Morimoto, Prashant Sharma, Lyse Ruaud, Newell Belnap, Daniel G. Calame, Yuri Uchiyama, Naomichi Matsumoto, Machteld M. Oud, Elise A. Ferreira, Vinodh Narayanan, Sampath Rangasamy, Matt Huentelman, Lisa T. Emrick, Ikuko Sato-Shirai, Satoko Kumada, Nicole I. Wolf, Peter J. Steinbach, Yan Huang, Barbara N. Pusey, Sandrine Passemard, Jonathan Levy, Séverine Drunat, Marie Vincent, Agnès Guet, Emanuele Agolini, Antonio Novelli, Maria Cristina Digilio, Jill A. Rosenfeld, Jennifer L. Murphy, James R. Lupski, Gilbert Vezina, Ellen F. Macnamara, David R. Adams, Maria T. Acosta, Cynthia J. Tifft, William A. Gahl, and May Christine V. Malicdan

Subjects
All institutes and research themes of the Radboud University Medical Center, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Genetics, Genetics (clinical)
Abstract

Item does not contain fulltext The vast majority of human genes encode multiple isoforms through alternative splicing, and the temporal and spatial regulation of those isoforms is critical for organismal development and function. The spliceosome, which regulates and executes splicing reactions, is primarily composed of small nuclear ribonucleoproteins (snRNPs) that consist of small nuclear RNAs (snRNAs) and protein subunits. snRNA gene transcription is initiated by the snRNA-activating protein complex (SNAPc). Here, we report ten individuals, from eight families, with bi-allelic, deleterious SNAPC4 variants. SNAPC4 encoded one of the five SNAPc subunits that is critical for DNA binding. Most affected individuals presented with delayed motor development and developmental regression after the first year of life, followed by progressive spasticity that led to gait alterations, paraparesis, and oromotor dysfunction. Most individuals had cerebral, cerebellar, or basal ganglia volume loss by brain MRI. In the available cells from affected individuals, SNAPC4 abundance was decreased compared to unaffected controls, suggesting that the bi-allelic variants affect SNAPC4 accumulation. The depletion of SNAPC4 levels in HeLa cell lines via genomic editing led to decreased snRNA expression and global dysregulation of alternative splicing. Analysis of available fibroblasts from affected individuals showed decreased snRNA expression and global dysregulation of alternative splicing compared to unaffected cells. Altogether, these data suggest that these bi-allelic SNAPC4 variants result in loss of function and underlie the neuroregression and progressive spasticity in these affected individuals.

Published
2023

29. Expansion of the clinical and molecular spectrum of WWOX ‐related epileptic encephalopathy

Author

Shuk Ching, Chong, Ye, Cao, Eva L W, Fung, Soledad, Kleppe, Karen W, Gripp, Jozef, Hertecant, Ayman W, El-Hattab, Jehan, Suleiman, Gary, Clark, Gretchen, von Allmen, Olga, Rodziyevska, Richard A, Lewis, Jill A, Rosenfeld, Jie, Dong, Xia, Wang, Marcus J, Miller, Weimin, Bi, Pengfei, Liu, and Fernando, Scaglia

Subjects
Genetics, Genetics (clinical)
Abstract

WWOX biallelic loss-of-function pathogenic single nucleotide variants (SNVs) and copy number variants (CNVs) including exonic deletions and duplications cause WWOX-related epileptic encephalopathy (WOREE) syndrome. This disorder is characterized by refractory epilepsy, axial hypotonia, peripheral hypertonia, progressive microcephaly, and premature death. Here we report five patients with WWOX biallelic predicted null variants identified by exome sequencing (ES), genome sequencing (GS), and/or chromosomal microarray analysis (CMA). SNVs and intragenic deletions of one or more exons were commonly reported in WOREE syndrome patients which made the genetic diagnosis challenging and required a combination of different diagnostic technologies. These patients presented with severe, developmental and epileptic encephalopathy (DEE), and other cardinal features consistent with WOREE syndrome. This report expands the clinical phenotype associated with this condition, including failure to thrive in most patients and epilepsy that responded to a ketogenic diet in three patients. Dysmorphic features and abnormal prenatal findings were not commonly observed. Additionally, recurrent pancreatitis and sensorineural hearing loss each were observed in single patients. In summary, these phenotypic features broaden the clinical spectrum of WOREE syndrome.

Published
2022

31. TCEAL1 loss-of-function results in an X-linked dominant neurodevelopmental syndrome and drives the neurological disease trait in Xq22.2 deletions

Author

Hadia Hijazi, Linda M. Reis, Davut Pehlivan, Jonathan A. Bernstein, Michael Muriello, Erin Syverson, Devon Bonner, Mehrdad A. Estiar, Ziv Gan-Or, Guy A. Rouleau, Ekaterina Lyulcheva, Lynn Greenhalgh, Marine Tessarech, Estelle Colin, Agnès Guichet, Dominique Bonneau, R.H. van Jaarsveld, A.M.A. Lachmeijer, Lyse Ruaud, Jonathan Levy, Anne-Claude Tabet, Rafal Ploski, Małgorzata Rydzanicz, Łukasz Kępczyński, Katarzyna Połatyńska, Yidan Li, Jawid M. Fatih, Dana Marafi, Jill A. Rosenfeld, Zeynep Coban-Akdemir, Weimin Bi, Richard A. Gibbs, Grace M. Hobson, Jill V. Hunter, Claudia M.B. Carvalho, Jennifer E. Posey, Elena V. Semina, and James R. Lupski

Subjects
Male, Phenotype, Report, Intellectual Disability, Genetics, Humans, Muscle Hypotonia, Female, Syndrome, Autistic Disorder, Genetics (clinical), Transcription Factors
Abstract

An Xq22.2 region upstream of PLP1 has been proposed to underly a neurological disease trait when deleted in 46,XX females. Deletion mapping revealed that heterozygous deletions encompassing the smallest region of overlap (SRO) spanning six Xq22.2 genes (BEX3, RAB40A, TCEAL4, TCEAL3, TCEAL1, and MORF4L2) associate with an early-onset neurological disease trait (EONDT) consisting of hypotonia, intellectual disability, neurobehavioral abnormalities, and dysmorphic facial features. None of the genes within the SRO have been associated with monogenic disease in OMIM. Through local and international collaborations facilitated by GeneMatcher and Matchmaker Exchange, we have identified and herein report seven de novo variants involving TCEAL1 in seven unrelated families: three hemizygous truncating alleles; one hemizygous missense allele; one heterozygous TCEAL1 full gene deletion; one heterozygous contiguous deletion of TCEAL1, TCEAL3, and TCEAL4; and one heterozygous frameshift variant allele. Variants were identified through exome or genome sequencing with trio analysis or through chromosomal microarray. Comparison with previously reported Xq22 deletions encompassing TCEAL1 identified a more-defined syndrome consisting of hypotonia, abnormal gait, developmental delay/intellectual disability especially affecting expressive language, autistic-like behavior, and mildly dysmorphic facial features. Additional features include strabismus, refractive errors, variable nystagmus, gastroesophageal reflux, constipation, dysmotility, recurrent infections, seizures, and structural brain anomalies. An additional maternally inherited hemizygous missense allele of uncertain significance was identified in a male with hypertonia and spasticity without syndromic features. These data provide evidence that TCEAL1 loss of function causes a neurological rare disease trait involving significant neurological impairment with features overlapping the EONDT phenotype in females with the Xq22 deletion.

Published
2022

32. Rare pathogenic variants in WNK3 cause X-linked intellectual disability

Author

Sébastien Küry, Jinwei Zhang, Thomas Besnard, Alfonso Caro-Llopis, Xue Zeng, Stephanie M. Robert, Sunday S. Josiah, Emre Kiziltug, Anne-Sophie Denommé-Pichon, Benjamin Cogné, Adam J. Kundishora, Le T. Hao, Hong Li, Roger E. Stevenson, Raymond J. Louie, Wallid Deb, Erin Torti, Virginie Vignard, Kirsty McWalter, F. Lucy Raymond, Farrah Rajabi, Emmanuelle Ranza, Detelina Grozeva, Stephanie A. Coury, Xavier Blanc, Elise Brischoux-Boucher, Boris Keren, Katrin Õunap, Karit Reinson, Pilvi Ilves, Ingrid M. Wentzensen, Eileen E. Barr, Solveig Heide Guihard, Perrine Charles, Eleanor G. Seaby, Kristin G. Monaghan, Marlène Rio, Yolande van Bever, Marjon van Slegtenhorst, Wendy K. Chung, Ashley Wilson, Delphine Quinquis, Flora Bréhéret, Kyle Retterer, Pierre Lindenbaum, Emmanuel Scalais, Lindsay Rhodes, Katrien Stouffs, Elaine M. Pereira, Sara M. Berger, Sarah S. Milla, Ankita B. Jaykumar, Melanie H. Cobb, Shreyas Panchagnula, Phan Q. Duy, Marie Vincent, Sandra Mercier, Brigitte Gilbert-Dussardier, Xavier Le Guillou, Séverine Audebert-Bellanger, Sylvie Odent, Sébastien Schmitt, Pierre Boisseau, Dominique Bonneau, Annick Toutain, Estelle Colin, Laurent Pasquier, Richard Redon, Arjan Bouman, Jill. A. Rosenfeld, Michael J. Friez, Helena Pérez-Peña, Syed Raza Akhtar Rizvi, Shozeb Haider, Stylianos E. Antonarakis, Charles E. Schwartz, Francisco Martínez, Stéphane Bézieau, Kristopher T. Kahle, Bertrand Isidor, Clinical Genetics, Clinical sciences, Medical Genetics, Reproduction and Genetics, Centre hospitalier universitaire de Nantes (CHU Nantes), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), University of Exeter, MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), The Greenwood Genetic Center, GeneDx [Gaithersburg, MD, USA], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), CHU Pontchaillou [Rennes], Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Genève = University of Geneva (UNIGE), Yale School of Medicine [New Haven, Connecticut] (YSM), This work was granted by the French network of University Hospitals HUGO ('Hôpitaux Universitaires du Grand Ouest'), the French Ministry of Health, and and the Health Regional Agencies from Poitou-Charentes (represented by Frédérique Allaire), Bretagne, Pays de la Loire, and Centre-Val de Loire (HUGODIMS, 2013, RC14_0107). W.K.C. was supported by grants from Simons Foundation Autism Research Initiative, United

Subjects
MESH: Symporters, Exome sequencing, Male, KCC2, Mutation, Missense, MESH: Catalytic Domain, Neurodevelopmental disease, Protein Serine-Threonine Kinases, X-linked intellectual disability, MESH: Brain, WNK3, SDG 3 - Good Health and Well-being, Loss of Function Mutation, Catalytic Domain, MESH: Mental Retardation, X-Linked, Humans, Phosphorylation, MESH: Hemizygote, Genetics (clinical), Hemizygote, MESH: Mutation, Missense, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, MESH: Phosphorylation, Symporters, Brain, MESH: Loss of Function Mutation, MESH: Protein Serine-Threonine Kinases, MESH: Male, Mental Retardation, X-Linked, Maternal Inheritance, MESH: Maternal Inheritance
Abstract

PURPOSE: WNK3 kinase (PRKWNK3) has been implicated in the development and function of the brain via its regulation of the cation-chloride cotransporters, but the role of WNK3 in human development is unknown. METHOD: We ascertained exome or genome sequences of individuals with rare familial or sporadic forms of intellectual disability (ID). RESULTS: We identified a total of 6 different maternally-inherited, hemizygous, 3 loss-of-function or 3 pathogenic missense variants (p.Pro204Arg, p.Leu300Ser, p.Glu607Val) in WNK3 in 14 male individuals from 6 unrelated families. Affected individuals had identifier with variable presence of epilepsy and structural brain defects. WNK3 variants cosegregated with the disease in 3 different families with multiple affected individuals. This included 1 large family previously diagnosed with X-linked Prieto syndrome. WNK3 pathogenic missense variants localize to the catalytic domain and impede the inhibitory phosphorylation of the neuronal-specific chloride cotransporter KCC2 at threonine 1007, a site critically regulated during the development of synaptic inhibition. CONCLUSION: Pathogenic WNK3 variants cause a rare form of human X-linked identifier with variable epilepsy and structural brain abnormalities and implicate impaired phospho-regulation of KCC2 as a pathogenic mechanism.

Published
2022

33. Discovering a new part of the phenotypic spectrum of Coffin-Siris syndrome in a fetal cohort

Author

Pleuntje J. van der Sluijs, Marieke Joosten, Caroline Alby, Tania Attié-Bitach, Kelly Gilmore, Christele Dubourg, Mélanie Fradin, Tianyun Wang, Evangeline C. Kurtz-Nelson, Kaitlyn P. Ahlers, Peer Arts, Christopher P. Barnett, Myla Ashfaq, Anwar Baban, Myrthe van den Born, Sarah Borrie, Tiffany Busa, Alicia Byrne, Miriam Carriero, Claudia Cesario, Karen Chong, Anna Maria Cueto-González, Jennifer C. Dempsey, Karin E.M. Diderich, Dan Doherty, Stense Farholt, Erica H. Gerkes, Svetlana Gorokhova, Lutgarde C.P. Govaerts, Pernille A. Gregersen, Scott E. Hickey, Mathilde Lefebvre, Francesca Mari, Jelena Martinovic, Hope Northrup, Melanie O’Leary, Kareesma Parbhoo, Sophie Patrier, Bernt Popp, Fernando Santos-Simarro, Corinna Stoltenburg, Christel Thauvin-Robinet, Elisabeth Thompson, Anneke T. Vulto-van Silfhout, Farah R. Zahir, Hamish S. Scott, Rachel K. Earl, Evan E. Eichler, Neeta L. Vora, Yael Wilnai, Jessica L. Giordano, Ronald J. Wapner, Jill A. Rosenfeld, Monique C. Haak, Gijs W.E. Santen, Leiden University Medical Center (LUMC), Universiteit Leiden, Erasmus University Medical Center [Rotterdam] (Erasmus MC), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], Hôpital de la Timone [CHU - APHM] (TIMONE), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), CHU Rouen, Normandie Université (NU), Columbia University Medical Center (CUMC), Columbia University [New York], Baylor College of Medicine (BCM), Baylor University, This work was supported, in part, by grants from the National Institutes of Health (Grant No. R01 MH101221 [to E.E.E.]). E.E.E. is an investigator of the Howard Hughes Medical Institute.Sequencing and analysis for individual 30 was provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics and was funded by the National Human Genome Research Institute, the National Eye Institute, and the National Heart, Lung, and Blood Institute (Grant Nos. UM1 HG008900 and R01 HG009141).Sequencing and analysis of cases 5 and 18 was funded by the National Institute of Child Human Development (Grant Nos. K23 HD088742 and R01 HD105868 [to N.L.V.])., Emergency Medicine, Clinical Genetics, van der Sluijs, Pleuntje J, Joosten, Marieke, Alby, Caroline, Attié-Bitach, Tania, Arts, Peer, Byrne, Alicia, Scott, Hamish S, and Santen, Gijs WE

Subjects
prenatal, genetic association, Chromosomal Proteins, Non-Histone, Micrognathism, SMARCB1, genetic vulnerability, Article, Fetal, SMARCA4, Intellectual Disability, Humans, Coffin-Siris syndrome, Abnormalities, Multiple, Genetic Association Studies, Genetics (clinical), Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], BAF-complex, SMARCB, ARID1A, ARID1B BAFopathy, Phenotype, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Face, abnormalities, Hand Deformities, Congenital, Neck
Abstract

Purpose: Genome-wide sequencing is increasingly being performed during pregnancy to identify the genetic cause of congenital anomalies. The interpretation of prenatally identified variants can be challenging and is hampered by our often limited knowledge of prenatal phenotypes. To better delineate the prenatal phenotype of Coffin-Siris syndrome (CSS), we collected clinical data from patients with a prenatal phenotype and a pathogenic variant in one of the CSS-associated genes. Methods: Clinical data was collected through an extensive web-based survey. Results: We included 44 patients with a variant in a CSS-associated gene and a prenatal phenotype; 9 of these patients have been reported before. Prenatal anomalies that were frequently observed in our cohort include hydrocephalus, agenesis of the corpus callosum, hypoplastic left heart syndrome, persistent left vena cava, diaphragmatic hernia, renal agenesis, and intrauterine growth restriction. Anal anomalies were frequently identified after birth in patients with ARID1A variants (6/14, 43%). Interestingly, pathogenic ARID1A variants were much more frequently identified in the current prenatal cohort (16/44, 36%) than in postnatal CSS cohorts (5%-9%). Conclusion: Our data shed new light on the prenatal phenotype of patients with pathogenic variants in CSS genes. (C) 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.

Published
2022

34. Identifying phenotypic expansions for congenital diaphragmatic hernia plus ( <scp>CDH</scp> +) using <scp>DECIPHER</scp> data

Author

Amy Hardcastle, Aliska M. Berry, Ian M. Campbell, Xiaonan Zhao, Pengfei Liu, Amanda E. Gerard, Jill A. Rosenfeld, Saumya D. Sisoudiya, Andres Hernandez‐Garcia, Sara Loddo, Silvia Di Tommaso, Antonio Novelli, Maria L. Dentici, Rossella Capolino, Maria C. Digilio, Ludovico Graziani, Cecilie F. Rustad, Katherine Neas, Giovanni B. Ferrero, Alfredo Brusco, Eleonora Di Gregorio, Diana Wellesley, Claire Beneteau, Madeleine Joubert, Kris Van Den Bogaert, Anneleen Boogaerts, Dominic J. McMullan, John Dean, Maria G. Giuffrida, Laura Bernardini, Vinod Varghese, Nora L. Shannon, Rachel E. Harrison, Wayne W. K. Lam, Shane McKee, Peter D. Turnpenny, Trevor Cole, Jenny Morton, Jacqueline Eason, Marilyn C. Jones, Rebecca Hall, Michael Wright, Karen Horridge, Chad A. Shaw, Wendy K. Chung, and Daryl A. Scott

Subjects
DNA Copy Number Variations, Diaphragm, USP9X, CREBBP, DECIPHER database, SMARCA4, UBA2, congenital diaphragmatic hernia, Mice, Genetics, Animals, Hernias, Diaphragmatic, Congenital, Genetics (clinical)
Abstract

Congenital diaphragmatic hernia (CDH) can occur in isolation or in conjunction with other birth defects (CDH+). A molecular etiology can only be identified in a subset of CDH cases. This is due, in part, to an incomplete understanding of the genes that contribute to diaphragm development. Here, we used clinical and molecular data from 36 individuals with CDH+ who are cataloged in the DECIPHER database to identify genes that may play a role in diaphragm development and to discover new phenotypic expansions. Among this group, we identified individuals who carried putatively deleterious sequence or copy number variants affecting CREBBP, SMARCA4, UBA2, and USP9X. The role of these genes in diaphragm development was supported by their expression in the developing mouse diaphragm, their similarity to known CDH genes using data from a previously published and validated machine learning algorithm, and/or the presence of CDH in other individuals with their associated genetic disorders. Our results demonstrate how data from DECIPHER, and other public databases, can be used to identify new phenotypic expansions and suggest that CREBBP, SMARCA4, UBA2, and USP9X play a role in diaphragm development.

Published
2022

35. Bi-allelic variants in HMGCR cause an autosomal-recessive progressive limb-girdle muscular dystrophy

Author

Joel A. Morales-Rosado, Tanya L. Schwab, Sarah K. Macklin-Mantia, A. Reghan Foley, Filippo Pinto e Vairo, Davut Pehlivan, Sandra Donkervoort, Jill A. Rosenfeld, Grace E. Boyum, Ying Hu, Anh T.Q. Cong, Timothy E. Lotze, Carrie A. Mohila, Dimah Saade, Diana Bharucha-Goebel, Katherine R. Chao, Christopher Grunseich, Christine C. Bruels, Hannah R. Littel, Elicia A. Estrella, Lynn Pais, Peter B. Kang, Michael T. Zimmermann, James R. Lupski, Brendan Lee, Matthew J. Schellenberg, Karl J. Clark, Klaas J. Wierenga, Carsten G. Bönnemann, and Eric W. Klee

Subjects
Genetics, Genetics (clinical)
Published
2023

36. Rare variants in PPFIA3 cause delayed development, intellectual disability, autism, and epilepsy

Author

Maimuna S. Paul, Sydney L. Michener, Hongling Pan, Jessica M. Pfliger, Jill A. Rosenfeld, Vanesa C. Lerma, Alyssa Tran, Megan A. Longley, Richard A. Lewis, Monika Weisz-Hubshman, Mir Reza Bekheirnia, Nasim Bekheirnia, Lauren Massingham, Michael Zech, Matias Wagner, Hartmut Engels, Kirsten Cremer, Elisabeth Mangold, Sophia Peters, Jessica Trautmann, Jessica L. Mester, Maria J. Guillen Sacoto, Richard Person, Pamela P. McDonnell, Stacey R. Cohen, Laina Lusk, Ana S.A. Cohen, Jean-Baptiste Le Pichon, Tomi Pastinen, Dihong Zhou, Kendra Engleman, Caroline Racine, Laurence Faivre, Sébastien Moutton, Anne-Sophie Denommé- Pichon, Sarah Schuhmann, Georgia Vasileiou, Sophie Russ-Hall, Ingrid E. Scheffer, Gemma L. Carvill, Heather Mefford, Undiagnosed Diseases Network, Carlos A. Bacino, Brendan H. Lee, and Hsiao-Tuan Chao

Subjects
Article
Abstract

PPFIA3encodes the Protein-Tyrosine Phosphatase, Receptor-Type, F Polypeptide-Interacting Protein Alpha-3 (PPFIA3), which is a member of the LAR protein-tyrosine phosphatase-interacting protein (liprin) family involved in synaptic vesicle transport and presynaptic active zone assembly. The protein structure and function are well conserved in both invertebrates and vertebrates, but human diseases related to PPFIA3 dysfunction are not yet known. Here, we report 14 individuals with rare mono-allelicPPFIA3variants presenting with features including developmental delay, intellectual disability, hypotonia, autism, and epilepsy. To determine the pathogenicity ofPPFIA3variantsin vivo, we generated transgenic fruit flies expressing either human PPFIA3 wildtype (WT) or variant protein using GAL4-UAS targeted gene expression systems. Ubiquitous expression with Actin-GAL4 showed that thePPFIA3variants had variable penetrance of pupal lethality, eclosion defects, and anatomical leg defects. Neuronal expression with elav-GAL4 showed that thePPFIA3variants had seizure-like behaviors, motor defects, and bouton loss at the 3rdinstar larval neuromuscular junction (NMJ). Altogether, in the fly overexpression assays, we found that thePPFIA3variants in the N-terminal coiled coil domain exhibited stronger phenotypes compared to those in the C-terminal region. In the loss-of-function fly assay, we show that the homozygous loss of flyLiprin-α leads to embryonic lethality. This lethality is partially rescued by the expression of humanPPFIA3WT, suggesting human PPFIA3 protein function is partially conserved in the fly. However, thePPFIA3variants failed to rescue lethality. Altogether, the human and fruit fly data reveal that the rarePPFIA3variants are dominant negative loss-of-function alleles that perturb multiple developmental processes and synapse formation.

Published
2023

37. Functional analysis of a novel de novo variant in PPP5C associated with microcephaly, seizures, and developmental delay

Author

Sara M. Fielder, Jill A. Rosenfeld, Lindsay C. Burrage, Lisa Emrick, Seema Lalani, Ruben Attali, Joshua N. Bembenek, Hieu Hoang, Dustin Baldridge, Gary A. Silverman, Tim Schedl, and Stephen C. Pak

Subjects
Developmental Disabilities, F-Box Proteins, Endocrinology, Diabetes and Metabolism, Mutation, Missense, Nuclear Proteins, Biochemistry, Article, Phenotype, Endocrinology, Seizures, Microcephaly, Phosphoprotein Phosphatases, Genetics, Animals, Humans, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Child, Molecular Biology, Separase
Abstract

We describe a proband evaluated through the Undiagnosed Diseases Network (UDN) who presented with microcephaly, developmental delay, and refractory epilepsy with a de novo p.Ala47Thr missense variant in the protein phosphatase gene, PPP5C. This gene has not previously been associated with a Mendelian disease, and based on the population database, gnomAD, the gene has a low tolerance for loss-of-function variants (pLI = 1, o/e = 0.07). We functionally evaluated the PPP5C variant in C. elegans by knocking the variant into the orthologous gene, pph-5, at the corresponding residue, Ala48Thr. We employed assays in three different biological processes where pph-5 was known to function through opposing the activity of genes, mec-15 and sep-1. We demonstrated that, in contrast to control animals, the pph-5 Ala48Thr variant suppresses the neurite growth phenotype and the GABA signaling defects of mec-15 mutants, and the embryonic lethality of sep-1 mutants. The Ala48Thr variant did not display dominance and behaved similarly to the reference pph-5 null, indicating that the variant is likely a strong hypomorph or complete loss-of-function. We conclude that pph-5 Ala48Thr is damaging in C. elegans. By extension in the proband, PPP5C p.Ala47Thr is likely damaging, the de novo dominant presentation is consistent with haplo-insufficiency, and the PPP5C variant is likely responsible for one or more of the proband's phenotypes.

Published
2022

38. Centers for Mendelian Genomics: A decade of facilitating gene discovery

Author

Samantha M. Baxter, Jennifer E. Posey, Nicole J. Lake, Nara Sobreira, Jessica X. Chong, Steven Buyske, Elizabeth E. Blue, Lisa H. Chadwick, Zeynep H. Coban-Akdemir, Kimberly F. Doheny, Colleen P. Davis, Monkol Lek, Christopher Wellington, Shalini N. Jhangiani, Mark Gerstein, Richard A. Gibbs, Richard P. Lifton, Daniel G. MacArthur, Tara C. Matise, James R. Lupski, David Valle, Michael J. Bamshad, Ada Hamosh, Shrikant Mane, Deborah A. Nickerson, Heidi L. Rehm, Anne O’Donnell-Luria, Marcia Adams, François Aguet, Gulsen Akay, Peter Anderson, Corina Antonescu, Harindra M. Arachchi, Mehmed M. Atik, Christina A. Austin-Tse, Larry Babb, Tamara J. Bacus, Vahid Bahrambeigi, Suganthi Balasubramanian, Yavuz Bayram, Arthur L. Beaudet, Christine R. Beck, John W. Belmont, Jennifer E. Below, Kaya Bilguvar, Corinne D. Boehm, Eric Boerwinkle, Philip M. Boone, Sara J. Bowne, Harrison Brand, Kati J. Buckingham, Alicia B. Byrne, Daniel Calame, Ian M. Campbell, Xiaolong Cao, Claudia Carvalho, Varuna Chander, Jaime Chang, Katherine R. Chao, Ivan K. Chinn, Declan Clarke, Ryan L. Collins, Beryl Cummings, Zain Dardas, Moez Dawood, Kayla Delano, Stephanie P. DiTroia, Harshavardhan Doddapaneni, Haowei Du, Renqian Du, Ruizhi Duan, Mohammad Eldomery, Christine M. Eng, Eleina England, Emily Evangelista, Selin Everett, Jawid Fatih, Adam Felsenfeld, Laurent C. Francioli, Christian D. Frazar, Jack Fu, Emmanuel Gamarra, Tomasz Gambin, Weiniu Gan, Mira Gandhi, Vijay S. Ganesh, Kiran V. Garimella, Laura D. Gauthier, Danielle Giroux, Claudia Gonzaga-Jauregui, Julia K. Goodrich, William W. Gordon, Sean Griffith, Christopher M. Grochowski, Shen Gu, Sanna Gudmundsson, Stacey J. Hall, Adam Hansen, Tamar Harel, Arif O. Harmanci, Isabella Herman, Kurt Hetrick, Hadia Hijazi, Martha Horike-Pyne, Elvin Hsu, Jianhong Hu, Yongqing Huang, Jameson R. Hurless, Steve Jahl, Gail P. Jarvik, Yunyun Jiang, Eric Johanson, Angad Jolly, Ender Karaca, Michael Khayat, James Knight, J. Thomas Kolar, Sushant Kumar, Seema Lalani, Kristen M. Laricchia, Kathryn E. Larkin, Suzanne M. Leal, Gabrielle Lemire, Richard A. Lewis, He Li, Hua Ling, Rachel B. Lipson, Pengfei Liu, Alysia Kern Lovgren, Francesc López-Giráldez, Melissa P. MacMillan, Brian E. Mangilog, Stacy Mano, Dana Marafi, Beth Marosy, Jamie L. Marshall, Renan Martin, Colby T. Marvin, Michelle Mawhinney, Sean McGee, Daniel J. McGoldrick, Michelle Mehaffey, Betselote Mekonnen, Xiaolu Meng, Tadahiro Mitani, Christina Y. Miyake, David Mohr, Shaine Morris, Thomas E. Mullen, David R. Murdock, Mullai Murugan, Donna M. Muzny, Ben Myers, Juanita Neira, Kevin K. Nguyen, Patrick M. Nielsen, Natalie Nudelman, Emily O’Heir, Melanie C. O’Leary, Chrissie Ongaco, Jordan Orange, Ikeoluwa A. Osei-Owusu, Ingrid S. Paine, Lynn S. Pais, Justin Paschall, Karynne Patterson, Davut Pehlivan, Benjamin Pelle, Samantha Penney, Jorge Perez de Acha Chavez, Emma Pierce-Hoffman, Cecilia M. Poli, Jaya Punetha, Aparna Radhakrishnan, Matthew A. Richardson, Eliete Rodrigues, Gwendolin T. Roote, Jill A. Rosenfeld, Erica L. Ryke, Aniko Sabo, Alice Sanchez, Isabelle Schrauwen, Daryl A. Scott, Fritz Sedlazeck, Jillian Serrano, Chad A. Shaw, Tameka Shelford, Kathryn M. Shively, Moriel Singer-Berk, Joshua D. Smith, Hana Snow, Grace Snyder, Matthew Solomonson, Rachel G. Son, Xiaofei Song, Pawel Stankiewicz, Taylorlyn Stephan, V. Reid Sutton, Abigail Sveden, Diana Cornejo Sánchez, Monica Tackett, Michael Talkowski, Machiko S. Threlkeld, Grace Tiao, Miriam S. Udler, Laura Vail, Zaheer Valivullah, Elise Valkanas, Grace E. VanNoy, Qingbo S. Wang, Gao Wang, Lu Wang, Michael F. Wangler, Nicholas A. Watts, Ben Weisburd, Jeffrey M. Weiss, Marsha M. Wheeler, Janson J. White, Clara E. Williamson, Michael W. Wilson, Wojciech Wiszniewski, Marjorie A. Withers, Dane Witmer, Lauren Witzgall, Elizabeth Wohler, Monica H. Wojcik, Isaac Wong, Jordan C. Wood, Nan Wu, Jinchuan Xing, Yaping Yang, Qian Yi, Bo Yuan, Jordan E. Zeiger, Chaofan Zhang, Peng Zhang, Yan Zhang, Xiaohong Zhang, Yeting Zhang, Shifa Zhang, Huda Zoghbi, and Igna van den Veyver

Subjects
Phenotype, Exome Sequencing, Humans, Exome, Genomics, Article, Genetic Association Studies, Genetics (clinical)
Abstract

PURPOSE: Mendelian disease genomic research has undergone a massive transformation over the past decade. With increasing availability of exome and genome sequencing, the role of Mendelian research has expanded beyond data collection, sequencing, and analysis to worldwide data sharing and collaboration. METHODS: Over the past 10 years, the National Institutes of Health–supported Centers for Mendelian Genomics (CMGs) have played a major role in this research and clinical evolution. RESULTS: We highlight the cumulative gene discoveries facilitated by the program, biomedical research leveraged by the approach, and the larger impact on the research community. Beyond generating a list of gene-phenotype relationships and participating in widespread data sharing, the CMGs have created resources, tools, and training for the larger community to foster understanding of genes and genome variation. The CMGs have participated in a wide range of data sharing activities, including deposition of all eligible CMG data into the Analysis, Visualization, and Informatics Lab-space (AnVIL), sharing candidate genes through the Matchmaker Exchange and the CMG website, and sharing variants in Genotypes to Mendelian Phenotypes (Geno2MP) and VariantMatcher. CONCLUSION: The work is far from complete; strengthening communication between research and clinical realms, continued development and sharing of knowledge and tools, and improving access to richly characterized data sets are all required to diagnose the remaining molecularly undiagnosed patients.

Published
2022

39. Rare germline heterozygous missense variants in BRCA1-associated protein 1, BAP1, cause a syndromic neurodevelopmental disorder

Author

Sébastien Küry, Frédéric Ebstein, Alice Mollé, Thomas Besnard, Ming-Kang Lee, Virginie Vignard, Tiphaine Hery, Mathilde Nizon, Grazia M.S. Mancini, Jacques C. Giltay, Benjamin Cogné, Kirsty McWalter, Wallid Deb, Hagar Mor-Shaked, Hong Li, Rhonda E. Schnur, Ingrid M. Wentzensen, Anne-Sophie Denommé-Pichon, Cynthia Fourgeux, Frans W. Verheijen, Eva Faurie, Rachel Schot, Cathy A. Stevens, Daphne J. Smits, Eileen Barr, Ruth Sheffer, Jonathan A. Bernstein, Chandler L. Stimach, Eliana Kovitch, Vandana Shashi, Kelly Schoch, Whitney Smith, Richard H. van Jaarsveld, Anna C.E. Hurst, Kirstin Smith, Evan H. Baugh, Suzanne G. Bohm, Emílie Vyhnálková, Lukáš Ryba, Capucine Delnatte, Juanita Neira, Dominique Bonneau, Annick Toutain, Jill A. Rosenfeld, Séverine Audebert-Bellanger, Brigitte Gilbert-Dussardier, Sylvie Odent, Frédéric Laumonnier, Seth I. Berger, Ann C.M. Smith, Franck Bourdeaut, Marc-Henri Stern, Richard Redon, Elke Krüger, Raphaël Margueron, Stéphane Bézieau, Jeremie Poschmann, Bertrand Isidor, Centre hospitalier universitaire de Nantes (CHU Nantes), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Universität Greifswald - University of Greifswald, Centre de Recherche en Transplantation et Immunologie - Center for Research in Transplantation and Translational Immunology (U1064 Inserm - CR2TI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Génétique et Biologie du Développement, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Erasmus University Medical Center [Rotterdam] (Erasmus MC), University Medical Center [Utrecht], GeneDx [Gaithersburg, MD, USA], Hadassah Hebrew University Medical Center [Jerusalem], Emory University School of Medicine, Emory University [Atlanta, GA], Laboratoire de Biologie Neurovasculaire Intégrée [Angers] (CNRS UMR6214 - INSERM U771), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers, MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Tennessee System, Stanford University, Duke University Medical Center, University of Alabama at Birmingham [ Birmingham] (UAB), Columbia University [New York], Charles University [Prague] (CU), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Baylor College of Medicine (BCM), Baylor University, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Unité neurovasculaire et troubles cognitifs (Neuvacod), Université de Poitiers, CHU Pontchaillou [Rennes], Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre de référence Maladies Rares CLAD-Ouest [Rennes], Children's National Medical Center, National Human Genome Research Institute (NHGRI), Institut Curie [Paris], Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Greifswald University Hospital, Research reported in this manuscript was supported by the NIH Common Fund through the Office of Strategic Coordination/Office of the NIH Director under award number U01HG007672 to V.S. Further support was obtained by funding from the German Research Foundation (SFBTR 167 A4, GRK2719 B4) to E.K, and Clinical Genetics

Subjects
Male, Heterozygote, Proteasome Endopeptidase Complex, tumor, Adolescent, T-Lymphocytes, Ubiquitin-Protein Ligases, [SDV]Life Sciences [q-bio], Mutation, Missense, UPS, ubiquitin-proteasome system, chromatin remodeling, Histones, SDG 3 - Good Health and Well-being, Loss of Function Mutation, Report, ubiquitin, Genetics, Humans, cancer, Family, BAP1, Child, deubiquitination, Germ-Line Mutation, Genetics (clinical), [SDV.GEN]Life Sciences [q-bio]/Genetics, neurodevelopment, BRCA1 Protein, Tumor Suppressor Proteins, Ubiquitination, Infant, Chromatin Assembly and Disassembly, BRCA1, Chromatin, Gene Expression Regulation, Neurodevelopmental Disorders, intellectual disability, Child, Preschool, histone 2A, Female, Host Cell Factor C1, Ubiquitin Thiolesterase
Abstract

International audience; Nuclear deubiquitinase BAP1 (BRCA1-associated protein 1) is a core component of multiprotein complexes that promote transcription by reversing the ubiquitination of histone 2A (H2A). BAP1 is a tumor suppressor whose germline loss-of-function variants predispose to cancer. To our knowledge, there are very rare examples of different germline variants in the same gene causing either a neurodevelopmental disorder (NDD) or a tumor predisposition syndrome. Here, we report a series of 11 de novo germline heterozygous missense BAP1 variants associated with a rare syndromic NDD. Functional analysis showed that most of the variants cannot rescue the consequences of BAP1 inactivation, suggesting a loss-of-function mechanism. In T cells isolated from two affected children, H2A deubiquitination was impaired. In matching peripheral blood mononuclear cells, histone H3 K27 acetylation ChIP-seq indicated that these BAP1 variants induced genome-wide chromatin state alterations, with enrichment for regulatory regions surrounding genes of the ubiquitin-proteasome system (UPS). Altogether, these results define a clinical syndrome caused by rare germline missense BAP1 variants that alter chromatin remodeling through abnormal histone ubiquitination and lead to transcriptional dysregulation of developmental genes.

Published
2022

40. Retrospective analysis of a clinical exome sequencing cohort reveals the mutational spectrum and identifies candidate disease–associated loci for BAFopathies

Author

Lei Wang, Mauricio R. Delgado, Margarita Saenz, Hongzheng Dai, Daryl A. Scott, Kathryn Curry, Bo Yuan, Anh Dang, Wenmiao Zhu, John Lattier, Rui Xiao, Suneeta Madan-Khetarpal, Linyan Meng, Tiana M. Scott, Pilar L. Magoulas, Haley Streff, Jessica Sebastian, Jill A. Rosenfeld, Haowei Du, Seema R. Lalani, James R. Lupski, Jennifer E. Posey, Ronit Marom, Vipulkumar Patel, Weimin Bi, Neil A. Hanchard, Chun-An Chen, Shayna Svihovec, Pengfei Liu, Fan Xia, and Christine M. Eng

Subjects
Chromosomal Proteins, Non-Histone, Micrognathism, Computational biology, Disease, Biology, Actins, Article, DNA-Binding Proteins, Cohort, Retrospective analysis, Humans, Abnormalities, Multiple, Exome, Hand Deformities, Congenital, Genetics (clinical), Exome sequencing, Retrospective Studies
Abstract

PURPOSE: The BRG1/BRM-associated factor (BAF) complex is a chromatin remodeling complex playing a critical role in gene regulation. Defects in the genes encoding the BAF subunits lead to BAFopathies, a group of neurodevelopmental disorders with extensive locus and phenotypic heterogeneity. METHODS: We retrospectively analyzed data from 16,243 patients referred for clinical exome sequencing (ES) with a focus on the BAF complex. We applied a genotype-first approach combining predicted genic constraints to propose candidate BAFopathy genes. RESULTS: We identified 127 patients carrying pathogenic, likely pathogenic variants or de novo variants of unknown clinical significance (VUS) in 11 known BAFopathy genes. Those include 34 patients molecularly diagnosed through ES reanalysis with new gene-disease evidence (N= 21) or variant re-classifications in known BAFopathy genes (N=13). We also identified de novo or predicted loss-of-function variants in four candidate BAFopathy genes, ACTL6A, BICRA (implicated in BAFopathy during this study), PBRM1, and SMARCC1. CONCLUSION: We report the mutational spectrum of BAFopathies in an ES cohort. A genotype-driven and a pathway-based reanalysis of ES data identified new evidence for candidate genes for BAFopathies. Further mechanistic and phenotypic characterization of additional patients are warranted to confirm their roles in human disease and to delineate their associated phenotypic spectrums.

Published
2022

41. Stankiewicz-Isidor syndrome

Author

Ignacio Briceño, Frédéric Ebstein, Alberto Gómez, Heidi Cope, Wallid Deb, Krzysztof Szczaluba, Hutton M. Kearney, Dominique Bonneau, Elke Krüger, Marie Vincent, Jill A. Rosenfeld, Karin E. M. Diderich, Dominique Bourgeois, Kay Metcalfe, Bryce A. Mendelssohn, Magalie Barth, Solène Conrad, Alanna Strong, Patrick R. Blackburn, Amanda Gerard, McKinsey L. Goodenberger, Benjamin Cogné, Geneviève Baujat, Caroline Camby, Thomas Besnard, Natasha L. Rudy, Karin Dahan, Estelle Colin, Carlos A. Bacino, Caleb Bupp, Christel Thauvin-Robinet, Yolande van Bever, Rafał Płoski, Anne de Saint Martin, Johannes A. Mayr, Ingrid Bader, Yong-Hui Jiang, Virginie Vignard, Kathryn Warren, Judith D. Ranells, Yves Alembik, Joanna Kennedy, Stéphane Bézieau, Bertrand Isidor, Anna C.E. Hurst, Amélie Piton, Sébastien Küry, Ange-Line Bruel, PaweƗ Stankiewicz, Ingrid Scurr, Anja Brehm, and Clinical Genetics

Subjects
Genetics, Phenotype, Intellectual Disability, Molecular phenotype, Humans, Language Development Disorders, Haploinsufficiency, Biology, Genetics (clinical), Musculoskeletal Abnormalities
Abstract

Purpose: Haploinsufficiency of PSMD12 has been reported in individuals with neurodevelopmental phenotypes, including developmental delay/intellectual disability (DD/ID), facial dysmorphism, and congenital malformations, defined as Stankiewicz-Isidor syndrome (STISS). Investigations showed that pathogenic variants in PSMD12 perturb intracellular protein homeostasis. Our objective was to further explore the clinical and molecular phenotypic spectrum of STISS. Methods: We report 24 additional unrelated patients with STISS with various truncating single nucleotide variants or copy-number variant deletions involving PSMD12. We explore disease etiology by assessing patient cells and CRISPR/Cas9-engineered cell clones for various cellular pathways and inflammatory status. Results: The expressivity of most clinical features in STISS is highly variable. In addition to previously reported DD/ID, speech delay, cardiac and renal anomalies, we also confirmed preaxial hand abnormalities as a feature of this syndrome. Of note, 2 patients also showed chilblains resembling signs observed in interferonopathy. Remarkably, our data show that STISS patient cells exhibit a profound remodeling of the mTORC1 and mitophagy pathways with an induction of type I interferon-stimulated genes. Conclusion: We refine the phenotype of STISS and show that it can be clinically recognizable and biochemically diagnosed by a type I interferon gene signature.

Published
2022

42. Alternative polyadenylation alters protein dosage by switching between intronic and 3′UTR sites

Author

Nicola de Prisco, Caitlin Ford, Nathan D. Elrod, Winston Lee, Lauren C. Tang, Kai-Lieh Huang, Ai Lin, Ping Ji, Venkata S. Jonnakuti, Lia Boyle, Maximilian Cabaj, Salvatore Botta, Katrin Õunap, Karit Reinson, Monica H. Wojcik, Jill A. Rosenfeld, Weimin Bi, Kristian Tveten, Trine Prescott, Thorsten Gerstner, Audrey Schroeder, Chin-To Fong, Jaya K. George-Abraham, Catherine A. Buchanan, Andrea Hanson-Khan, Jonathan A. Bernstein, Aikaterini A. Nella, Wendy K. Chung, Vicky Brandt, Marko Jovanovic, Kimara L. Targoff, Hari Krishna Yalamanchili, Eric J. Wagner, and Vincenzo A. Gennarino

Subjects
Multidisciplinary
Abstract

Alternative polyadenylation (APA) creates distinct transcripts from the same gene by cleaving the pre-mRNA at poly(A) sites that can lie within the 3′ untranslated region (3′UTR), introns, or exons. Most studies focus on APA within the 3′UTR; however, here, we show that CPSF6 insufficiency alters protein levels and causes a developmental syndrome by deregulating APA throughout the transcript. In neonatal humans and zebrafish larvae, CPSF6 insufficiency shifts poly(A) site usage between the 3′UTR and internal sites in a pathway-specific manner. Genes associated with neuronal function undergo mostly intronic APA, reducing their expression, while genes associated with heart and skeletal function mostly undergo 3′UTR APA and are up-regulated. This suggests that, under healthy conditions, cells toggle between internal and 3′UTR APA to modulate protein expression.

Published
2023

43. Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition

Author

Elizabeth E. Palmer, Michael Pusch, Alessandra Picollo, Caitlin Forwood, Matthew H. Nguyen, Vanessa Suckow, Jessica Gibbons, Alva Hoff, Lisa Sigfrid, Andre Megarbane, Mathilde Nizon, Benjamin Cogné, Claire Beneteau, Fowzan S. Alkuraya, Aziza Chedrawi, Mais O. Hashem, Hannah Stamberger, Sarah Weckhuysen, Arnaud Vanlander, Berten Ceulemans, Sulekha Rajagopalan, Kenneth Nunn, Stéphanie Arpin, Martine Raynaud, Constance S. Motter, Catherine Ward-Melver, Katrien Janssens, Marije Meuwissen, Diane Beysen, Nicola Dikow, Mona Grimmel, Tobias B. Haack, Emma Clement, Amy McTague, David Hunt, Sharron Townshend, Michelle Ward, Linda J. Richards, Cas Simons, Gregory Costain, Lucie Dupuis, Roberto Mendoza-Londono, Tracy Dudding-Byth, Jackie Boyle, Carol Saunders, Emily Fleming, Salima El Chehadeh, Marie-Aude Spitz, Amelie Piton, Bénédicte Gerard, Marie-Thérèse Abi Warde, Gillian Rea, Caoimhe McKenna, Sofia Douzgou, Siddharth Banka, Cigdem Akman, Jennifer M. Bain, Tristan T. Sands, Golder N. Wilson, Erin J. Silvertooth, Lauren Miller, Damien Lederer, Rani Sachdev, Rebecca Macintosh, Olivier Monestier, Deniz Karadurmus, Felicity Collins, Melissa Carter, Luis Rohena, Marjolein H. Willemsen, Charlotte W. Ockeloen, Rolph Pfundt, Sanne D. Kroft, Michael Field, Francisco E. R. Laranjeira, Ana M. Fortuna, Ana R. Soares, Vincent Michaud, Sophie Naudion, Sailaja Golla, David D. Weaver, Lynne M. Bird, Jennifer Friedman, Virginia Clowes, Shelagh Joss, Laura Pölsler, Philippe M. Campeau, Maria Blazo, Emilia K. Bijlsma, Jill A. Rosenfeld, Christian Beetz, Zöe Powis, Kirsty McWalter, Tracy Brandt, Erin Torti, Mikaël Mathot, Shekeeb S. Mohammad, Ruth Armstrong, Vera M. Kalscheuer, UCL - SSS/IREC/MONT - Pôle Mont Godinne, UCL - (MGD) Service de pédiatrie, Growth and Development, Pediatrics, Centre for Medical Genetics, Brussels Heritage Lab, and Medical Genetics

Subjects
Male, DISRUPTION, Chloride Channels/genetics, EXCHANGER, Mutation, Missense, LYSOSOMAL STORAGE DISEASE, VARIANTS, Neurodevelopmental Disorders/genetics, PHENOTYPE, Cellular and Molecular Neuroscience, All institutes and research themes of the Radboud University Medical Center, Genes, X-Linked, CLC CHLORIDE, Medicine and Health Sciences, Humans, Molecular Biology, MUTATION, Biology, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], CHANNELS, LINKED MENTAL-RETARDATION, ASSOCIATION, GENE, Psychiatry and Mental health, Chemistry, Female, Human medicine
Abstract

Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a “shift” of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis.

Published
2023

44. SRSF1 haploinsufficiency is responsible for a syndromic developmental disorder associated with intellectual disability

Author

Elke Bogaert, Aurore Garde, Thierry Gautier, Kathleen Rooney, Yannis Duffourd, Pontus LeBlanc, Emma van Reempts, Frederic Tran Mau-Them, Ingrid M. Wentzensen, Kit Sing Au, Kate Richardson, Hope Northrup, Vincent Gatinois, David Geneviève, Raymond J. Louie, Michael J. Lyons, Lone Walentin Laulund, Charlotte Brasch-Andersen, Trine Maxel Juul, Fatima El It, Nathalie Marle, Patrick Callier, Raissa Relator, Sadegheh Haghshenas, Haley McConkey, Jennifer Kerkhof, Claudia Cesario, Antonio Novelli, Nicola Brunetti-Pierri, Michele Pinelli, Perrine Pennamen, Sophie Naudion, Marine Legendre, Cécile Courdier, Aurelien Trimouille, Martine Doco Fenzy, Lynn Pais, Alison Yeung, Kimberly Nugent, Elizabeth R. Roeder, Tadahiro Mitani, Jennifer E. Posey, Daniel Calame, Hagith Yonath, Jill A. Rosenfeld, Luciana Musante, Flavio Faletra, Francesca Montanari, Giovanna Sartor, Alessandra Vancini, Marco Seri, Claude Besmond, Karine Poirier, Laurence Hubert, Dimitri Hemelsoet, Arnold Munnich, James R. Lupski, Christophe Philippe, Christel Thauvin-Robinet, Laurence Faivre, Bekim Sadikovic, Jérôme Govin, Bart Dermaut, Antonio Vitobello, Bogaert, Elke, Garde, Aurore, Gautier, Thierry, Rooney, Kathleen, Duffourd, Yanni, Leblanc, Pontu, van Reempts, Emma, Tran Mau-Them, Frederic, Wentzensen, Ingrid M, Au, Kit Sing, Richardson, Kate, Northrup, Hope, Gatinois, Vincent, Geneviève, David, Louie, Raymond J, Lyons, Michael J, Laulund, Lone Walentin, Brasch-Andersen, Charlotte, Maxel Juul, Trine, El It, Fatima, Marle, Nathalie, Callier, Patrick, Relator, Raissa, Haghshenas, Sadegheh, Mcconkey, Haley, Kerkhof, Jennifer, Cesario, Claudia, Novelli, Antonio, Brunetti-Pierri, Nicola, Pinelli, Michele, Pennamen, Perrine, Naudion, Sophie, Legendre, Marine, Courdier, Cécile, Trimouille, Aurelien, Fenzy, Martine Doco, Pais, Lynn, Yeung, Alison, Nugent, Kimberly, Roeder, Elizabeth R, Mitani, Tadahiro, Posey, Jennifer E, Calame, Daniel, Yonath, Hagith, Rosenfeld, Jill A, Musante, Luciana, Faletra, Flavio, Montanari, Francesca, Sartor, Giovanna, Vancini, Alessandra, Seri, Marco, Besmond, Claude, Poirier, Karine, Hubert, Laurence, Hemelsoet, Dimitri, Munnich, Arnold, Lupski, James R, Philippe, Christophe, Thauvin-Robinet, Christel, Faivre, Laurence, Sadikovic, Bekim, Govin, Jérôme, Dermaut, Bart, and Vitobello, Antonio

Subjects
SRSF1, splicing, epigenetic signature, Medicine and Health Sciences, Genetics, Drosophila, neurodevelopmental disorder, Genetics (clinical), haploinsufficiency
Abstract

SRSF1 (also known as ASF/SF2) is a non-small nuclear ribonucleoprotein (non-snRNP) that belongs to the arginine/serine (R/S) domain family. It recognizes and binds to mRNA, regulating both constitutive and alternative splicing. The complete loss of this proto-oncogene in mice is embryonically lethal. Through international data sharing, we identified 17 individuals (10 females and 7 males) with a neurodevelopmental disorder (NDD) with heterozygous germline SRSF1 variants, mostly de novo, including three frameshift variants, three nonsense variants, seven missense variants, and two microdeletions within region 17q22 encompassing SRSF1. Only in one family, the de novo origin could not be established. All individuals featured a recurrent phenotype including developmental delay and intellectual disability (DD/ID), hypotonia, neurobehavioral problems, with variable skeletal (66.7%) and cardiac (46%) anomalies. To investigate the functional consequences of SRSF1 variants, we performed in silico structural modeling, developed an in vivo splicing assay in Drosophila, and carried out episignature analysis in blood-derived DNA from affected individuals. We found that all loss-of-function and 5 out of 7 missense variants were pathogenic, leading to a loss of SRSF1 splicing activity in Drosophila, correlating with a detectable and specific DNA methylation episignature. In addition, our orthogonal in silico, in vivo, and epigenetics analyses enabled the separation of clearly pathogenic missense variants from those with uncertain significance. Overall, these results indicated that haploinsufficiency of SRSF1 is responsible for a syndromic NDD with ID due to a partial loss of SRSF1-mediated splicing activity.

Published
2023

45. Variants in the zinc transporter TMEM163 cause a hypomyelinating leukodystrophy

Author

Michelle C do Rosario, Guillermo Rodriguez Bey, Bruce Nmezi, Fang Liu, Talia Oranburg, Ana S A Cohen, Keith A Coffman, Maya R Brown, Kirill Kiselyov, Quinten Waisfisz, Myrthe T Flohil, Shahyan Siddiqui, Jill A Rosenfeld, Alejandro Iglesias, Katta Mohan Girisha, Nicole I Wolf, Quasar Saleem Padiath, Anju Shukla, Human genetics, CCA - Cancer biology and immunology, Pediatrics, and Amsterdam Neuroscience - Cellular & Molecular Mechanisms

Subjects
Zinc, Pelizaeus-Merzbacher Disease, Mutation, Missense, Humans, Membrane Proteins, Neurology (clinical), Myelin Sheath
Abstract

Hypomyelinating leukodystrophies comprise a subclass of genetic disorders with deficient myelination of the CNS white matter. Here we report four unrelated families with a hypomyelinating leukodystrophy phenotype harbouring variants in TMEM163 (NM_030923.5). The initial clinical presentation resembled Pelizaeus–Merzbacher disease with congenital nystagmus, hypotonia, delayed global development and neuroimaging findings suggestive of significant and diffuse hypomyelination. Genomic testing identified three distinct heterozygous missense variants in TMEM163 with two unrelated individuals sharing the same de novo variant. TMEM163 is highly expressed in the CNS particularly in newly myelinating oligodendrocytes and was recently revealed to function as a zinc efflux transporter. All the variants identified lie in highly conserved residues in the cytoplasmic domain of the protein, and functional in vitro analysis of the mutant protein demonstrated significant impairment in the ability to efflux zinc out of the cell. Expression of the mutant proteins in an oligodendroglial cell line resulted in substantially reduced mRNA expression of key myelin genes, reduced branching and increased cell death. Our findings indicate that variants in TMEM163 cause a hypomyelinating leukodystrophy and uncover a novel role for zinc homeostasis in oligodendrocyte development and myelin formation.

Published
2022

46. Biallelic variants in SLC38A3 encoding a glutamine transporter cause epileptic encephalopathy

Author

E El-Anany, Jennifer E. Posey, Shalini N. Jhangiani, S Guliyeva, Jill A. Rosenfeld, Khalid A. Fakhro, Vasiliki Karageorgou, A A Subhi, R. A. Gibbs, A Al-Maraghi, Sarah H. Elsea, Amal Alhashem, Henry Houlden, Charul Gijavanekar, M S Breilyn, Dana Marafi, Joseph G. Gleeson, Christian Beetz, E Sites, Hessa S. Alsaif, Vernon R. Sutton, Jill V. Hunter, Fowzan S. Alkuraya, M Zakkariah, C Gaba, James R. Lupski, Erin Torti, Davut Pehlivan, Z. Coban Akdemir, Matteo P. Ferla, S Duberstein, Haowei Du, Mohamed S. Abdel-Hamid, Ulviyya Guliyeva, M Sebastin, Jenny C. Taylor, E Danish, Reza Maroofian, A Haseeb, Rauan Kaiyrzhanov, Maha S. Zaki, Mohammed Al-Owain, S V Mullegama, Ning Liu, Jawid M Fatih, and Tadahiro Mitani

Subjects
Genetics, Microcephaly, Nitrogen, Glutamine, Biology, medicine.disease, Sodium-Calcium Exchanger, Hypotonia, Solute carrier family, Epilepsy, Metabolome, medicine, Humans, Original Article, Epilepsy, Generalized, Histidine, Neurology (clinical), Global developmental delay, medicine.symptom, Gene, Exome sequencing
Abstract

The solute carrier (SLC) superfamily encompasses >400 transmembrane transporters involved in the exchange of amino acids, nutrients, ions, metals, neurotransmitters and metabolites across biological membranes. SLCs are highly expressed in the mammalian brain; defects in nearly 100 unique SLC-encoding genes (OMIM: https://www.omim.org) are associated with rare Mendelian disorders including developmental and epileptic encephalopathy and severe neurodevelopmental disorders. Exome sequencing and family-based rare variant analyses on a cohort with neurodevelopmental disorders identified two siblings with developmental and epileptic encephalopathy and a shared deleterious homozygous splicing variant in SLC38A3. The gene encodes SNAT3, a sodium-coupled neutral amino acid transporter and a principal transporter of the amino acids asparagine, histidine, and glutamine, the latter being the precursor for the neurotransmitters GABA and glutamate. Additional subjects with a similar developmental and epileptic encephalopathy phenotype and biallelic predicted-damaging SLC38A3 variants were ascertained through GeneMatcher and collaborations with research and clinical molecular diagnostic laboratories. Untargeted metabolomic analysis was performed to identify novel metabolic biomarkers. Ten individuals from seven unrelated families from six different countries with deleterious biallelic variants in SLC38A3 were identified. Global developmental delay, intellectual disability, hypotonia, and absent speech were common features while microcephaly, epilepsy, and visual impairment were present in the majority. Epilepsy was drug-resistant in half. Metabolomic analysis revealed perturbations of glutamate, histidine, and nitrogen metabolism in plasma, urine, and CSF of selected subjects, potentially representing biomarkers of disease. Our data support the contention that SLC38A3 is a novel disease gene for developmental and epileptic encephalopathy and illuminate the likely pathophysiology of the disease as perturbations in glutamine homeostasis.

Published
2021

47. Heterozygous loss-of-function variants significantly expand the phenotypes associated with loss of GDF11

Author

Thomas A. Ravenscroft, Jennifer B. Phillips, Elizabeth Fieg, Sameer S. Bajikar, Judy Peirce, Jeremy Wegner, Alia A. Luna, Eric J. Fox, Yi-Lin Yan, Jill A. Rosenfeld, Jonathan Zirin, Oguz Kanca, Maria T. Acosta, Margaret Adam, David R. Adams, Pankaj B. Agrawal, Mercedes E. Alejandro, Justin Alvey, Laura Amendola, Ashley Andrews, Euan A. Ashley, Mahshid S. Azamian, Carlos A. Bacino, Guney Bademci, Eva Baker, Ashok Balasubramanya, Dustin Baldridge, Jim Bale, Michael Bamshad, Deborah Barbouth, Pinar Bayrak-Toydemir, Anita Beck, Alan H. Beggs, Edward Behrens, Gill Bejerano, Jimmy Bennet, Beverly Berg-Rood, Jonathan A. Bernstein, Gerard T. Berry, Anna Bican, Stephanie Bivona, Elizabeth Blue, John Bohnsack, Carsten Bonnenmann, Devon Bonner, Lorenzo Botto, Brenna Boyd, Lauren C. Briere, Elly Brokamp, Gabrielle Brown, Elizabeth A. Burke, Lindsay C. Burrage, Manish J. Butte, Peter Byers, William E. Byrd, John Carey, Olveen Carrasquillo, Ta Chen Peter Chang, Sirisak Chanprasert, Hsiao-Tuan Chao, Gary D. Clark, Terra R. Coakley, Laurel A. Cobban, Joy D. Cogan, Matthew Coggins, F. Sessions Cole, Heather A. Colley, Cynthia M. Cooper, Heidi Cope, William J. Craigen, Andrew B. Crouse, Michael Cunningham, Precilla D’Souza, Hongzheng Dai, Surendra Dasari, Joie Davis, Jyoti G. Dayal, Matthew Deardorff, Esteban C. Dell’Angelica, Shweta U. Dhar, Katrina Dipple, Daniel Doherty, Naghmeh Dorrani, Argenia L. Doss, Emilie D. Douine, David D. Draper, Laura Duncan, Dawn Earl, David J. Eckstein, Lisa T. Emrick, Christine M. Eng, Cecilia Esteves, Marni Falk, Liliana Fernandez, Carlos Ferreira, Elizabeth L. Fieg, Laurie C. Findley, Paul G. Fisher, Brent L. Fogel, Irman Forghani, Laure Fresard, William A. Gahl, Ian Glass, Bernadette Gochuico, Rena A. Godfrey, Katie Golden-Grant, Alica M. Goldman, Madison P. Goldrich, David B. Goldstein, Alana Grajewski, Catherine A. Groden, Irma Gutierrez, Sihoun Hahn, Rizwan Hamid, Neil A. Hanchard, Kelly Hassey, Nichole Hayes, Frances High, Anne Hing, Fuki M. Hisama, Ingrid A. Holm, Jason Hom, Martha Horike-Pyne, Alden Huang, Yong Huang, Laryssa Huryn, Rosario Isasi, Fariha Jamal, Gail P. Jarvik, Jeffrey Jarvik, Suman Jayadev, Lefkothea Karaviti, Jennifer Kennedy, Dana Kiley, Isaac S. Kohane, Jennefer N. Kohler, Deborah Krakow, Donna M. Krasnewich, Elijah Kravets, Susan Korrick, Mary Koziura, Joel B. Krier, Seema R. Lalani, Byron Lam, Christina Lam, Grace L. LaMoure, Brendan C. Lanpher, Ian R. Lanza, Lea Latham, Kimberly LeBlanc, Brendan H. Lee, Hane Lee, Roy Levitt, Richard A. Lewis, Sharyn A. Lincoln, Pengfei Liu, Xue Zhong Liu, Nicola Longo, Sandra K. Loo, Joseph Loscalzo, Richard L. Maas, John MacDowall, Ellen F. Macnamara, Calum A. MacRae, Valerie V. Maduro, Marta M. Majcherska, Bryan C. Mak, May Christine V. Malicdan, Laura A. Mamounas, Teri A. Manolio, Rong Mao, Kenneth Maravilla, Thomas C. Markello, Ronit Marom, Gabor Marth, Beth A. Martin, Martin G. Martin, Julian A. Martínez-Agosto, Shruti Marwaha, Jacob McCauley, Allyn McConkie-Rosell, Colleen E. McCormack, Alexa T. McCray, Elisabeth McGee, Heather Mefford, J. Lawrence Merritt, Matthew Might, Ghayda Mirzaa, Eva Morava, Paolo Moretti, Paolo M. Moretti, Deborah Mosbrook-Davis, John J. Mulvihill, David R. Murdock, Anna Nagy, Mariko Nakano-Okuno, Avi Nath, Stan F. Nelson, John H. Newman, Sarah K. Nicholas, Deborah Nickerson, Shirley Nieves-Rodriguez, Donna Novacic, Devin Oglesbee, James P. Orengo, Laura Pace, Stephen Pak, J. Carl Pallais, Christina GS. Palmer, Jeanette C. Papp, Neil H. Parker, John A. Phillips, Jennifer E. Posey, Lorraine Potocki, Bradley Power, Barbara N. Pusey, Aaron Quinlan, Wendy Raskind, Archana N. Raja, Deepak A. Rao, Genecee Renteria, Chloe M. Reuter, Lynette Rives, Amy K. Robertson, Lance H. Rodan, Natalie Rosenwasser, Francis Rossignol, Maura Ruzhnikov, Ralph Sacco, Jacinda B. Sampson, Susan L. Samson, Mario Saporta, C. Ron Scott, Judy Schaechter, Timothy Schedl, Kelly Schoch, Daryl A. Scott, Vandana Shashi, Jimann Shin, Rebecca Signer, Edwin K. Silverman, Janet S. Sinsheimer, Kathy Sisco, Edward C. Smith, Kevin S. Smith, Emily Solem, Lilianna Solnica-Krezel, Ben Solomon, Rebecca C. Spillmann, Joan M. Stoler, Jennifer A. Sullivan, Kathleen Sullivan, Angela Sun, Shirley Sutton, David A. Sweetser, Virginia Sybert, Holly K. Tabor, Amelia L.M. Tan, Queenie K.-G. Tan, Mustafa Tekin, Fred Telischi, Willa Thorson, Audrey Thurm, Cynthia J. Tifft, Camilo Toro, Alyssa A. Tran, Brianna M. Tucker, Tiina K. Urv, Adeline Vanderver, Matt Velinder, Dave Viskochil, Tiphanie P. Vogel, Colleen E. Wahl, Stephanie Wallace, Nicole M. Walley, Chris A. Walsh, Melissa Walker, Jennifer Wambach, Jijun Wan, Lee-kai Wang, Michael F. Wangler, Patricia A. Ward, Daniel Wegner, Mark Wener, Tara Wenger, Katherine Wesseling Perry, Monte Westerfield, Matthew T. Wheeler, Jordan Whitlock, Lynne A. Wolfe, Jeremy D. Woods, Shinya Yamamoto, John Yang, Muhammad Yousef, Diane B. Zastrow, Wadih Zein, Chunli Zhao, Stephan Zuchner, Paul J. Benke, Eric S. Cameron, Vincent Strehlow, Konrad Platzer, Rami Abou Jamra, Chiara Klöckner, Matthew Osmond, Thomas Licata, Samantha Rojas, David Dyment, Josephine S.C. Chong, Sharyn Lincoln, John H. Postlethwait, Joel Krier, and Hugo J. Bellen

Subjects
0301 basic medicine, Craniofacial abnormality, Mutation, Missense, 030105 genetics & heredity, Biology, Article, Frameshift mutation, Craniofacial Abnormalities, 03 medical and health sciences, medicine, Animals, Humans, Missense mutation, Craniofacial, Allele, Zebrafish, Genetics (clinical), Loss function, Genetics, medicine.disease, biology.organism_classification, Phenotype, Spine, Growth Differentiation Factors, 030104 developmental biology, Bone Morphogenetic Proteins
Abstract

Purpose Growth differentiation factor 11 (GDF11) is a key signaling protein required for proper development of many organ systems. Only one prior study has associated an inherited GDF11 variant with a dominant human disease in a family with variable craniofacial and vertebral abnormalities. Here, we expand the phenotypic spectrum associated with GDF11 variants and document the nature of the variants. Methods We present a cohort of six probands with de novo and inherited nonsense/frameshift (4/6 patients) and missense (2/6) variants in GDF11. We generated gdf11 mutant zebrafish to model loss of gdf11 phenotypes and used an overexpression screen in Drosophila to test variant functionality. Results Patients with variants in GDF11 presented with craniofacial (5/6) , vertebral (5/6), neurological (6/6), visual (4/6), cardiac (3/6), auditory (3/6) and connective tissue abnormalities (3/6). gdf11 mutant zebrafish show craniofacial abnormalities and body segmentation defects that match some patient phenotypes. Expression of the patients’ variants in the fly showed that one nonsense variant in GDF11 is a severe loss-of-function (LOF) alleles whereas the missense variants in our cohort are partial LOF variants. Conclusion GDF11 is needed for human development, particularly neuronal development, and LOF GDF11 alleles can affect the development of numerous organs and tissues.

Published
2021

48. A novel DPH5-related diphthamide-deficiency syndrome causing embryonic lethality or profound neurodevelopmental disorder

Author

Suma P. Shankar, Kristin Grimsrud, Louise Lanoue, Alena Egense, Brandon Willis, Johanna Hörberg, Lama AlAbdi, Klaus Mayer, Koray Ütkür, Kristin G. Monaghan, Joel Krier, Joan Stoler, Maha Alnemer, Prabhu R. Shankar, Raffael Schaffrath, Fowzan S. Alkuraya, Ulrich Brinkmann, Leif A. Eriksson, Kent Lloyd, Katherine A. Rauen, Maria T. Acosta, Margaret Adam, David R. Adams, Justin Alvey, Laura Amendola, Ashley Andrews, Euan A. Ashley, Mahshid S. Azamian, Carlos A. Bacino, Guney Bademci, Ashok Balasubramanyam, Dustin Baldridge, Jim Bale, Michael Bamshad, Deborah Barbouth, Pinar Bayrak-Toydemir, Anita Beck, Alan H. Beggs, Edward Behrens, Gill Bejerano, Jimmy Bennet, Beverly Berg-Rood, Jonathan A. Bernstein, Gerard T. Berry, Anna Bican, Stephanie Bivona, Elizabeth Blue, John Bohnsack, Devon Bonner, Lorenzo Botto, Brenna Boyd, Lauren C. Briere, Elly Brokamp, Gabrielle Brown, Elizabeth A. Burke, Lindsay C. Burrage, Manish J. Butte, Peter Byers, William E. Byrd, John Carey, Olveen Carrasquillo, Thomas Cassini, Ta Chen Peter Chang, Sirisak Chanprasert, Hsiao-Tuan Chao, Gary D. Clark, Terra R. Coakley, Laurel A. Cobban, Joy D. Cogan, Matthew Coggins, F. Sessions Cole, Heather A. Colley, Cynthia M. Cooper, Heidi Cope, William J. Craigen, Andrew B. Crouse, Michael Cunningham, Precilla D'Souza, Hongzheng Dai, Surendra Dasari, Joie Davis, Jyoti G. Dayal, Matthew Deardorff, Esteban C. Dell'Angelica, Katrina Dipple, Daniel Doherty, Naghmeh Dorrani, Argenia L. Doss, Emilie D. Douine, Laura Duncan, Dawn Earl, David J. Eckstein, Lisa T. Emrick, Christine M. Eng, Cecilia Esteves, Marni Falk, Liliana Fernandez, Elizabeth L. Fieg, Paul G. Fisher, Brent L. Fogel, Irman Forghani, William A. Gahl, Ian Glass, Bernadette Gochuico, Rena A. Godfrey, Katie Golden-Grant, Madison P. Goldrich, Alana Grajewski, Irma Gutierrez, Don Hadley, Sihoun Hahn, Rizwan Hamid, Kelly Hassey, Nichole Hayes, Frances High, Anne Hing, Fuki M. Hisama, Ingrid A. Holm, Jason Hom, Martha Horike-Pyne, Alden Huang, Yong Huang, Wendy Introne, Rosario Isasi, Kosuke Izumi, Fariha Jamal, Gail P. Jarvik, Jeffrey Jarvik, Suman Jayadev, Orpa Jean-Marie, Vaidehi Jobanputra, Lefkothea Karaviti, Jennifer Kennedy, Shamika Ketkar, Dana Kiley, Gonench Kilich, Shilpa N. Kobren, Isaac S. Kohane, Jennefer N. Kohler, Deborah Krakow, Donna M. Krasnewich, Elijah Kravets, Susan Korrick, Mary Koziura, Seema R. Lalani, Byron Lam, Christina Lam, Grace L. LaMoure, Brendan C. Lanpher, Ian R. Lanza, Kimberly LeBlanc, Brendan H. Lee, Roy Levitt, Richard A. Lewis, Pengfei Liu, Xue Zhong Liu, Nicola Longo, Sandra K. Loo, Joseph Loscalzo, Richard L. Maas, Ellen F. Macnamara, Calum A. MacRae, Valerie V. Maduro, Bryan C. Mak, May Christine V. Malicdan, Laura A. Mamounas, Teri A. Manolio, Rong Mao, Kenneth Maravilla, Ronit Marom, Gabor Marth, Beth A. Martin, Martin G. Martin, Julian A. Martínez-Agosto, Shruti Marwaha, Jacob McCauley, Allyn McConkie-Rosell, Alexa T. McCray, Elisabeth McGee, Heather Mefford, J. Lawrence Merritt, Matthew Might, Ghayda Mirzaa, Eva Morava, Paolo M. Moretti, Mariko Nakano-Okuno, Stan F. Nelson, John H. Newman, Sarah K. Nicholas, Deborah Nickerson, Shirley Nieves-Rodriguez, Donna Novacic, Devin Oglesbee, James P. Orengo, Laura Pace, Stephen Pak, J. Carl Pallais, Christina G.S. Palmer, Jeanette C. Papp, Neil H. Parker, John A. Phillips, Jennifer E. Posey, Lorraine Potocki, Barbara N. Pusey, Aaron Quinlan, Wendy Raskind, Archana N. Raja, Deepak A. Rao, Anna Raper, Genecee Renteria, Chloe M. Reuter, Lynette Rives, Amy K. Robertson, Lance H. Rodan, Jill A. Rosenfeld, Natalie Rosenwasser, Francis Rossignol, Maura Ruzhnikov, Ralph Sacco, Jacinda B. Sampson, Mario Saporta, C. Ron Scott, Judy Schaechter, Timothy Schedl, Kelly Schoch, Daryl A. Scott, Vandana Shashi, Jimann Shin, Edwin K. Silverman, Janet S. Sinsheimer, Kathy Sisco, Edward C. Smith, Kevin S. Smith, Emily Solem, Lilianna Solnica-Krezel, Ben Solomon, Rebecca C. Spillmann, Joan M. Stoler, Jennifer A. Sullivan, Kathleen Sullivan, Angela Sun, Shirley Sutton, David A. Sweetser, Virginia Sybert, Holly K. Tabor, Amelia L.M. Tan, K.-G. Queenie, Tan, Mustafa Tekin, Fred Telischi, Willa Thorson, Cynthia J. Tifft, Camilo Toro, Alyssa A. Tran, Brianna M. Tucker, Tiina K. Urv, Adeline Vanderver, Matt Velinder, Dave Viskochil, Tiphanie P. Vogel, Colleen E. Wahl, Stephanie Wallace, Nicole M. Walley, Melissa Walker, Jennifer Wambach, Jijun Wan, Lee-kai Wang, Michael F. Wangler, Patricia A. Ward, Daniel Wegner, Monika Weisz-Hubshman, Mark Wener, Tara Wenger, Katherine Wesseling Perry, Monte Westerfield, Matthew T. Wheeler, Jordan Whitlock, Lynne A. Wolfe, Kim Worley, Changrui Xiao, Shinya Yamamoto, John Yang, Diane B. Zastrow, Zhe Zhang, Chunli Zhao, Stephan Zuchner, Hugo Bellen, and Rachel Mahoney

Subjects
Adenosine Diphosphate, Mice, Inbred C57BL, Mice, Saccharomyces cerevisiae Proteins, Neurodevelopmental Disorders, Animals, Humans, Histidine, Methyltransferases, Saccharomyces cerevisiae, Syndrome, Genetics (clinical), Article
Abstract

Diphthamide is a post-translationally modified histidine essential for messenger RNA translation and ribosomal protein synthesis. We present evidence for DPH5 as a novel cause of embryonic lethality and profound neurodevelopmental delays (NDDs).Molecular testing was performed using exome or genome sequencing. A targeted Dph5 knockin mouse (C57BL/6Ncrl-Dph5DPH5 variants p.His260Arg (homozygous), p.Asn110Ser and p.Arg207Ter (heterozygous), and p.Asn174LysfsTer10 (homozygous) were identified in 3 unrelated families with distinct overlapping craniofacial features, profound NDDs, multisystem abnormalities, and miscarriages. Dph5 p.His260Arg homozygous knockin was embryonically lethal with only 1 subviable mouse exhibiting impaired growth, craniofacial dysmorphology, and multisystem dysfunction recapitulating the human phenotype. Adenosine diphosphate-ribosylation assays showed absent to decreased function in DPH5-knockout human and yeast cells. In silico modeling of the variants showed altered DPH5 structure and disruption of its interaction with eEF2.We provide strong clinical, biochemical, and functional evidence for DPH5 as a novel cause of embryonic lethality or profound NDDs with multisystem involvement and expand diphthamide-deficiency syndromes and ribosomopathies.

Published
2022

49. Biallelic variants in WARS1 cause a highly variable neurodevelopmental syndrome and implicate a critical exon for normal auditory function

Author

Sheng‐Jia Lin, Barbara Vona, Hillary M. Porter, Mahmoud Izadi, Kevin Huang, Yves Lacassie, Jill A. Rosenfeld, Saadullah Khan, Cassidy Petree, Tayyiba A. Ali, Nazif Muhammad, Sher A. Khan, Noor Muhammad, Pengfei Liu, Marie‐Louise Haymon, Franz Rüschendorf, Il‐Keun Kong, Linda Schnapp, Natasha Shur, Lynn Chorich, Lawrence Layman, Thomas Haaf, Ehsan Pourkarimi, Hyung‐Goo Kim, and Gaurav K. Varshney

Subjects
Amino Acyl-tRNA Synthetases, RNA, Transfer, Charcot-Marie-Tooth Disease, Cardiovascular and Metabolic Diseases, Mutation, Genetics, Humans, Tryptophan-tRNA Ligase, Exons, Syndrome, Genetics (clinical), Pedigree
Abstract

Aminoacyl-tRNA synthetases (ARSs) are essential enzymes for faithful assignment of amino acids to their cognate tRNA. Variants in ARS genes are frequently associated with clinically heterogeneous phenotypes in humans and follow both autosomal dominant or recessive inheritance patterns in many instances. Variants in tryptophanyl-tRNA synthetase 1 (WARS1) cause autosomal dominantly inherited distal hereditary motor neuropathy and Charcot-Marie-Tooth disease. Presently, only one family with biallelic WARS1 variants has been described. We present three affected individuals from two families with biallelic variants (p.Met1? and p.(Asp419Asn)) in WARS1, showing varying severities of developmental delay and intellectual disability. Hearing impairment and microcephaly, as well as abnormalities of the brain, skeletal system, movement/gait, and behavior were variable features. Phenotyping of knocked down wars-1 in a C. elegans model showed depletion is associated with defects in germ cell development. A wars1 knockout vertebrate model recapitulates the human clinical phenotypes, confirms variant pathogenicity and uncovers evidence implicating the p.Met1? variant as potentially impacting an exon critical for normal hearing. Together, our findings provide consolidating evidence for biallelic disruption of WARS1 as causal for an autosomal recessive neurodevelopmental syndrome and present a vertebrate model that recapitulates key phenotypes observed in patients. This article is protected by copyright. All rights reserved.

Published
2022

50. A recurrent single-exon deletion in TBCK might be under-recognized in patients with infantile hypotonia and psychomotor delay

Author

Hongzheng, Dai, Wenmiao, Zhu, Bo, Yuan, Nicole, Walley, Kelly, Schoch, Yong-Hui, Jiang, John A, Phillips, Melissa S, Jones, Pengfei, Liu, David R, Murdock, Lindsay C, Burrage, Brendan, Lee, Jill A, Rosenfeld, and Rui, Xiao

Subjects
DNA Copy Number Variations, Muscular Diseases, Exome Sequencing, Genetics, Humans, Muscle Hypotonia, Infant, Exome, Exons, Protein Serine-Threonine Kinases, Genetics (clinical), Retrospective Studies
Abstract

Advanced bioinformatics algorithms allow detection of multiple-exon copy-number variations (CNVs) from exome sequencing (ES) data, while detection of single-exon CNVs remains challenging. A retrospective review of Baylor Genetics' clinical ES patient cohort identified four individuals with homozygous single-exon deletions of TBCK (exon 23, NM_001163435.2), a gene associated with an autosomal recessive neurodevelopmental phenotype. To evaluate the prevalence of this deletion and its contribution to disease, we retrospectively analyzed single nucleotide polymorphism (SNP) array data for 8194 individuals undergoing ES, followed by PCR confirmation and RT-PCR on individuals carrying homozygous or heterozygous exon 23 TBCK deletions. A fifth individual was diagnosed with the TBCK-related disorder due to a heterozygous exon 23 deletion in trans with a c.1860+1GA (NM_001163435.2) pathogenic variant, and three additional heterozygous carriers were identified. Affected individuals and carriers were from diverse ethnicities including European Caucasian, South Asian, Middle Eastern, Hispanic American and African American, with only one family reporting consanguinity. RT-PCR revealed two out-of-frame transcripts related to the exon 23 deletion. Our results highlight the importance of identifying single-exon deletions in clinical ES, especially for genes carrying recurrent deletions. For patients with early-onset hypotonia and psychomotor delay, this single-exon TBCK deletion might be under-recognized due to technical limitations of ES.

Published
2022

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