Journal of Medical Genetics最新文献

{"title":"Genetic evidence for splicing-dependent structural and functional plasticity in CASK protein","authors":"Paras A Patel, Leslie E W LaConte, Chen Liang, Thomas Cecere, Deepa Rajan, Sarika Srivastava, Konark Mukherjee","doi":"10.1136/jmg-2023-109747","DOIUrl":"https://doi.org/10.1136/jmg-2023-109747","url":null,"abstract":"Background Pontocerebellar hypoplasia (PCH) may present with supratentorial phenotypes and is often accompanied by microcephaly. Damaging mutations in the X-linked gene CASK produce self-limiting microcephaly with PCH in females but are often lethal in males. CASK deficiency leads to early degeneration of cerebellar granule cells but its role in other regions of the brain remains uncertain. Method We generated a conditional Cask knockout mice and deleted Cask ubiquitously after birth at different times. We examined the clinical features in several subjects with damaging mutations clustered in the central part of the CASK protein. We have performed phylogenetic analysis and RT-PCR to assess the splicing pattern within the same protein region and performed in silico structural analysis to examine the effect of splicing on the CASK’s structure. Result We demonstrate that deletion of murine Cask after adulthood does not affect survival but leads to cerebellar degeneration and ataxia over time. Intriguingly, damaging hemizygous CASK mutations in boys who display microcephaly and cerebral dysfunction but without PCH are known. These mutations are present in two vertebrate-specific CASK exons. These exons are subject to alternative splicing both in forebrain and hindbrain. Inclusion of these exons differentially affects the molecular structure and hence possibly the function/s of the CASK C-terminus. Conclusion Loss of CASK function disproportionately affects the cerebellum. Clinical data, however, suggest that CASK may have additional vertebrate-specific function/s that play a role in the mammalian forebrain. Thus, CASK has an ancient function shared between invertebrates and vertebrates as well as novel vertebrate-specific function/s. Data are available upon reasonable request.","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":"14 1","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140804409","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":"Mosaic RASopathies concept: different skin lesions, same systemic manifestations?","authors":"Marie-Anne Morren, Heidi Fodstad, Hilde Brems, Nicola Bedoni, Emmanuella Guenova, Martine Jacot-Guillarmod, Kanetee Busiah, Fabienne Giuliano, Michel Gilliet, Isis Atallah","doi":"10.1136/jmg-2023-109306","DOIUrl":"10.1136/jmg-2023-109306","url":null,"abstract":"<p><strong>Background: </strong>Cutaneous epidermal nevi are genotypically diverse mosaic disorders. Pathogenic hotspot variants in <i>HRAS</i>, <i>KRAS</i>, and less frequently<i>, NRAS</i> and <i>BRAF</i> may cause isolated keratinocytic epidermal nevi and sebaceous nevi or several different syndromes when associated with extracutaneous anomalies. Therefore, some authors suggest the concept of mosaic RASopathies to group these different disorders.</p><p><strong>Methods: </strong>In this paper, we describe three new cases of syndromic epidermal nevi caused by mosaic <i>HRAS</i> variants: one associating an extensive keratinocytic epidermal nevus with hypomastia, another with extensive mucosal involvement and a third combining a small sebaceous nevus with seizures and intellectual deficiency. Moreover, we performed extensive literature of all cases of syndromic epidermal nevi and related disorders with confirmed pathogenic postzygotic variants in <i>HRAS, KRAS, NRAS</i> or <i>BRAF</i>.</p><p><strong>Results: </strong>Most patients presented with bone, ophthalmological or neurological anomalies. Rhabdomyosarcoma, urothelial cell carcinoma and pubertas praecox are also repeatedly reported. <i>KRAS</i> pathogenic variants are involved in 50% of the cases, especially in sebaceous nevi, oculoectodermal syndrome and encephalocraniocutaneous lipomatosis. They are frequently associated with eye and brain anomalies. Pathogenic variants in <i>HRAS</i> are rather present in syndromic keratinocytic epidermal nevi and phacomatosis pigmentokeratotica.</p><p><strong>Conclusion: </strong>This review delineates genotype/phenotype correlations of syndromic epidermal nevi with somatic <i>RAS</i> and <i>BRAF</i> pathogenic variants and may help improve their follow-up.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"411-419"},"PeriodicalIF":4.0,"publicationDate":"2024-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139642327","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":"Childhood-onset hypertrophic cardiomyopathy caused by thin-filament sarcomeric variants.","authors":"Gabrielle Norrish, Marisa Gasparini, Ella Field, Elena Cervi, Juan Pablo Kaski","doi":"10.1136/jmg-2023-109684","DOIUrl":"10.1136/jmg-2023-109684","url":null,"abstract":"<p><p>Up to 20% of children with sarcomeric hypertrophic cardiomyopathy (HCM) have disease-causing variants in genes coding for thin-filament proteins. However, data on genotype-phenotype correlations for thin-filament disease are limited. This study describes the natural history and outcomes of children with thin-filament-associated HCM and compares it to thick-filament-associated disease.Longitudinal data were collected from 40 children under 18 years with a disease-causing variant in a thin-filament protein from a single quaternary referral centre. Twenty-one (female n=6, 35.5%) were diagnosed with HCM at a median age of 13.0 years (IQR 8.3-14.0). Over a median follow-up of 5.0 years (IQR 4.0-8.5), three (14.3%) experienced one or more major adverse cardiac events (MACE) (two patients had an out-of-hospital arrest and eight appropriate implantable cardiac defibrillator (ICD) therapies in three patients). One gene carrier died suddenly at age 9 years. Compared with those with thick-filament disease, children with thin-filament variants more commonly experienced non-sustained ventricular tachycardia [NSVT; n=6 (28.6%) vs n=14 (10.8%), p=0.024] or underwent ICD insertion (thin, n=13 (61.9%) vs thick, n=50 (38.5%), p=0.040). However, there was no difference in the incidence of MACE (thin 2.47/100 pt years (95% CI 0.80 to 7.66) vs thick 3.63/100 pt years (95% CI 2.25 to 5.84)) or an arrhythmic event (thin 1.65/100 pt years (95% CI 0.41 to 6.58) vs thick 2.55/100 pt years (95% CI 1.45 to 4.48), p value 0.43).This study suggests that adverse events in thin-filament disease are predominantly arrhythmic and may occur in the absence of hypertrophy, but overall short-term outcomes do not differ significantly from thick-filament disease.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"420-422"},"PeriodicalIF":3.5,"publicationDate":"2024-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11041581/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139650909","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":"Dissecting genetic architecture of rare dystonia: genetic, molecular and clinical insights.","authors":"Burcu Atasu, Javier Simón-Sánchez, Hasmet Hanagasi, Basar Bilgic, Ann-Kathrin Hauser, Gamze Guven, Peter Heutink, Thomas Gasser, Ebba Lohmann","doi":"10.1136/jmg-2022-109099","DOIUrl":"10.1136/jmg-2022-109099","url":null,"abstract":"<p><strong>Background: </strong>Dystonia is one of the most common movement disorders. To date, the genetic causes of dystonia in populations of European descent have been extensively studied. However, other populations, particularly those from the Middle East, have not been adequately studied. The purpose of this study is to discover the genetic basis of dystonia in a clinically and genetically well-characterised dystonia cohort from Turkey, which harbours poorly studied populations.</p><p><strong>Methods: </strong>Exome sequencing analysis was performed in 42 Turkish dystonia families. Using co-expression network (CEN) analysis, identified candidate genes were interrogated for the networks including known dystonia-associated genes and genes further associated with the protein-protein interaction, animal model-based characteristics and clinical findings.</p><p><strong>Results: </strong>We identified potentially disease-causing variants in the established dystonia genes (<i>PRKRA, SGCE, KMT2B, SLC2A1, GCH1, THAP1, HPCA, TSPOAP1, AOPEP</i>; n=11 families (26%)), in the uncommon forms of dystonia-associated genes (<i>PCCB, CACNA1A, ALDH5A1, PRKN</i>; n=4 families (10%)) and in the candidate genes prioritised based on the pathogenicity of the variants and CEN-based analyses (n=11 families (21%)). The diagnostic yield was found to be 36%. Several pathways and gene ontologies implicated in immune system, transcription, metabolic pathways, endosomal-lysosomal and neurodevelopmental mechanisms were over-represented in our CEN analysis.</p><p><strong>Conclusions: </strong>Here, using a structured approach, we have characterised a clinically and genetically well-defined dystonia cohort from Turkey, where dystonia has not been widely studied, and provided an uncovered genetic basis, which will facilitate diagnostic dystonia research.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"443-451"},"PeriodicalIF":4.0,"publicationDate":"2024-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11041572/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140065222","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":"Iron and risk of dementia: Mendelian randomisation analysis in UK Biobank.","authors":"Francesco Casanova, Qu Tian, Janice L Atkins, Andrew R Wood, Daniel Williamson, Yong Qian, David Zweibaum, Jun Ding, David Melzer, Luigi Ferrucci, Luke C Pilling","doi":"10.1136/jmg-2023-109295","DOIUrl":"10.1136/jmg-2023-109295","url":null,"abstract":"<p><strong>Background: </strong>Brain iron deposition is common in dementia, but whether serum iron is a causal risk factor is unknown. We aimed to determine whether genetic predisposition to higher serum iron status biomarkers increased risk of dementia and atrophy of grey matter.</p><p><strong>Methods: </strong>We analysed UK Biobank participants clustered into European (N=451284), African (N=7477) and South Asian (N=9570) groups by genetic similarity to the 1000 genomes project. Using Mendelian randomisation methods, we estimated the association between genetically predicted serum iron (transferrin saturation [TSAT] and ferritin), grey matter volume and genetic liability to clinically defined dementia (including Alzheimer's disease [AD], non-AD dementia, and vascular dementia) from hospital and primary care records. We also performed time-to-event (competing risks) analysis of the TSAT polygenic score on risk of clinically defined non-AD dementia.</p><p><strong>Results: </strong>In Europeans, higher genetically predicted TSAT increased genetic liability to dementia (Odds Ratio [OR]: 1.15, 95% Confidence Intervals [CI] 1.04 to 1.26, p=0.0051), non-AD dementia (OR: 1.27, 95% CI 1.12 to 1.45, p=0.00018) and vascular dementia (OR: 1.37, 95% CI 1.12 to 1.69, p=0.0023), but not AD (OR: 1.00, 95% CI 0.86 to 1.15, p=0.97). Higher TSAT was also associated with increased risk of non-AD dementia in participants of African, but not South Asian groups. In survival analysis using a TSAT polygenic score, the effect was independent of apolipoprotein-E ε4 genotype (with adjustment subdistribution Hazard Ratio: 1.74, 95% CI 1.33 to 2.28, p=0.00006). Genetically predicted TSAT was associated with lower grey matter volume in caudate, putamen and thalamus, and not in other areas of interest.</p><p><strong>Discussion: </strong>Genetic evidence supports a causal relationship between higher TSAT and risk of clinically defined non-AD and vascular dementia, in European and African groups. This association appears to be independent of apolipoprotein-E ε4.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"435-442"},"PeriodicalIF":4.0,"publicationDate":"2024-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11041574/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139403219","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":"BTB domain mutations perturbing KCTD15 oligomerisation cause a distinctive frontonasal dysplasia syndrome.","authors":"Kerry A Miller, David A Cruz Walma, Daniel M Pinkas, Rebecca S Tooze, Joshua C Bufton, William Richardson, Charlotte E Manning, Alice E Hunt, Julien Cros, Verity Hartill, Michael J Parker, Simon J McGowan, Stephen R F Twigg, Rod Chalk, David Staunton, David Johnson, Andrew O M Wilkie, Alex N Bullock","doi":"10.1136/jmg-2023-109531","DOIUrl":"10.1136/jmg-2023-109531","url":null,"abstract":"<p><strong>Introduction: </strong><i>KCTD15</i> encodes an oligomeric BTB domain protein reported to inhibit neural crest formation through repression of Wnt/beta-catenin signalling, as well as transactivation by TFAP2. Heterozygous missense variants in the closely related paralogue KCTD1 cause scalp-ear-nipple syndrome.</p><p><strong>Methods: </strong>Exome sequencing was performed on a two-generation family affected by a distinctive phenotype comprising a lipomatous frontonasal malformation, anosmia, cutis aplasia of the scalp and/or sparse hair, and congenital heart disease. Identification of a de novo missense substitution within <i>KCTD15</i> led to targeted sequencing of DNA from a similarly affected sporadic patient, revealing a different missense mutation. Structural and biophysical analyses were performed to assess the effects of both amino acid substitutions on the KCTD15 protein.</p><p><strong>Results: </strong>A heterozygous c.310G>C variant encoding p.(Asp104His) within the BTB domain of <i>KCTD15</i> was identified in an affected father and daughter and segregated with the phenotype. In the sporadically affected patient, a de novo heterozygous c.263G>A variant encoding p.(Gly88Asp) was present in KCTD15. Both substitutions were found to perturb the pentameric assembly of the BTB domain. A crystal structure of the BTB domain variant p.(Gly88Asp) revealed a closed hexameric assembly, whereas biophysical analyses showed that the p.(Asp104His) substitution resulted in a monomeric BTB domain likely to be partially unfolded at physiological temperatures.</p><p><strong>Conclusion: </strong>BTB domain substitutions in KCTD1 and KCTD15 cause clinically overlapping phenotypes involving craniofacial abnormalities and cutis aplasia. The structural analyses demonstrate that missense substitutions act through a dominant negative mechanism by disrupting the higher order structure of the KCTD15 protein complex.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"490-501"},"PeriodicalIF":4.0,"publicationDate":"2024-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11041601/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139650908","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":"Pathogenic variants affecting the TB5 domain of the fibrillin-1 protein: not only in geleophysic/acromicric dysplasias but also in Marfan syndrome.","authors":"Pauline Arnaud, Zakaria Mougin, Genevieve Baujat, Valérie Drouin-Garraud, Salima El Chehadeh, Laurent Gouya, Sylvie Odent, Guillaume Jondeau, Catherine Boileau, Nadine Hanna, Carine Le Goff","doi":"10.1136/jmg-2023-109646","DOIUrl":"10.1136/jmg-2023-109646","url":null,"abstract":"<p><strong>Background: </strong>Marfan syndrome (MFS) is a multisystem disease with a unique combination of skeletal, cardiovascular and ocular features. Geleophysic/acromicric dysplasias (GPHYSD/ACMICD), characterised by short stature and extremities, are described as 'the mirror image' of MFS. The numerous <i>FBN1</i> pathogenic variants identified in MFS are located all along the gene and lead to the same final pathogenic sequence. Conversely, in GPHYSD/ACMICD, the 28 known heterozygous <i>FBN1</i> pathogenic variants all affect exons 41-42 encoding TGFβ-binding protein-like domain 5 (TB5).</p><p><strong>Methods: </strong>Since 1996, more than 5000 consecutive probands have been referred nationwide to our laboratory for molecular diagnosis of suspected MFS.</p><p><strong>Results: </strong>We identified five MFS probands carrying distinct heterozygous pathogenic in-frame variants affecting the TB5 domain of FBN1. The clinical data showed that the probands displayed a classical form of MFS. Strikingly, one missense variant affects an amino acid that was previously involved in GPHYSD.</p><p><strong>Conclusion: </strong>Surprisingly, pathogenic variants in the TB5 domain of FBN1 can lead to two opposite phenotypes: GPHYSD/ACMICD and MFS, suggesting the existence of different pathogenic sequences with the involvement of tissue specificity. Further functional studies are ongoing to determine the precise role of this domain in the physiopathology of each disease.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"469-476"},"PeriodicalIF":4.0,"publicationDate":"2024-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11041597/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140065223","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":"Molecular diagnosis, clinical evaluation and phenotypic spectrum of Townes-Brocks syndrome: insights from a large Chinese hearing loss cohort.","authors":"Xiaohong Yan, Jing Wang, Wen Yang, Linke Li, Tian Shen, Jia Geng, Qian Zhang, Mingjun Zhong, Wenyu Xiong, Fengxiao Bu, Yu Lu, Yu Zhao, Jing Cheng, Huijun Yuan","doi":"10.1136/jmg-2023-109579","DOIUrl":"10.1136/jmg-2023-109579","url":null,"abstract":"<p><strong>Background: </strong>Townes-Brocks syndrome (TBS) is a rare genetic disorder characterised by multiple malformations. Due to its phenotypic heterogeneity and rarity, diagnosis and recognition of TBS can be challenging and there has been a lack of investigation of patients with atypical TBS in large cohorts and delineation of their phenotypic characteristics.</p><p><strong>Methods: </strong>We screened <i>SALL1</i> and <i>DACT1</i> variants using next-generation sequencing in the China Deafness Genetics Consortium (CDGC) cohort enrolling 20 666 unrelated hearing loss (HL) cases. Comprehensive clinical evaluations were conducted on seven members from a three-generation TBS family. Combining data from previously reported cases, we also provided a landscape of phenotypes and genotypes of patients with TBS.</p><p><strong>Results: </strong>We identified five novel and two reported pathogenic/likely pathogenic (P/LP) <i>SALL1</i> variants from seven families. Audiological features in patients differed in severity and binaural asymmetry. Moreover, previously undocumented malformations in the middle and inner ear were detected in one patient. By comprehensive clinical evaluations, we further provide evidence for the causal relationship between <i>SALL1</i> variation and certain endocrine abnormalities. Penetrance analysis within familial contexts revealed incomplete penetrance among first-generation patients with TBS and a higher disease burden among their affected offspring.</p><p><strong>Conclusion: </strong>This study presents the first insight of genetic screening for patients with TBS in a large HL cohort. We broadened the phenotypic-genotypic spectrum of TBS and our results supported an underestimated prevalence of TBS. Due to the rarity and phenotypic heterogeneity of rare diseases, broader spectrum molecular tests, especially whole genome sequencing, can improve the situation of underdiagnosis and provide effective recommendations for clinical management.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"459-468"},"PeriodicalIF":4.0,"publicationDate":"2024-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11041606/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139650911","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":"Clinical and genetic spectrum of <i>RNF216</i>-related disorder: a new case and literature review.","authors":"Chujun Wu, Zaiqiang Zhang","doi":"10.1136/jmg-2023-109397","DOIUrl":"10.1136/jmg-2023-109397","url":null,"abstract":"<p><strong>Background: </strong>Cases of <i>RNF216</i>-related disorder have been reported sporadically. However, the clinical and genetic spectrum of this disorder has not been fully studied.</p><p><strong>Methods: </strong>We identified an individual with a novel causative <i>RNF216</i> variant in our institution and reviewed all individuals with causative <i>RNF216</i> variants in previous reports. The clinical and genetic features of all the described individuals were analysed and summarised.</p><p><strong>Results: </strong>Twenty-four individuals from 17 families with causative <i>RNF216</i> variants were identified. The mean age at the onset of neurological symptoms was 29.2 years (range 18-49 years). Ataxia (57%) was the most frequent initial symptoms in individuals under 30 years old, while chorea (63%) was the most frequent initial symptom in individuals over 30 years old. Over 90% of individuals presented with cognitive impairment and hypogonadotropic hypogonadism throughout the disease. White matter lesions (96%) and cerebellar atrophy (92%) were the most common imaging findings. Twenty pathogenic variants in <i>RNF216</i> were detected. The variants in 12 (71%) families were inherited in a monogenic recessive pattern, whereas the variants in 5 (29%) were inherited in a digenic pattern by acting with variants in other genes. The majority of the <i>RNF216</i> variants (85%) resulted in amino acid changes or the truncation of the 'RING between RING' (RBR) domain or C-terminal extension.</p><p><strong>Conclusion: </strong><i>RNF216</i>-related disorder is an inherited neuroendocrine disease characterised by cerebellar ataxia, chorea, cognitive impairment and hypogonadotropic hypogonadism. Most causative variants in patients with <i>RNF216</i>-related disorder influence the RBR domain or C-terminal extension of RNF216.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"430-434"},"PeriodicalIF":4.0,"publicationDate":"2024-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138482467","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":"Novel mutation leading to splice donor loss in a conserved site of DMD gene causes Duchenne muscular dystrophy with cryptorchidism","authors":"Jianhai Chen, Yangying Jia, Jie Zhong, Kun Zhang, Hongzheng Dai, Guanglin He, Fuping Li, Li Zeng, Chuanzhu Fan, Huayan Xu","doi":"10.1136/jmg-2024-109896","DOIUrl":"https://doi.org/10.1136/jmg-2024-109896","url":null,"abstract":"Background As one of the most common congenital abnormalities in male births, cryptorchidism has been found to have a polygenic aetiology according to previous studies of common variants. However, little is known about genetic predisposition of rare variants for cryptorchidism, since rare variants have larger effective size on diseases than common variants. Methods In this study, a cohort of 115 Chinese probands with cryptorchidism was analysed using whole-genome sequencing, alongside 19 parental controls and 2136 unaffected men. Additionally, CRISPR-Cas9 editing of a conserved variant was performed in a mouse model, with MRI screening used to observe the phenotype. Results In 30 of 115 patients (26.1%), we identified four novel genes ( ARSH , DMD , MAGEA4 and SHROOM2 ) affecting at least five unrelated patients and four known genes ( USP9Y , UBA1 , BCORL1 and KDM6A ) with the candidate rare pathogenic variants affecting at least two cases. Burden tests of rare variants revealed the genome-wide significances for newly identified genes (p<2.5×10−6) under the Bonferroni correction. Surprisingly, novel and known genes were mainly found on X chromosome (seven on X and one on Y) and all rare X-chromosomal segregating variants exhibited a maternal inheritance rather than de novo origin. CRISPR-Cas9 mouse modelling of a splice donor loss variant in DMD (NC_000023.11:g.32454661C>G), which resides in a conserved site across vertebrates, replicated bilateral cryptorchidism phenotypes, confirmed by MRI at 4 and 10 weeks. The movement tests further revealed symptoms of Duchenne muscular dystrophy (DMD) in transgenic mice. Conclusion Our results revealed the role of the DMD gene mutation in causing cryptorchidism. The results also suggest that maternal-X inheritance of pathogenic defects could have a predominant role in the development of cryptorchidism. All data relevant to the study are included in the article or uploaded as supplementary information.","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":"52 1","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140588948","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}