Journal of Medical Genetics最新文献

{"title":"Optimising the molecular investigation of the FSHD locus: an integrated workflow using single molecule optical mapping and Southern blot analysis.","authors":"Joowon Jang, Hobin Sung, Jung-Ae Lee, Sung Im Cho, Jee-Soo Lee, Moon-Woo Seong","doi":"10.1136/jmg-2024-110382","DOIUrl":"10.1136/jmg-2024-110382","url":null,"abstract":"<p><strong>Purpose: </strong>Facioscapulohumeral muscular dystrophy (FSHD) is a genetic disorder caused by contraction or hypomethylation of the D4Z4 repeat array located at chromosome 4q35. For the disease to manifest, a permissive haplotype is required, as it enables the pathogenic expression of the <i>DUX4</i> gene. FSHD cases often involve complex rearrangements, such as intrachromosomal rearrangements and translocations, which complicate diagnosis using conventional methods. This study focuses on evaluating the diagnostic potential of single molecule optical mapping (SMOM) for FSHD with complex rearrangements, particularly in cases involving 4q-10q translocations, which present challenges for detection by SMOM alone. Furthermore, we propose an integrated diagnostic strategy, combining SMOM with complementary methods, to improve accuracy in these challenging cases.</p><p><strong>Methods: </strong>We reviewed the test results of 238 patients with suspected FSHD, and 25 participants with presumed complex rearrangements were included in this study. SMOM was performed on these participants, and the results were manually reviewed and compared with those obtained from Southern blot (SB) analysis.</p><p><strong>Results: </strong>Nine patients carrying 4q-10q translocation exhibited discrepancies between the two methods. Linear regression analysis revealed a significant discrepancy in chromosomal assignment between SB and SMOM in cases suspected of translocation.</p><p><strong>Conclusions: </strong>Given the complex nature of FSHD, none of the current methods can independently provide a definitive diagnosis. As misdiagnosis may occur when relying on a single technique, we propose an integrated diagnostic approach, with SMOM as the first-line test.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"467-475"},"PeriodicalIF":3.7,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12322434/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144024661","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of <i>MACF1</i> as a causative gene of generalised epilepsy.","authors":"Xiao-Yun Lei, Meng-Wen Zhang, Hui Sun, Wang Song, Xiao-Yu Liang, Cui-Shan Wang, Sheng Luo, Bing-Mei Li, Xiao-Rong Liu, Yao Wang, Yang Tian, Qian Peng, Jie Wang, Heng Meng, Na He, Wei-Ping Liao","doi":"10.1136/jmg-2025-110699","DOIUrl":"10.1136/jmg-2025-110699","url":null,"abstract":"<p><strong>Background: </strong>The microtubule actin crosslinking factor 1 (<i>MACF1)</i> gene encodes microtubule-microfilament cross-linking factor 1 that plays an essential role in the embryonic brain development. <i>MACF1</i> variants were associated with lissencephaly-9 (LIS9). However, the <i>MACF1</i>-epilepsy relationship was unknown.</p><p><strong>Methods: </strong>Trios-based whole-exome sequencing was performed on a cohort with generalised epilepsy from the China Epilepsy Gene 1.0 project. The spatial-temporal expression, single-cell sequencing and genotype-phenotype correlation were analysed to explore the role of <i>MACF1</i> in epilepsy and neurodevelopment.</p><p><strong>Results: </strong>Two de novo heterozygous and eight biallelic <i>MACF1</i> variants were identified in 10 unrelated patients. The variants presented significantly high excess by multiple statistical analyses. All patients were diagnosed with generalised epilepsy, among whom three patients presented with neurodevelopmental delay. <i>MACF1</i> was expressed throughout the lifespan, with three major peaks in the fetal, early childhood and adulthood stages, consistent with seizure onset ages of the patients. The highest expression in adulthood was in the thalamus nucleus, potentially associated with the pathogenesis of generalised epilepsy. The single-cell sequencing in organoids showed <i>MACF1</i> is widely expressed in the developing brain, especially in the early stage, suggesting a vital role in neurodevelopment. Genotype-phenotype association analysis revealed that LIS9-associated variants were featured by de novo monoallelic variants clustered within the C-terminal; the autism spectrum disorder-associated variants were mainly de novo monoallelic variants located at the spectrin-repeat rod domains. In contrast, the epilepsy-associated variants were biallelic missense variants, and those in the plakin domain were potentially associated with neurodevelopment delay.</p><p><strong>Significance: </strong><i>MACF1</i> is potentially a novel causative gene of generalised epilepsy.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"484-493"},"PeriodicalIF":3.7,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12322448/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144021446","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rare missense variants in <i>FNDC1</i> are associated with severe adolescent idiopathic scoliosis.","authors":"Wu-Lin Charng, Gabe Haller, Julia Whittle, Momchil Nikolov, Addison Avery, Jose Morcuende, Philip Giampietro, Cathy Raggio, Nancy Miller, Anne E Justice, Natasha T Strande, Mark Seeley, Dale L Bodian, Carol A Wise, Diane S Sepich, Matthew B Dobbs, Christina A Gurnett","doi":"10.1136/jmg-2024-110586","DOIUrl":"10.1136/jmg-2024-110586","url":null,"abstract":"<p><strong>Background: </strong>Scoliosis is the most common paediatric spinal deformity. More than 80% of scoliosis is idiopathic and appears during the adolescent growth spurt. Spinal fusion surgery is often required for patients with progressive adolescent idiopathic scoliosis (AIS), and the genetic risk factors for severe disease (defined here as curve >35 degrees) are largely unknown.</p><p><strong>Methods: </strong>To explore the role of rare variants in severe AIS, exome sequence data from 1221 individuals with AIS were compared with both 1397 in-house European ancestry controls and 56885 gnomAD non-Finish European controls. Segregation analysis of variants in prioritised genes was performed in additional family members. A replication study was performed using the Geisinger MyCode cohort. <i>FNDC1</i> function was investigated in <i>fndc1</i> null mutant zebrafish.</p><p><strong>Results: </strong>Rare variants were enriched in 84 genes, including <i>RAF1</i> (Noonan syndrome), <i>FBN1</i> (Marfan syndrome) and <i>FNDC1,</i> in individuals with severe AIS. <i>FNDC1</i>, which had previously been associated with joint hypermobility, harboured missense variants in 4.0% of individuals with AIS compared with 2.3% of controls (p=0.00764, OR=1.78). <i>FNDC1</i> variants segregated with AIS in five multiplex families with incomplete penetrance. In addition, <i>FNDC1</i> rare variants were also associated with scoliosis in the Geisinger MyCode cohort (p=0.0002, OR=3.6). Disruption of the <i>fndc1</i> locus in zebrafish resulted in increased bone mineral density.</p><p><strong>Conclusion: </strong>We broadened the phenotype associated with <i>RAF1</i> and <i>FBN1</i> variants and identified <i>FNDC1</i> as a novel gene associated with severe AIS. Mechanistic alterations of bone mineral density or joint hypermobility may explain the association of <i>FNDC1</i> missense variants with AIS.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"427-435"},"PeriodicalIF":3.5,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12187536/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144015097","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Electronic health record-based registry for identification of individuals at risk for hereditary cancer syndromes.","authors":"Vinit Singh, Thomas E Rafter, Mohamad Sharbatji, Jing Liu, Quiana Brown, Karina Brierley, Claire Healy, Rosa M Xicola, Nitu M Kashyap, Xavier Llor","doi":"10.1136/jmg-2025-110718","DOIUrl":"10.1136/jmg-2025-110718","url":null,"abstract":"<p><strong>Background: </strong>Despite well-established criteria for genetic testing to rule out hereditary cancer syndromes (HCSs), most pathogenic variant (PV) carriers are not being tested. Thus, mechanisms that allow for better identification and a streamlined process for testing need to be implemented. The main purpose was to develop a self-updating, guideline-driven tool integrated with the electronic health record (EHR) to prospectively identify at-risk individuals and facilitate outreach and diagnosis.</p><p><strong>Methods: </strong>National Comprehensive Cancer Network/American College of Medical Genetics criteria for genetic testing were translated into three distinct rule-based conditional logic statements in the EHR from 218 rules that serially evaluate each aspect of individual criteria, which together roll up into a logic statement of 'at-risk'. The rules evaluate personal or family history, determine age at onset and categorise family relationships. This tool is applied to a system-wide registry of active patients.</p><p><strong>Results: </strong>Out of 1 325 545 individuals, 59 377 (4.48%) were identified as at-risk and thus constitute the At-Risk Cancer Genetic Syndrome Identification (ARCAGEN-ID) registry. Of those, only 12 377 (20.9%) had previously been evaluated, and 2506 had a PV. ARCAGEN-ID appropriately included 96.2% of cases. ARCAGEN-ID individuals not previously evaluated were more often included based on family history criteria (79.8% vs 49.3%), and less often because of both personal and family history of cancer (13% vs 41%) (p<0.001).</p><p><strong>Conclusions: </strong>This study is the first to use an EHR-based registry for the automatic and prospective identification of individuals eligible for genetic testing based on current criteria for all major HCS. By streamlining the identification process, this approach has the potential to dramatically increase diagnostic rates and improve cancer-related survival.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"457-463"},"PeriodicalIF":3.5,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143996437","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Short stature, brachydactyly and joint contractures associated with novel <i>FBN2</i> variants in two families.","authors":"Petra Loid, Fan Wang, Otto Lennartsson, Mari Muurinen, Alice Costantini, Sakshi Vats, Maria Lodefalk, Ola Nilsson, Outi Mäkitie","doi":"10.1136/jmg-2024-110533","DOIUrl":"10.1136/jmg-2024-110533","url":null,"abstract":"<p><strong>Background: </strong>Fibrillinopathies comprise allelic disorders with opposing phenotypes. Pathogenic variants in fibrillin-2, encoded by <i>FBN2</i>, have mainly been associated with congenital contractural arachnodactyly but in a few cases also with brachydactyly.</p><p><strong>Methods and results: </strong>We recruited two families with index patients presenting with short stature (heights ≤3 SD scores), brachydactyly, joint contractures and facial dysmorphism as major features. In Family 2, the proband and father also had carpal tunnel syndrome. Radiographs showed signs of mild skeletal dysplasia with short long bones, brachydactyly and mild metaphyseal and vertebral irregularity. Whole genome sequencing revealed novel variants in the <i>FBN2</i> gene that segregated with the phenotype: in Family 1, a novel heterozygous missense variant c.4862G>A, p.(Cys1621Tyr) and in Family 2, a novel heterozygous deletion of exons 9-11. The missense variant affects a highly conserved residue and is predicted to be deleterious by most in silico tools. The <i>FBN2</i> deletion affects a well-conserved region and leads to loss of the transforming growth factor β binding-like 2 domain and part of the calcium-binding epidermal growth factor-like domain.</p><p><strong>Conclusion: </strong>Our findings suggest that short stature and mild skeletal dysplasia might be part of the spectrum of <i>FBN2-</i>related phenotypes. The study supports the role of <i>FBN2</i> variants in growth failure and expands the molecular spectrum of <i>FBN2</i> variants.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"436-440"},"PeriodicalIF":3.5,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143811499","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phenotypic heterogeneity in <i>DYNC2H1</i>-related short-rib thoracic dysplasia: antenatal indicators and postnatal outcomes.","authors":"Nikhil Pattani, Nour Elkhateeb, Aakash Joshi, Juan Carlos Del Rey Jimenez, Joy L Barber, Pilar Palmrich, Helen Firth, Sarju G Mehta, Leila Amel Riazat Kesh, Jennifer Campbell, Jenny Carmichael, Sahar Mansour","doi":"10.1136/jmg-2024-110369","DOIUrl":"10.1136/jmg-2024-110369","url":null,"abstract":"<p><strong>Introduction: </strong><i>DYNC2H1</i>-related short-rib thoracic dysplasia with/without polydactyly (SRTD), formerly asphyxiating thoracic dystrophy-Jeune syndrome, is a rare genetic skeletal disorder characterised by a narrow thorax, short ribs, shortened long bones and brachydactyly/polydactyly. <i>DYNC2H1</i>-related SRTD shows significant phenotypic variability. There is limited information regarding correlations between genotypes, antenatal ultrasound findings and clinical phenotypes and severity.</p><p><strong>Methods: </strong>A retrospective study of confirmed <i>DYNC2H1</i>-related SRTD cases was conducted through paper and digital medical records. Data collected included patient demographics, initial presentation, postnatal progression, childhood follow-up, antenatal ultrasound imaging, postnatal skeletal surveys and genetic variant analysis.</p><p><strong>Results: </strong>Nine individuals from eight families across three tertiary genetic centres in England were included in the study. Eight presented in the antenatal period (gestation 14-36 weeks) and one in the postnatal period at 6 weeks. All nine displayed a narrow thorax and eight displayed shortened long bones (humerus and/or femur). Polydactyly was less common and seen in only four individuals. Phenotypic severity was variable, including mild (n=4), moderate requiring respiratory support (n=2) and severe/lethal (n=3) cases. Earlier antenatal presentation and more significant femur shortening and bowing were predictive of poor postnatal prognosis, and there were no clear genotype-phenotype correlations. We also report seven novel <i>DYNC2H1</i> variants, not previously reported.</p><p><strong>Conclusion: </strong><i>DYNC2H1</i>-related SRTD exhibits significant phenotypic variability which cannot be reliably predicted by genotype but has some correlation with time of gestational presentation.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"476-483"},"PeriodicalIF":3.5,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144010606","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>AOPEP</i>-related autosomal recessive dystonia: update on Zech-Boesch syndrome.","authors":"Sylvia Boesch, Michael Zech","doi":"10.1136/jmg-2025-110656","DOIUrl":"10.1136/jmg-2025-110656","url":null,"abstract":"<p><p>Gene discovery efforts have contributed to a better understanding of the molecular causes of dystonia, but knowledge of the individual monogenic forms remains limited. This review seeks to summarise all available data on the recently identified autosomal recessive subtype of dystonia caused by variants in <i>AOPEP</i>, focusing on the geographical origins of affected families, mutational spectrum, phenotypic expressions and pathophysiology. <i>AOPEP</i>-related dystonia, documented as Zech-Boesch syndrome in the Online Mendelian Inheritance in Man database, has been diagnosed in cohorts around the globe including under-represented populations with increased rates of consanguinity. Predictably leading to loss of protein function, the majority (74%) of disease-associated <i>AOPEP</i> alleles are protein-truncating variants comprising homozygous and compound heterozygous stop-gain, frameshift and splice-site changes. The dystonic disorder shows onset from childhood to the fourth decade and generalises in a significant proportion of cases (60%). Variable expressivity and age-related penetrance are likely to play a role in manifestation of the condition, consistent with occasional occurrence of <i>AOPEP</i> homozygous pathogenic variants in subjects without a diagnosis of dystonia. <i>AOPEP</i> encodes aminopeptidase O, a proteolytic processing enzyme that is preferentially expressed in glia and potentially linked to endosomal-lysosomal pathways. <i>AOPEP</i>-related autosomal recessive Zech-Boesch syndrome is of worldwide relevance for the diagnosis of genetic dystonia. Future research focusing on <i>AOPEP</i>`s role in cellular protein metabolism may provide new insights into dystonia pathogenesis and yet-unidentified therapeutic targets.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"388-395"},"PeriodicalIF":3.5,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143729551","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"STIM1 in-frame deletion of eight amino acids in a patient with moderate tubular aggregate myopathy/Stormorken syndrome.","authors":"Emma Lafabrie, Maja Vrdoljak Pažur, Jocelyn Laporte, Johann Böhm","doi":"10.1136/jmg-2024-110273","DOIUrl":"10.1136/jmg-2024-110273","url":null,"abstract":"<p><p>Store-operated Ca²⁺ entry (SOCE) is a ubiquitous mechanism controlling Ca²⁺ homeostasis and relies on the reticular Ca²⁺ sensor STIM1 and the plasma membrane Ca²⁺ channel ORAI1. <i>STIM1</i> and <i>ORAI1</i> gain-of-function mutations induce excessive Ca²⁺ influx through SOCE overactivation and cause tubular aggregate myopathy (TAM) and Stormorken syndrome (STRMK), two overlapping disorders characterised by muscle weakness and additional signs such as short stature, thrombocytopenia and hyposplenism. Most patients carry missense mutations in the STIM1 Ca²⁺-sensing EF-hands or in the CC1 domain implicated in ORAI1 activation.Here we report the first STIM1 deletion in a patient with moderate TAM/STRMK phenotype encompassing exercise-induced muscle weakness, elevated creatine kinase levels, asplenia and transient thrombocytopenia. The c.702_725del mutation occurred de novo and is predicted to involve the deletion of eight amino acids between EF-hands and the CC1 domain. We conducted a series of functional experiments in mouse and human cells lines and provided the evidence that the in-frame deletion causes constitutive STIM1 clustering and ORAI1 recruitment, resulting in profuse extracellular Ca²⁺ entry and major nuclear translocation of the transcription factor NFAT1. Overall, this work illustrated the pathogenicity of the STIM1 in-frame deletion at different levels of the SOCE pathway and provided a molecular diagnosis for the affected family.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"381-387"},"PeriodicalIF":3.5,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143700464","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Very early-onset symptomatic CNS haemangioblastoma in Von Hippel-Lindau disease.","authors":"Marina Caballero, Vicente Santa-Maria Lopez, Laura Marti, Loreto Martorell, Diana Salinas, Jose Hinojosa, Maria Victoria Becerra, Miriam Pavon-Mengual, Andres Morales La Madrid, Ofelia Cruz, Jordi Muchart, Hector Salvador","doi":"10.1136/jmg-2024-110477","DOIUrl":"10.1136/jmg-2024-110477","url":null,"abstract":"<p><p>Von Hippel-Lindau disease is a genetic disorder characterised by the development of a variety of tumours and cysts, with central nervous system (CNS) haemangioblastoma being the most common manifestation. Early diagnosis through genetic counselling and surveillance is crucial for detecting asymptomatic stages of the disease to minimise morbidity and mortality associated with tumour complications and treatment interventions. In this report, we describe two cases of very early-onset symptomatic CNS haemangioblastoma and discuss the potential improvement in surveillance protocols by including both clinical and genetic factors.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"409-412"},"PeriodicalIF":3.5,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143729947","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical utility of genome sequencing in autism: illustrative examples from a genomic research study.","authors":"Thanuja Selvanayagam, Ny Hoang, Ege Sarikaya, Jennifer Howe, Carolyn Russell, Alana Iaboni, Morgan Quirbach, Christian R Marshall, Peter Szatmari, Evdokia Anagnostou, Jacob Vorstman, Dean M Hartley, Stephen W Scherer","doi":"10.1136/jmg-2024-110463","DOIUrl":"10.1136/jmg-2024-110463","url":null,"abstract":"<p><strong>Background: </strong>Genetics is an important contributor to autism spectrum disorder (ASD). Clinical guidelines endorse genetic testing in the medical workup of ASD, particularly tests that use whole genome sequencing (WGS) technology. While the clinical utility of genetic testing in ASD is demonstrated, the breadth of impact of results can depend on the variant and/or gene being reported.</p><p><strong>Methods: </strong>We reviewed research results returned to families enrolled in our ASD WGS study between 2012 and 2023. For significant results, we grouped the outcome of each genetic finding into three outcome categories: (1) genetic diagnosis, (2) counselling benefits and (3) support to family.</p><p><strong>Results: </strong>Out of 202 families who received genome sequencing results, 100 had at least one clinically relevant finding related to ASD. With detailed examples, we show that all significant results led to a genetic diagnosis and counselling benefits.</p><p><strong>Conclusion: </strong>Our findings show the relevance of genome sequencing in ASD and provide illustrative examples of how the information can be used.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"413-421"},"PeriodicalIF":3.5,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12116238/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143764113","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}