Genetics in Medicine最新文献

{"title":"Biallelic variants in GTF3C3 result in an autosomal recessive disorder with intellectual disability","authors":"Lachlan De Hayr ,&nbsp;Laura E.R. Blok ,&nbsp;Kerith-Rae Dias ,&nbsp;Jingyi Long ,&nbsp;Anaïs Begemann ,&nbsp;Robyn D. Moir ,&nbsp;Ian M. Willis ,&nbsp;Martina Mocera ,&nbsp;Gabriele Siegel ,&nbsp;Katharina Steindl ,&nbsp;Carey-Anne Evans ,&nbsp;Ying Zhu ,&nbsp;Futao Zhang ,&nbsp;Michael Field ,&nbsp;Alan Ma ,&nbsp;Lesley Adès ,&nbsp;Sarah Josephi-Taylor ,&nbsp;Rolph Pfundt ,&nbsp;Maha S. Zaki ,&nbsp;Hoda Tomoum ,&nbsp;Robert J. Harvey","doi":"10.1016/j.gim.2024.101253","DOIUrl":"10.1016/j.gim.2024.101253","url":null,"abstract":"<div><h3>Purpose</h3><div>This study details a novel syndromic form of autosomal recessive intellectual disability resulting from recessive variants in <em>GTF3C3</em>, encoding a key component of the DNA-binding transcription factor IIIC, which has a conserved role in RNA polymerase III-mediated transcription.</div></div><div><h3>Methods</h3><div>Exome sequencing, minigene analysis, molecular modeling, RNA polymerase III reporter gene assays, and <em>Drosophila</em> knockdown models were utilized to characterize <em>GTF3C3</em> variants.</div></div><div><h3>Results</h3><div>Twelve affected individuals from 7 unrelated families were identified with homozygous or compound heterozygous missense variants in <em>GTF3C3</em> including c.503C&gt;T p.(Ala168Val), c.1268T&gt;C p.(Leu423Pro), c.1436A&gt;G p.(Tyr479Cys), c.2419C&gt;T p.(Arg807Cys), and c.2420G&gt;A p.(Arg807His). The cohort presented with intellectual disability, variable nonfamilial facial features, motor impairments, seizures, and cerebellar/corpus callosum malformations. Consistent with disruptions in intra- and intermolecular interactions observed in molecular modeling, RNA polymerase III reporter assays confirmed that the majority of missense variants resulted in a loss of function. Minigene analysis of the recurrent c.503C&gt;T p.(Ala168Val) variant confirmed the introduction of a cryptic donor site into exon 4, resulting in mRNA missplicing. Consistent with the clinical features of this cohort, neuronal loss of <em>Gtf3c3</em> in <em>Drosophila</em> induced seizure-like behavior, motor impairment, and learning deficits.</div></div><div><h3>Conclusion</h3><div>These findings confirm that <em>GTF3C3</em> variants result in an autosomal recessive form of syndromic intellectual disability.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 1","pages":"Article 101253"},"PeriodicalIF":6.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142785029","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Australian Genomics Mitochondrial Flagship: A national program delivering mitochondrial diagnoses","authors":"Rocio Rius ,&nbsp;Alison G. Compton ,&nbsp;Naomi L. Baker ,&nbsp;Shanti Balasubramaniam ,&nbsp;Stephanie Best ,&nbsp;Kaustuv Bhattacharya ,&nbsp;Kirsten Boggs ,&nbsp;Tiffany Boughtwood ,&nbsp;Jeffrey Braithwaite ,&nbsp;Drago Bratkovic ,&nbsp;Alessandra Bray ,&nbsp;Marie-Jo Brion ,&nbsp;Jo Burke ,&nbsp;Sarah Casauria ,&nbsp;Belinda Chong ,&nbsp;David Coman ,&nbsp;Shannon Cowie ,&nbsp;Mark Cowley ,&nbsp;Michelle G. de Silva ,&nbsp;Martin B. Delatycki ,&nbsp;David R. Thorburn","doi":"10.1016/j.gim.2024.101271","DOIUrl":"10.1016/j.gim.2024.101271","url":null,"abstract":"<div><h3>Purpose</h3><div>Families living with mitochondrial diseases (MD) often endure prolonged diagnostic journeys and invasive testing, yet many remain without a molecular diagnosis. The Australian Genomics Mitochondrial Flagship, comprising clinicians, diagnostic, and research scientists, conducted a prospective national study to identify the diagnostic utility of singleton genomic sequencing using blood samples.</div></div><div><h3>Methods</h3><div>A total of 140 children and adults living with suspected MD were recruited using modified Nijmegen criteria (MNC) and randomized to either exome + mitochondrial DNA (mtDNA) sequencing or genome sequencing.</div></div><div><h3>Results</h3><div>Diagnostic yield was 55% (<em>n</em> = 77) with variants in nuclear (<em>n</em> = 37) and mtDNA (<em>n</em> = 18) MD genes, as well as phenocopy genes (<em>n</em> = 22). A nuclear gene etiology was identified in 77% of diagnoses, irrespective of disease onset. Diagnostic rates were higher in pediatric-onset (71%) than adult-onset (31%) cases and comparable in children with non-European (78%) vs European (67%) ancestry. For children, higher MNC scores correlated with increased diagnostic yield and fewer diagnoses in phenocopy genes. Additionally, 3 adult patients had a mtDNA deletion discovered in skeletal muscle that was not initially identified in blood.</div></div><div><h3>Conclusion</h3><div>Genomic sequencing from blood can simplify the diagnostic pathway for individuals living with suspected MD, especially those with childhood onset diseases and high MNC scores.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 1","pages":"Article 101271"},"PeriodicalIF":6.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142284364","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Critically unwell infants and children with mitochondrial disorders diagnosed by ultrarapid genomic sequencing","authors":"Megan Ball ,&nbsp;Sophie E. Bouffler ,&nbsp;Christopher B. Barnett ,&nbsp;Mary-Louise Freckmann ,&nbsp;Matthew F. Hunter ,&nbsp;Benjamin Kamien ,&nbsp;Karin S. Kassahn ,&nbsp;Sebastian Lunke ,&nbsp;Chirag V. Patel ,&nbsp;Jason Pinner ,&nbsp;Tony Roscioli ,&nbsp;Sarah A. Sandaradura ,&nbsp;Hamish S. Scott ,&nbsp;Tiong Y. Tan ,&nbsp;Mathew Wallis ,&nbsp;Alison G. Compton ,&nbsp;David R. Thorburn ,&nbsp;Zornitza Stark ,&nbsp;John Christodoulou","doi":"10.1016/j.gim.2024.101293","DOIUrl":"10.1016/j.gim.2024.101293","url":null,"abstract":"<div><h3>Purpose</h3><div>To characterize the diagnostic and clinical outcomes of a cohort of critically ill infants and children with suspected mitochondrial disorders (MD) undergoing ultrarapid genomic testing as part of a national program.</div></div><div><h3>Methods</h3><div>Ultrarapid genomic sequencing was performed in 454 families (genome sequencing: <em>n</em> = 290, exome sequencing +/− mitochondrial DNA sequencing: <em>n</em> = 164). In 91 individuals, MD was considered, prompting analysis using an MD virtual gene panel. These individuals were reviewed retrospectively and scored according to modified Nijmegen Mitochondrial Disease Criteria.</div></div><div><h3>Results</h3><div>A diagnosis was achieved in 47% (43/91) of individuals, 40% (17/43) of whom had an MD. Seven additional individuals in whom an MD was not suspected were diagnosed with an MD after broader analysis. Gene-agnostic analysis led to the discovery of 2 novel disease genes, with pathogenicity validated through targeted functional studies (<em>CRLS1</em> and <em>MRPL39</em>). Functional studies enabled diagnosis in another 4 individuals. Of the 24 individuals ultimately diagnosed with an MD, 79% had a change in management, which included 53% whose care was redirected to palliation.</div></div><div><h3>Conclusion</h3><div>Ultrarapid genetic diagnosis of MD in acutely unwell infants and children is critical for guiding decisions about the need for additional investigations and clinical management.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 1","pages":"Article 101293"},"PeriodicalIF":6.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142463205","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biomarker testing for lysosomal diseases: A technical standard of the American College of Medical Genetics and Genomics (ACMG)","authors":"Ashlee R. Stiles ,&nbsp;Taraka R. Donti ,&nbsp;Patricia L. Hall ,&nbsp;William R. Wilcox ,&nbsp;ACMG Laboratory Quality Assurance Committee","doi":"10.1016/j.gim.2024.101242","DOIUrl":"10.1016/j.gim.2024.101242","url":null,"abstract":"<div><div>Measurement of lysosomal disease (LD) biomarkers can reveal valuable information about disease status. Lyso-globotriaosylceramide (lyso-Gb₃), glucosylsphingosine (lyso-Gb₁), galactosylsphingosine (psychosine), and glucose tetrasaccharide (Glca1-6Glca1-4Glca1-4Glc, Glc₄) are biomarkers associated with Fabry, Gaucher, Krabbe, and Pompe disease, respectively. Clinical biomarker testing is performed to guide patient management, including monitoring disease progression and initiating treatment, and in diagnostic evaluations of either symptomatic patients or asymptomatic individuals with a positive family history or abnormal newborn screen. Biomarker analysis can be performed through independent analysis of a single analyte or as a multiplex assay measuring analytes for more than one disorder utilizing liquid chromatographic separation and tandem mass spectrometric detection. These guidelines were developed to provide technical standards for biomarker analysis, results interpretation, and results reporting, highlighting Fabry, Gaucher, Krabbe, and Pompe diseases as examples.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 1","pages":"Article 101242"},"PeriodicalIF":6.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582845","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Expanding the phenotype and genotype spectrum of TAOK1 neurodevelopmental disorder and delineating TAOK2 neurodevelopmental disorder","authors":"Nour Elkhateeb ,&nbsp;Renarta Crookes ,&nbsp;Michael Spiller ,&nbsp;Lisa Pavinato ,&nbsp;Flavia Palermo ,&nbsp;Alfredo Brusco ,&nbsp;Michael Parker ,&nbsp;Soo-Mi Park ,&nbsp;Ariana Costa Mendes ,&nbsp;Jorge M. Saraiva ,&nbsp;Trine Bjørg Hammer ,&nbsp;Lusine Nazaryan-Petersen ,&nbsp;Tahsin Stefan Barakat ,&nbsp;Martina Wilke ,&nbsp;Elizabeth Bhoj ,&nbsp;Rebecca C. Ahrens-Nicklas ,&nbsp;Dong Li ,&nbsp;Tomoki Nomakuchi ,&nbsp;Eva H. Brilstra ,&nbsp;David Hunt ,&nbsp;Meena Balasubramanian","doi":"10.1016/j.gim.2024.101348","DOIUrl":"10.1016/j.gim.2024.101348","url":null,"abstract":"<div><h3>Purpose</h3><div>The thousand and one kinase (TAOK) proteins are a group of serine/threonine-protein kinases involved in signaling pathways, cytoskeleton regulation, and neuronal development. <em>TAOK1</em> variants are associated with a neurodevelopmental disorder (NDD) characterized by distinctive facial features, hypotonia, and feeding difficulties. <em>TAOK2</em> variants have been reported to be associated with autism and early-onset obesity. However, a distinct <em>TAOK2</em>-NDD has not yet been delineated.</div></div><div><h3>Methods</h3><div>We retrospectively studied the clinical and genetic data of individuals recruited from several centers with <em>TAOK1</em> and <em>TAOK2</em> variants that were detected through exome and genome sequencing.</div></div><div><h3>Results</h3><div>We report 50 individuals with <em>TAOK1</em> variants with associated phenotypes, including neurodevelopmental abnormalities (100%), macrocephaly (83%), and hypotonia (58%). We report male genital anomalies and hypoglycemia as novel phenotypes. Thirty-seven unique <em>TAOK1</em> variants were identified. Most of the missense variants clustered in the protein kinase domain at residues that are intolerant to missense variation. We report 10 patients with <em>TAOK2</em> variants with associated phenotypes, including neurodevelopmental abnormalities (100%), macrocephaly (75%), autism (75%), and obesity (70%).</div></div><div><h3>Conclusion</h3><div>We describe the largest cohort of <em>TAOK1</em>-NDD to date, to our knowledge, expanding its phenotype and genotype spectrum with 30 novel variants. We delineated the phenotype of a novel <em>TAOK2</em>-NDD associated with neurodevelopmental abnormalities, autism, macrocephaly, and obesity.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 3","pages":"Article 101348"},"PeriodicalIF":6.6,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142907000","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluating the impact of modeling choices on the performance of integrated genetic and clinical models","authors":"Theodore J. Morley ,&nbsp;Drew Willimitis ,&nbsp;Michael Ripperger ,&nbsp;Hyunjoon Lee ,&nbsp;Yu Zhou ,&nbsp;Lide Han ,&nbsp;Jooeun Kang ,&nbsp;William U. Meyerson ,&nbsp;Jordan W. Smoller ,&nbsp;Karmel W. Choi ,&nbsp;Colin G. Walsh ,&nbsp;Douglas M. Ruderfer","doi":"10.1016/j.gim.2024.101353","DOIUrl":"10.1016/j.gim.2024.101353","url":null,"abstract":"<div><h3>Purpose</h3><div>The value of genetic information for improving the performance of clinical risk prediction models has yielded variable conclusions. Many methodological decisions have the potential to contribute to differential results. We performed multiple modeling experiments integrating clinical and demographic data from electronic health records with genetic data to understand which decisions may affect performance.</div></div><div><h3>Methods</h3><div>Clinical data in the form of structured diagnostic codes, medications, procedural codes, and demographics were extracted from 2 large independent health systems, and polygenic risk scores (PRS) were generated across all patients of European ancestry with genetic data in the corresponding biobanks. Crohn’s disease was studied based on its substantial genetic component, established electronic health records-based definition, and sufficient prevalence for training and testing. We investigated the impact of choices regarding the PRS integration method, training sample, model complexity, and performance metrics.</div></div><div><h3>Results</h3><div>Overall, our results showed that including PRS resulted in higher performance, but this gain was only robust in situations with limited clinical information. We found consistent performance increases from more compute-intensive models, such as random forest, but the impact of other decisions varied by site.</div></div><div><h3>Conclusion</h3><div>This work highlights the importance of considering methodological decision points in interpreting the impact of PRS on prediction performance in clinical models.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 4","pages":"Article 101353"},"PeriodicalIF":6.6,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142894015","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quantitative natural history modeling of HPDL-related disease based on cross-sectional data reveals genotype-phenotype correlations","authors":"Julian E. Alecu ,&nbsp;Amy Tam ,&nbsp;Silja Richter ,&nbsp;Vicente Quiroz ,&nbsp;Luca Schierbaum ,&nbsp;Afshin Saffari ,&nbsp;Darius Ebrahimi-Fakhari","doi":"10.1016/j.gim.2024.101349","DOIUrl":"10.1016/j.gim.2024.101349","url":null,"abstract":"<div><h3>Purpose</h3><div>Biallelic <em>HPDL</em> variants have been identified as the cause of a progressive childhood-onset movement disorder, with a broad clinical spectrum from severe neurodevelopmental disorder to juvenile-onset pure hereditary spastic paraplegia type 83. This study aims at delineating the geno- and phenotypic spectra of patients with <em>HPDL</em>-related disease, quantitatively modeling the natural history, and uncovering genotype-phenotype associations.</div></div><div><h3>Methods</h3><div>A cross-sectional analysis of 90 published and 1 novel case was performed, using a Human-Phenotype-Ontology-based approach. Unsupervised phenotypic clustering was used alongside in silico analyses to identify distinct patient subgroups.</div></div><div><h3>Results</h3><div>The study models the natural history of the <em>HPDL</em>-related disease in a global cohort, clarifying the molecular and phenotypic spectrum and identifying 3 distinct subgroups characterized by differences in onset, clinical trajectories, and survival. It establishes genotype-phenotype associations, showing that the presence of moderately pathogenic missense variants in 1 allele leads to a milder, spastic paraplegic phenotype with later disease onset, whereas biallelic, highly pathogenic missense or truncating variants are associated with a more severe phenotype and reduced life span.</div></div><div><h3>Conclusion</h3><div>Quantitative and unbiased natural history modeling in <em>HPDL</em>-related disease reveals significant genotype-phenotype associations, providing a foundation for variant interpretation, anticipatory guidance, and choice of outcome measures in future prospective and functional studies.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 3","pages":"Article 101349"},"PeriodicalIF":6.6,"publicationDate":"2024-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142894062","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Family genetic risk communication and reverse cascade testing in the BabySeq project","authors":"Melissa K. Uveges ,&nbsp;Hadley Stevens Smith ,&nbsp;Stacey Pereira ,&nbsp;Casie Genetti ,&nbsp;Amy L. McGuire ,&nbsp;Alan H. Beggs ,&nbsp;Robert C. Green ,&nbsp;Ingrid A. Holm","doi":"10.1016/j.gim.2024.101350","DOIUrl":"10.1016/j.gim.2024.101350","url":null,"abstract":"<div><h3>Purpose</h3><div>Genomic sequencing of newborns can initiate disease surveillance and therapy for children and may identify at-risk relatives through reverse cascade testing. We explored genetic risk communication and reverse cascade testing among families of newborns who underwent exome sequencing and were identified as having a risk for an autosomal dominant disease.</div></div><div><h3>Methods</h3><div>We conducted semistructured interviews with parents of newborns enrolled in the BabySeq Project who had a pathogenic or likely pathogenic variant associated with an autosomal dominant childhood- and/or adult-onset disease returned. We used directed content analysis to derive themes.</div></div><div><h3>Results</h3><div>From 11 families, all first-degree relatives (<em>n</em> = 32, 100%), 29 second-degree relatives (76%), and 26 third-degree relatives (43%) were informed of their risk. All parents (<em>n</em> = 22, 69% of first-degree relatives), 4 (11%) second-degree relatives, and 1 (2%) third-degree relatives underwent cascade testing. Most parents preferred to handle risk communication themselves. Parents with positive cascade testing but no associated symptoms were less inclined to share findings with relatives but highly motivated to share results if the variant’s associated disease severity was high, as perceived with adult-onset conditions. One new subtheme, family member traits, was identified and defined as a relative’s propensity to anxiety/concern after risk communications but did not diminish risk communication.</div></div><div><h3>Conclusion</h3><div>Findings can inform more effective notification and testing practices for families of newborns at risk for hereditary genetic conditions.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 3","pages":"Article 101350"},"PeriodicalIF":6.6,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142894026","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The characterization of new de novo CACNA1G variants affecting the intracellular gate of Cav3.1 channel broadens the spectrum of neurodevelopmental phenotypes in SCA42ND","authors":"Leila Qebibo ,&nbsp;Amaël Davakan ,&nbsp;Mathilde Nesson-Dauphin ,&nbsp;Najlae Boulali ,&nbsp;Karine Siquier-Pernet ,&nbsp;Alexandra Afenjar ,&nbsp;Jeanne Amiel ,&nbsp;Deborah Bartholdi ,&nbsp;Magalie Barth ,&nbsp;Eléonore Blondiaux ,&nbsp;Ingrid Cristian ,&nbsp;Zoe Frazier ,&nbsp;Alice Goldenberg ,&nbsp;Jean-Marc Good ,&nbsp;Catherine Lourdes Salussolia ,&nbsp;Mustafa Sahin ,&nbsp;Helen McCullagh ,&nbsp;Kimberly McDonald ,&nbsp;Anne McRae ,&nbsp;Jennifer Morrison ,&nbsp;Philippe Lory","doi":"10.1016/j.gim.2024.101337","DOIUrl":"10.1016/j.gim.2024.101337","url":null,"abstract":"<div><h3>Purpose</h3><div>Missense de novo variants in <em>CACNA1G</em>, which encodes the Cav3.1 T-type calcium channel, have been associated with a severe, early-onset form of cerebellar disorder with neurodevelopmental deficits (SCA42ND). We explored a large series of pediatric cases carrying heterozygous variants in <em>CACNA1G</em> to further characterize genotype-phenotype correlations in SCA42ND.</div></div><div><h3>Methods</h3><div>We describe 19 patients with congenital <em>CACNA1G</em>-variants, including 6 new heterozygotes of the recurrent SCA42ND variants, p.(Ala961Thr) and p.(Met1531Val), and 8 unreported variants, including 7 missense variants, mainly de novo. We carried out genetic and structural analyses of all variants. Patch-clamp recordings were performed to measure their channel activity.</div></div><div><h3>Results</h3><div>We provide a consolidated clinical description for the patients carrying p.(Ala961Thr) and p.(Met1531Val). The new variants associated with the more severe phenotypes are found in the Cav3.1 channel intracellular gate. Calcium currents of these Cav3.1 variants showed slow inactivation and deactivation kinetics and an increase in window current, supporting a gain of channel activity. On the contrary, the p.(Met197Arg) variant (IS4-S5 loop) resulted in a loss of channel activity.</div></div><div><h3>Conclusion</h3><div>This detailed description of several de novo missense pathogenic variants in <em>CACNA1G</em>, including 13 previously reported cases, supports a clinical spectrum of congenital <em>CACNA1G</em> syndrome beyond spinocerebellar ataxia.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 3","pages":"Article 101337"},"PeriodicalIF":6.6,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142828198","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RORA-neurodevelopmental disorder: A unique triad of developmental disabilities, cerebellar anomalies, and myoclonic seizures","authors":"Mariagrazia Talarico ,&nbsp;Julitta de Bellescize ,&nbsp;Matthias De Wachter ,&nbsp;Xavier Le Guillou ,&nbsp;Guylène Le Meur ,&nbsp;Matthieu Egloff ,&nbsp;Bertrand Isidor ,&nbsp;Benjamin Cogné ,&nbsp;Diane Beysen ,&nbsp;Paul Rollier ,&nbsp;Melanie Fradin ,&nbsp;Laurent Pasquier ,&nbsp;Ilaria Guella ,&nbsp;Scott E. Hickey ,&nbsp;Paul J. Benke ,&nbsp;Amelle Shillington ,&nbsp;Candy Kumps ,&nbsp;Olivier Vanakker ,&nbsp;Erica H. Gerkes ,&nbsp;Shenela Lakhani ,&nbsp;Gaetan Lesca","doi":"10.1016/j.gim.2024.101347","DOIUrl":"10.1016/j.gim.2024.101347","url":null,"abstract":"<div><h3>Purpose</h3><div><em>RORA</em> encodes the RAR-related orphan receptor-α, playing a pivotal role in cerebellar maturation and function. Here, we report the largest series of individuals with <em>RORA</em>-related-neurodevelopmental disorder.</div></div><div><h3>Methods</h3><div>Forty individuals (30 unrelated; 10 siblings from 4 families) carrying <em>RORA</em> pathogenic/likely pathogenic variants were collected through an international collaboration.</div></div><div><h3>Results</h3><div>The 33 variants (29 de novo, 4 inherited, and 1 shared), identified by genome/exome sequencing (<em>n</em> = 21), chromosomal microarray analysis (<em>n</em> = 7), or gene panels (<em>n</em> = 4), included frameshift (<em>n</em> = 18/33), missense (<em>n</em> = 9/33), and stop codon (<em>n</em> = 6/33). Developmental disability (<em>n</em> = 32/37), intellectual disability (<em>n</em> = 22/32), and cerebellar signs (<em>n</em> = 25/34) were the most striking clinical features. Cerebellar symptoms were divided into early-onset, late-onset, and progressive subgroups. Cerebellar hypoplasia, atrophy, or both (<em>n</em> = 16/25) were more frequent in individuals with missense variants in the DNA-binding domain. Epilepsy (<em>n</em> = 18/38), with prominent myoclonic seizure types (<em>n</em> = 11/18), was classified in (1) genetic generalized epilepsy (<em>n</em> = 10/18) with a syndromic diagnosis identifiable for 6: epilepsy with eyelid myoclonia (<em>n</em> = 5/6) and epilepsy with myoclonic absence (<em>n</em> = 1/6); (2) developmental and epileptic encephalopathy (<em>n</em> = 5/18); and (3) unclassified (<em>n</em> = 3/18). A participant with rapid deterioration of visual acuity and cone/rod dystrophy was reported.</div></div><div><h3>Conclusion</h3><div>Missense variants in DNA-binding domain correlate to a more severe cerebellar phenotype. The <em>RORA</em>-related-neurodevelopmental disorder triad comprises developmental disability, cerebellar features, and a spectrum of myoclonic epilepsy.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 4","pages":"Article 101347"},"PeriodicalIF":6.6,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142871859","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}