Journal of Medical Genetics最新文献

{"title":"Arteriovenous malformation from a patient with JP-HHT harbours two second-hit somatic DNA alterations in <i>SMAD4</i>.","authors":"Evon DeBose-Scarlett, Andrew K Ressler, Cassi Friday, Kara K Prickett, James W Roberts, James R Gossage, Douglas A Marchuk","doi":"10.1136/jmg-2024-110569","DOIUrl":"10.1136/jmg-2024-110569","url":null,"abstract":"<p><strong>Background: </strong>Hereditary haemorrhagic telangiectasia (HHT) is an inherited disorder of vascular malformations. It is caused by inherited loss-of-function mutations in one of three genes, <i>ENG</i>, <i>ACVRL1</i> or <i>SMAD4</i>. We recently showed that HHT-associated vascular malformations from liver, lung, brain and skin develop via a two-hit genetic mechanism resulting from biallelic loss-of-function mutations in either <i>ENG</i> or <i>ACVRL1</i>. Second-hit somatic mutations in <i>SMAD4</i> have not been reported in HHT-associated vascular malformations. Here, we investigate a large, aggressively growing craniofacial arteriovenous malformation (AVM) from an individual with juvenile polyposis-HHT caused by a germline mutation in <i>SMAD4</i>.</p><p><strong>Methods: </strong>We sequenced DNA from the AVM using a targeted gene sequencing panel to at least 1000X to identify somatic mutations that might contribute to the development of the AVM. We analysed whole genome SNP genotyping data using the algorithm Mosaic Chromosomal Alterations (MoChA) to identify somatic loss of heterozygosity.</p><p><strong>Results: </strong>We confirmed the germline mutation in <i>SMAD4</i> (c.1610A>T, p.Asp537Val) and identified a second-hit somatic mutation also in <i>SMAD4</i> (c.350dup, p.Tyr117*) that occurred in <i>trans</i> relative to the germline mutation. We also identified somatic loss of heterozygosity on the q arm of chromosome 18, including <i>SMAD4</i>. Additionally, we confirmed that the loss of heterozygosity causes loss of the wild-type allele. Thus, we identified two independent somatic alterations in <i>SMAD4</i> causing biallelic loss of <i>SMAD4</i> function in the AVM tissue.</p><p><strong>Conclusion: </strong>We identified biallelic loss of function of <i>SMAD4</i> in a craniofacial AVM, evidence that <i>SMAD4</i> also follows the two-hit mutation mechanism of HHT-associated vascular malformation pathogenesis.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"281-288"},"PeriodicalIF":3.5,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11925654/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143408749","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":"Expanding the phenotypic spectrum of PROS: reclassifying isolated lateralised overgrowth.","authors":"Andrea Gazzin, Giuseppe Reynolds, Stefania Massuras, Maria Luca, Paola Coppo, Diana Carli, Marilidia Piglionica, Stefania Martino, Rosanna Bagnulo, Giovanni Battista Ferrero, Nicoletta Resta, Alessandro Mussa","doi":"10.1136/jmg-2024-110364","DOIUrl":"10.1136/jmg-2024-110364","url":null,"abstract":"<p><p>Lateralised overgrowth (LO) is characterised by the asymmetric increase in the size of any part of the body exceeding 10% compared with the unaffected contralateral one. LO is a key feature in various syndromic overgrowth disorders, such as Beckwith-Wiedemann spectrum and <i>PIK3CA</i>-related overgrowth spectrum (PROS). However, it can also present as isolated (ILO). Defining the aetiology of LO is critical due to the clinical implications and management strategies required for each condition. This report presents two patients who were followed up throughout childhood for ILO and were ultimately diagnosed with PROS through molecular analysis on DNA extracted from a skin biopsy, revealing the <i>PIK3CA</i>:c.263G>A (p.Arg88Gln) variant at a high variant allele frequency. This variant has been described in association with macrocephaly-capillary malformation syndrome but not with ILO. In conclusion, this is the first report of patients harbouring the (p.Arg88Gln) variant with a diagnosis of ILO, thus, highlighting the importance of considering ILO within the PROS and underscoring the necessity for somatic DNA testing. An early and accurate molecular diagnosis is crucial for guiding appropriate clinical management in order to ensure access to targeted therapies, emphasising the need for further research to refine diagnostic criteria and testing recommendations for ILO.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"276-280"},"PeriodicalIF":3.5,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143052802","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":"Enhancing clinical decision-making for CNVs of uncertain significance in neurodevelopmental disorders: the relevance (or uselessness) of scoring and segregating.","authors":"Jorge Diogo Da Silva, Nuno Maia, Paula Jorge, Vanessa Sousa, Nataliya Tkachenko, Ana Rita Soares","doi":"10.1136/jmg-2024-110144","DOIUrl":"10.1136/jmg-2024-110144","url":null,"abstract":"<p><strong>Background: </strong>Clinicians often deal with copy-number variants of unknown significance (CNVUS) when managing neurodevelopmental disorders (NDDs). Variant classification is often complemented with textual comments, while the American College of Medical Genetics and Genomics (ACMG)/Clinical Genome Resource (ClinGen) numerical scores are rarely reported. Our aim was to determine if the application of ACMG/ClinGen scoring and inheritance/segregation studies are relevant for the reclassification of CNVUS.</p><p><strong>Methods: </strong>We retrieved 167 CNVUS (112 duplications, 55 heterozygous deletions) from test reports of 141 patients with NDD in a 5-year period. None of those testing reports included ACMG/ClinGen scoring information for the CNVUS. One clinical and one laboratorial geneticist independently applied the ACMG/ClinGen scoring system for CNVs. Final scores/categories were assessed for potential modification when adding inheritance/segregation criteria.</p><p><strong>Results: </strong>138 (83%) of the CNVUS retained the VUS classification, 14 (8%) changed to benign and 15 (9%) to (likely) pathogenic. Variants deemed benign (11 duplications, 3 deletions) mostly overlapped with ClinGen-established benign regions or were common in the general population; variants deemed (likely) pathogenic (all deletions) were either associated with unrelated autosomal recessive/later-onset autosomal dominant (AD) conditions, or with an AD NDD phenotype in a single case. Inheritance studies were available for 20 (12%) variants (17 inherited, 3 de novo), and none led to a change in classification. A simulation showed that adding inheritance information would also not change the classification of any other variant.</p><p><strong>Conclusion: </strong>Application of the ACMG/ClinGen scoring system led by itself to reclassification of 17% of VUS, despite a very low increase in diagnostic yield (1/141, 0.7%). Additionally, segregation/inheritance studies in CNVUS were mostly irrelevant in most NDD cases, challenging their routine broad application in clinical practice.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"298-302"},"PeriodicalIF":3.5,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143433249","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":"Genetic features and pharmacological rescue of novel Kv7.2 variants in patients with epilepsy.","authors":"Yue Song, Yang Xia, Ziyue Peng, Yuhuan Meng, Wenwen Jing, Li Xie, Tianhua Cao, Jiahui Zhang, Huilin Song, Lingdi Meng, Yi Zhang, Shengbin Sui, Di Mao, Ying Jia, Shupei Qiao, Shihui Yu, Xue Zhang","doi":"10.1136/jmg-2024-110141","DOIUrl":"10.1136/jmg-2024-110141","url":null,"abstract":"<p><strong>Background: </strong>Increasing evidence indicates a robust correlation between epilepsy and variants of the Kv7.2 (<i>KCNQ2</i>) channel, which is critically involved in directing M-currents and regulating neuronal excitability within the nervous system. With the advancement of next-generation sequencing, the identification of <i>KCNQ2</i> variants has surged. Nonetheless, their functional impacts are still being determined, introducing uncertainty into the diagnostic process for affected families and potentially hindering their ability to participate in targeted precision medicine trials. This study aims to elucidate the pathogenicity of these novel variants and explore potential therapeutic interventions.</p><p><strong>Methods: </strong>Whole-cell patch-clamp recordings, western blotting, and immunofluorescent staining were performed to elucidate the functional consequences of the identified variants. Moreover, coimmunoprecipitation techniques were conducted to explore protein interactions, thus facilitating a deeper understanding of the underlying pathogenetic mechanisms contributing to the disease. Ultimately, the effects of pharmacological interventions were evaluated in vitro using the patch-clamp technique.</p><p><strong>Results: </strong>Herein, we identified 12 novel <i>KCNQ2</i> variants, further expanding the mutational spectrum of <i>KCNQ2</i>. Our investigation revealed that one gain-of-function variant (p.L102V (c.304C>G)) and three loss-of-function variants (p.H328Q (c.984C>G), p.A336V (c.1007C>T) and p.D563Efs*22 (c.1688_1689insACTT)) had different impacts on the binding of calmodulin and phosphati-dylinositol-4,5-bisphosphate, potentially altering their localisation and protein stability. Furthermore, the application of ML213, unlike Retigabine and ICA-069673, led to a significant increase in the current of p.H328Q.</p><p><strong>Conclusion: </strong>This study expanded the mutational spectrum of <i>KCNQ2</i> and analysed the genetic and functional consequences, as well as the pharmacological rescue, of four <i>de novo KCNQ2</i> variants. These findings offer valuable insights into the precise medicine of <i>KCNQ2</i>-related epilepsy.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"231-241"},"PeriodicalIF":3.5,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143006693","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>FLNA</i> genomic rearrangements in a 391 French bilateral periventricular nodular heterotopia cohort: prevalence and phenotypic correlations.","authors":"Henri Margot, Natalia Hernandez Poblete, Chloé Angelini, Julie Desforges, Julie Bouron, Benoit Arveiler, Caroline Rooryck, Cyril Goizet, Patricia Fergelot","doi":"10.1136/jmg-2024-110336","DOIUrl":"10.1136/jmg-2024-110336","url":null,"abstract":"<p><strong>Background: </strong><i>FLNA</i> loss of function manifests across a broad spectrum of phenotypes, ranging from severe prenatal onset to asymptomatic cases. Bilateral periventricular nodular heterotopia (BPNH) consistently occurs in affected individuals. This retrospective study involving French patients with BPNH evaluates the prevalence of <i>FLNA</i> gene dosage anomalies and investigates genotype-phenotype correlations in a large cohort of French patients with BPNH.</p><p><strong>Methods: </strong>A retrospective observational study was conducted on 391 individuals diagnosed with BPNH confirmed by brain MRI. Sequencing analysis using Sanger or next-generation sequencing was complemented by targeted array-comparative genomic hybridisation to identify copy number variants (CNVs).</p><p><strong>Results: </strong><i>FLNA</i> variants were identified in 40% of females and 12% of males. Among these, 87% were single nucleotide variants (SNVs), while CNVs accounted for 13%, all of which were deletions. Half of the CNVs involved a recurrent deletion spanning exons 31-48, often accompanied by a duplication of the neighbouring <i>EMD</i> gene. This del-dup was associated with a milder phenotype, whereas smaller de novo deletions correlated with severe outcomes. Mosaicism was also detected in three cases.</p><p><strong>Conclusion: </strong><i>FLNA</i> CNV analysis, particularly for recurrent deletions and mosaicism, is essential in the genetic evaluation of BPNH. Integrating CNV detection with SNV analysis improves diagnostic accuracy and enhances understanding of genotype-phenotype correlations.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"227-230"},"PeriodicalIF":3.5,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142950242","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":"Parental knowledge, attitudes, satisfaction and decisional conflict regarding whole genome sequencing in the Genomic Medicine Service: a multisite survey study in England.","authors":"Ria Patel, Bettina Friedrich, Saskia C Sanderson, Holly Ellard, Celine Lewis","doi":"10.1136/jmg-2024-110458","DOIUrl":"10.1136/jmg-2024-110458","url":null,"abstract":"<p><strong>Background: </strong>Whole genome sequencing (WGS) for paediatric rare disease diagnosis is now available as a first-line test for certain clinical indications in the Genomic Medicine Service in England. The aim of this study was to assess decisional conflict regarding WGS at the time of consent as well as parental knowledge, attitudes and satisfaction.</p><p><strong>Methods: </strong>We conducted a multisite quantitative survey including validated measures. Surveys were sent out across seven National Health Service Trusts in England to parents of children offered WGS, within 4 weeks of their appointment.</p><p><strong>Results: </strong>374/1366 survey responses were included in the final dataset. Parents were highly satisfied with their WGS appointment (mean=24.47/28), had low decisional conflict (mean=20.09/100) and felt they had received enough information and support to make an informed decision (83.9%). Parents had positive attitudes towards WGS (mean=18.17/20), and those who had discussed WGS with a genetic counsellor or genomic associate had significantly more positive attitudes than those seen by genetic consultants (p<0.001). Most parents (84.3%) strongly agreed (27.2%) or agreed (67.1%) that they had a clear understanding of what a genomic test is. Parents whose child's condition was reported as more serious (p=0.0011) felt less conflicted about their decision.</p><p><strong>Conclusions: </strong>The parents in this study had low decisional conflict and most felt they had made an informed decision. Further research after parents receive WGS results to assess whether any, and if so who, regrets their decision, is important.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"289-297"},"PeriodicalIF":3.5,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12015048/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143408784","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":"Neurodevelopmental delay, musculoskeletal disorders and dysmorphia associated with a novel pathogenic interstitial deletion of chromosome 10q21.1q21.3.","authors":"Dibyendu Dutta, Jennifer Black, Emily A Montoya, Thomas Andrew Burrow, Joseph Shieh, Bobbi McGivern, Michelle Raymond, Christina B Sheedy, Scott C Smith, Ria Garg","doi":"10.1136/jmg-2024-110367","DOIUrl":"10.1136/jmg-2024-110367","url":null,"abstract":"<p><strong>Background: </strong>Previous reports of distal deletions in chromosome 10q in patients have described distinct facial features combined with other neurodevelopmental abnormalities, including intellectual disability. However, the association of interstitial deletions in chromosome 10q with global developmental delay, musculoskeletal abnormalities, and dysmorphic features has not been previously reported.</p><p><strong>Methods: </strong>Genetic testing using whole exome sequencing (WES) was performed on three patients with neurodevelopmental delay, musculoskeletal abnormalities and dysmorphic features. Sequencing reads were aligned to the human genome build GRCh37/UCSC hg19 and analysed for both sequence and copy number variants.</p><p><strong>Results: </strong>WES identified similar interstitial deletions in the 10q21.1q21.3 locus in all three patients. The deleted region includes online Mendelian inheritance in man (OMIM)-annotated genes with clinical significance, such as <i>ANK3</i> (*600465), <i>JMJD1C</i> (*604503), <i>EGR2</i> (*129010), <i>BICC1</i> (*614295), <i>ZNF365</i> (*607818) and <i>TFAM</i> (*600438). Deletion of this region is considered pathogenic and is implicated in the aetiology of the clinical phenotypes observed in these patients.</p><p><strong>Conclusions: </strong>This is the first report associating interstitial deletions in the 10q21.1q21.3 locus with neurodevelopmental delay, musculoskeletal abnormalities and dysmorphic features. Our findings highlight the clinical significance of this deleted region and suggest possible mechanisms underlying the observed pathological phenotypes.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"268-275"},"PeriodicalIF":3.5,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143189026","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":"Aarskog-Scott syndrome: a clinical study based on a large series of 111 male patients with a pathogenic variant in <i>FGD1</i> and management recommendations.","authors":"Médéric Jeanne, Nathalie Ronce, Solène Remizé, Stéphanie Arpin, Geneviève Baujat, Sylvain Breton, Florence Petit, Clémence Vanlerberghe, Anne Coeslier-Dieux, Sylvie Manouvrier-Hanu, Catherine Vincent-Delorme, Philippe Khau Van Kien, Julien Van-Gils, Chloé Quélin, Laurent Pasquier, Sylvie Odent, Florence Demurger, Fanny Laffargue, Christine Francannet, Dominique Martin-Coignard, Alexandra Afenjar, Sandra Whalen, Alain Verloes, Yline Capri, Andrée Delahaye, Julie Plaisancié, Philippe Labrune, Anne Destree, Isabelle Maystadt, Viorca Ciorna Monferrato, Bertrand Isidor, Marie Vincent, Nolwen Jean Marçais, Sophie Nambot, Elise Schaefer, Salima El Chehadeh, James Lespinasse, Patrick Collignon, Tiffany Busa, Nicole Philip, Marjolaine Willems, Marc Planes, Olivier M Vanakker, Laetitia Lambert, Bruno Leheup, Michèle Mathieu-Dramard, Gilles Morin, Klaus Dieterich, Emmanuelle Ginglinger, Allan Bayat, Meena Balasubramanian, Benjamin Dauriat, Damien Haye, Jeanne Amiel, Marlène Rio, Valérie Cormier-Daire, Annick Toutain","doi":"10.1136/jmg-2022-108868","DOIUrl":"10.1136/jmg-2022-108868","url":null,"abstract":"<p><strong>Background: </strong>Aarskog-Scott syndrome (AAS) is a rare condition with multiple congenital anomalies, caused by hemizygote variants in the <i>FGD1</i> gene. Its description was based mostly on old case reports, in whom a molecular diagnosis was not always available, or on small series. The aim of this study was to better delineate the phenotype and the natural history of AAS and to provide clues for the diagnosis and the management of the patients.</p><p><strong>Methods: </strong>Phenotypic characterisation of the largest reported AAS cohort, comprising 111 male patients with proven causative variants in <i>FGD1</i>, through comprehensive analyses of clinical data including congenital anomalies, growth and neurodevelopment. Review of photographs and radiographs by experts in dysmorphology and skeletal disorders.</p><p><strong>Results: </strong>This study refines the phenotypic spectrum of AAS, with the description of new morphological and radiological features, and refines the prevalence of the features. Short stature is less frequent than previously reported and has a prenatal onset in more than half of the patients. The growth has a specific course with a catch-up during the first decade often leading to low-normal stature in adulthood. Whereas intellectual disability is rare, patients with AAS have a high prevalence of specific learning difficulties and attention hyperactivity disorder. In light of this better knowledge of AAS, we provide management recommendations.</p><p><strong>Conclusion: </strong>A better knowledge of the natural history and phenotypic spectrum of AAS will be helpful for the clinical diagnosis and for the interpretation of <i>FGD1</i> variants using a retrophenotyping strategy, which is becoming the most common way of diagnosis nowadays. Recommendations for care will improve the management of the patients.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"258-267"},"PeriodicalIF":3.5,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142971126","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":"Genetic and clinical analysis of <i>OPTN</i> in amyotrophic lateral sclerosis.","authors":"Yi Xiao, Yushan Tan, Chunyu Li, Qianqian Wei, Qirui Jiang, Shichan Wang, Tianmi Yang, Junyu Lin, Lingyu Zhang, Huifang Shang","doi":"10.1136/jmg-2024-109978","DOIUrl":"10.1136/jmg-2024-109978","url":null,"abstract":"<p><strong>Background: </strong>Considerable heterogeneity in genotypes and phenotypes has been observed among patients with amyotrophic lateral sclerosis (ALS) harbouring optineurin gene (<i>OPTN</i>) mutations, as reported in prior studies. The study aimed to elucidate the correlation between <i>OPTN</i> genotypes and phenotypes.</p><p><strong>Methods: </strong><i>OPTN</i> gene variants were screened within a substantial Chinese cohort of patients with ALS, encompassing LoF and rare missense variants. Additionally, a systematic literature review was conducted to compile the spectrum of <i>OPTN</i> mutations and explore the relationship between the genotype and phenotype of patients with ALS with <i>OPTN</i>.</p><p><strong>Results: </strong>A total of 33 unrelated patients with ALS with 24 rare <i>OPTN</i> variants, including 17 novel variants, were identified in 2279 patients with ALS. Among 24 variants in our cohort and 106 variants in previous studies, only 33.3% and 35.8% were pathogenic/likely pathogenic variants. Moreover, the frequency of <i>OPTN</i> variants in the Asian ALS population was higher (1.08%) than that of the Caucasian population (0.55%). For the phenotype of patients with ALS carrying OPTN variants, we found that patients with pathogenic/likely pathogenic variants had the highest baseline progression rate and the shortest survival time among groups in our cohort.</p><p><strong>Conclusion: </strong>Our study contributed to a broader understanding of the genotype and phenotype spectrum of patients with ALS carrying <i>OPTN</i> variants. Further investigations are warranted to definitively establish the genotype-phenotype associations.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"242-248"},"PeriodicalIF":3.5,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142950243","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":"Disease burden by <i>ALPL</i> variant number in patients with non-life-threatening hypophosphatasia in the Global HPP Registry.","authors":"Priya S Kishnani, Lothar Seefried, Kathryn M Dahir, Gabriel Á Martos-Moreno, Wolfgang Högler, Cheryl R Greenberg, Shona Fang, Anna Petryk, William R Mowrey, Agnès Linglart, Keiichi Ozono","doi":"10.1136/jmg-2024-110383","DOIUrl":"10.1136/jmg-2024-110383","url":null,"abstract":"<p><strong>Background: </strong>Hypophosphatasia (HPP) is a rare metabolic disease caused by autosomal dominant or recessive inheritance of <i>ALPL</i> variants resulting in low alkaline phosphatase activity. The objective of this analysis was to compare HPP disease burden between patients with non-life-threatening disease in the Global HPP Registry who have one <i>ALPL</i> variant versus two or more <i>ALPL</i> variants.</p><p><strong>Methods: </strong>Patients were included if they had one or more <i>ALPL</i> variants identified through genetic testing and first HPP manifestations after 6 months of age. Assessments included history of HPP manifestations, Brief Pain Inventory-Short Form (BPI-SF), Health Assessment Questionnaire-Disability Index (HAQ-DI), 6-Min Walk Test (6MWT), Paediatric Quality of Life Inventory (PedsQL) and 36-Item Short-Form Survey V.2 (SF-36v2).</p><p><strong>Results: </strong>Of 685 included patients, 568 (82.9%) had one <i>ALPL</i> variant, 116 (16.9%) had two variants, and one (0.1%) had three variants. Patients with two or more <i>ALPL</i> variants had higher proportions of skeletal (52.1% vs 32.6%), dental (73.5% vs 56.0%), muscular (36.8% vs 23.6%) and neurological (22.2% vs 8.8%) manifestations at last assessment. BPI-SF, HAQ-DI, PedsQL and SF-36v2 scores were similar between groups. Distances walked on the 6MWT were similar between groups for children. Distance walked was lower among adults with two or more variants (293 m (n=8)) than adults with one variant (466 m (n=103)), although the former group was very small.</p><p><strong>Conclusion: </strong>HPP disease burden is high in patients with HPP, regardless of <i>ALPL</i> variant number. While prevalence of HPP-specific manifestations was higher in patients with two or more variants than those with one variant, patient-reported outcomes were similar between groups.</p><p><strong>Trial registration number: </strong>NCT02306720; EUPAS13514.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"249-257"},"PeriodicalIF":3.5,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12015031/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143449315","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}