Clinical Genetics最新文献

{"title":"A Novel De Novo Missense Variant in Netrin-1 (NTN1) Associated With Chorioretinal Coloboma, Sensorineural Hearing Loss and Polydactyly.","authors":"Maria Toms, Cara Heppell, Nicholas Owen, Samantha Malka, Mariya Moosajee","doi":"10.1111/cge.14651","DOIUrl":"https://doi.org/10.1111/cge.14651","url":null,"abstract":"<p><p>Microphthalmia, anophthalmia and coloboma (MAC) comprise a highly heterogeneous spectrum of congenital ocular malformations with an estimated incidence of 1 in 5000 to 1 in 30 000 live births. Although there is likely to be a genetic component in the majority of cases, many remain without a molecular diagnosis. Netrin-1 was previously identified as a mediator of optic fissure closure from transcriptome analyses of chick and zebrafish and was shown to cause ocular coloboma when knocked out in both mouse and zebrafish. Here, we report the first patient with chorioretinal coloboma and microphthalmia harbouring a novel heterozygous likely pathogenic NTN1 missense variant, c.1483T>A p.(Tyr495Asn), validating a conserved gene function in ocular development. In addition, the patient displayed bilateral sensorineural hearing loss which was investigated by examining the sensory hair cells of ntn1a morphant zebrafish, suggesting a role for netrin-1 in hair cell development.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2024-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142794493","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biallelic Variants in LRRC45 Impair Ciliogenesis and Cause a Severe Neurological Disorder.","authors":"Periyasamy Radhakrishnan, Neha Quadri, Florian Erger, Nico Fuhrmann, Otilia-Maria Geist, Christian Netzer, Ibakordor Khyriem, Mamta Muranjan, Vrajesh Udani, Mayuri Yeole, Selinda Mascarenhas, Sanket Limaye, Shahyan Siddiqui, Priyanka Upadhyai, Anju Shukla","doi":"10.1111/cge.14663","DOIUrl":"https://doi.org/10.1111/cge.14663","url":null,"abstract":"<p><p>Leucine - rich repeat containing 45 protein (LRRC45) protein localizes at the proximal end of centrioles and forms a component of the proteinaceous linker between them, with an important role in centrosome cohesion. In addition, a pool of it localizes at the distal appendages of the modified parent centriole that forms the primary cilium and it has essential functions in the establishment of the transition zone and axonemal extension during early ciliogenesis. Here, we describe three individuals from two unrelated families with severe central nervous system anomalies. Exome sequencing identified biallelic variants in LRRC45 in the affected individuals: P1: c.1402-2A>G; P2 and P3: c.1262G>C (p.Arg421Thr). Investigation of the variant c.1402-2A>G in patient-derived skin fibroblasts revealed that it triggers aberrant splicing, leading to an abnormal LRRC45 transcript that lacks exon 14. Consistent with this the mRNA and protein levels of LRRC45 were drastically reduced in P1-derived fibroblast cells compared to the controls. P1 fibroblasts showed a significant reduction of primary cilia frequency and length. In silico modeling of the missense variant in P2/P3 suggested a destabilizing effect on LRRC45. Given these findings, we propose that the pathogenic loss-of-function variants in LRRC45 are associated with a novel spectrum of neurological ciliopathy phenotypes.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142784343","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unraveling the Genetic Basis of Congenital Limb Anomalies in Eight Families.","authors":"Inam Ullah Khan, Abdullah, Hammal Khan, Amjad Ali, Ayesha Sani, Fati Ullah Khan, Muhammad Tahir Ullah, Sohail Ahmed, Romana Liaqat, Awais Haider, Kifayat Ullah, Naseeb Ullah, Muhammad Sajid Khan, Shabir Hussain, Imran Ullah, Asmat Ullah, Mariam Anees, Outi Makitie, Wasim Ahmad","doi":"10.1111/cge.14668","DOIUrl":"https://doi.org/10.1111/cge.14668","url":null,"abstract":"<p><p>Limb abnormalities are the second most frequent birth defects seen in infants, after congenital heart disease. Over the past 150 years, more than 50 classifications for limb malformations based on morphology and osseous anatomy have been presented. The goal of the current study is to investigate the genetic basis of congenital limb abnormalities in the Pakistani population. Eight families, presenting different forms of limb anomalies, including syndactyly, polydactyly, synpolydactyly, and ectrodactyly in an autosomal dominant manner, were genetically and clinically investigated. Whole exome sequencing followed by Sanger sequencing was used to search for the disease-causing variants. Sequence analysis revealed five novel variants in LMBR1, GJA1, HOXD13, and TP63 and three previously reported variants in GJA1 and HOXD13. This study expanded the mutation spectrum in the identified genes and will also help in improved diagnosis of the limb anomalies in the local population.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142784344","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comprehensive Analysis of TEK Variants in Patients With Vascular Malformations.","authors":"Reza Ghasemi, Meagan M Corliss, Kevin M Bowling, Kilannin Krysiak, Jason Walker, Alexa M Dickson, Molly C Schroeder, Bijal A Parikh, Julie A Neidich, Katarzyna Polonis, Yang Cao","doi":"10.1111/cge.14667","DOIUrl":"https://doi.org/10.1111/cge.14667","url":null,"abstract":"<p><p>Pathogenic variants in the receptor tyrosine kinase TIE2, encoded by TEK, are known to cause vascular malformations (VMs). In this study, we retrospectively reviewed the deidentified data generated through clinical NGS testing in our laboratory and found 88 VM cases with a total of 107 clinically significant TEK variants. Among those, 23 unique variants at the amino acid level were identified, including five novel (p.Cys1040Arg, p.Arg1099PhefsTer12, p.Glu1109Ter, p.Phe1111LeufsTer7, p.Phe1111ValfsTer7) and 18 previously published variants. Missense variants were identified more often in the tyrosine kinase domain, while all nonsense/frameshift variants were clustered in the C-terminal tail (CTT). In addition, most variants occurred as solitary alterations, whereas certain variants always co-occurred with a second TEK variant. Five patterns of TEK variants (P1-P5) were identified: (P1) Arg849 + another variant; (P2) Tyr897 + another variant; (P3) Leu914 single variants; (P4) Arg915/918 single variants; and (P5) CTT single /co-occurring variants. This study provides the most comprehensive view of pathogenic TEK variants in VMs to date.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142779495","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Novel Homozygous Synonymous Variant in CCDC134 as a Cause of Osteogenesis Imperfecta Type XXII.","authors":"Haiping Ning, Cuili Liang, Huifen Mei, Dejian Yuan, Xiaobao Wei, Xiao Huang, Dongdong Tan, Jianqiang Tan","doi":"10.1111/cge.14664","DOIUrl":"https://doi.org/10.1111/cge.14664","url":null,"abstract":"<p><p>Osteogenesis imperfecta (OI) is a heterogeneous group of rare, inherited connective tissue disorders. It includes over 20 defined subtypes, each of which is associated with distinct causative genes that are listed in the Online Mendelian Inheritance in Man (OMIM) database. Type XXII OI (OI 22) is caused by a homozygous variant in the coiled-coil domain containing 134 (CCDC134) gene, which is located on chromosome 22q13. OI, which is associated with CCDC134, is extremely rare with only five cases reported worldwide. All known cases involve the c.2 T > C (p. Met1Thr) homozygous missense variant in the CCDC134 gene. We present the case of a 13-year-old Chinese girl with non-union fracture, short stature and specific radiographic findings, which include scoliosis, pelvic tilt, thin clavicles, ribs, and limbs. Whole exome sequencing revealed a novel, homozygous c.492G > C (p. Leu164=) variation in the CCDC134 gene. RNA sequencing (RNA-seq) analysis identified this variant as an abnormal splicing variant that causes the deletion of Exon 5, which result in the observed disease phenotype. This case demonstrates the clinical phenotype of OI 22 associated with the c.492G > C (p. Leu164=) novel synonymous variation in the coding region of the CCDC134 gene in a female patient. This is the first reported case of OI 22 in the Chinese population, the sixth reported worldwide and the fourth reported genotype for diseases associated with a CCDC134 variant. It also enriches the global clinical phenotype spectrum of OI 22 patients.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142766904","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"WDFY3 Haploinsufficiency Is Associated With Autosomal Dominant Neurodevelopmental Disorders and Macrocephaly.","authors":"Ludovico Graziani, Miriam Lucia Carriero, Valentina Ferradini, Chiara Conte, Mario Bengala, Federica Carla Sangiuolo, Giuseppe Novelli","doi":"10.1111/cge.14665","DOIUrl":"https://doi.org/10.1111/cge.14665","url":null,"abstract":"<p><p>WDFY3 (MIM#617485) defects may manifest neurodevelopmental disorders (NDDs) and opposite effects on brain size based on allelic effect. This case highlights a heterozygous WDFY3 nonsense variant linked to mild-to-moderate NDDs, macrocephaly, and unique facial features. Findings emphasize the importance of exome sequencing in NDDs for accurate diagnosis and clinical management.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142754762","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unique Genetic Profiles in Hypertrophic Cardiomyopathy Patients From São Miguel Island (Azores, Portugal).","authors":"Fabiana Duarte, Luís Oliveira, Márcia Baixia, Luísa Mota-Vieira, Carina Machado","doi":"10.1111/cge.14656","DOIUrl":"https://doi.org/10.1111/cge.14656","url":null,"abstract":"<p><p>To investigate the clinical features and mutational spectrum underlying hypertrophic cardiomyopathy (HCM) in São Miguel Island (Azores, Portugal), we analyzed 37 adult patients (12 sporadic, 25 familial) with positive genetic tests. Seven disease-causing variants were identified, being two novels, in three sarcomeric genes (MYH7, TNNT2, and MYBPC3) and one non-sarcomeric gene (ALPK3). The novel variants, classified as likely pathogenic (LP), involved large multi-exon deletions in MYBPC3 (exons 26-32 and 28-33). These deletions were found in heterozygosity in two young males who remained clinically stable, though early onset may predict a more severe prognosis. Segregation analysis in a consanguineous family revealed two new genotypes: a digenic heterozygous for MYH7:c.1750G>C (p.Gly584Arg; P) and TNNT2:c.842A>T (p.Asn281Ile; LP) variants, and a homozygous for the TNNT2 variant. The 70-year-old homozygous patient remained stable and without arrhythmic events, challenging the belief that homozygous variants have a worse prognosis. This study is the first molecular and clinical analysis of HCM in the Azores.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142738665","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the Cognitive and Behavioral Aspects of Shprintzen-Goldberg Syndrome; a Novel Cohort and Literature Review.","authors":"Emilie Sjøstrøm, Ange-Line Bruel, Christophe Philippe, Julian Delanne, Laurence Faivre, Leonie A Menke, P Y Billie Au, Jessica Jane Cormick, Shahida Moosa, Allan Bayat","doi":"10.1111/cge.14646","DOIUrl":"https://doi.org/10.1111/cge.14646","url":null,"abstract":"<p><p>Shprintzen-Goldberg-syndrome (SGS) is caused by pathogenic exon 1 variants of SKI. Symptoms include dysmorphic features, skeletal and cardiovascular comorbidities, and cognitive and developmental impairments. We delineated the neurodevelopmental and behavioral features of SGS, as they are not well-documented. We collected physician-reported data of people with molecularly confirmed SGS through an international collaboration. We identified and deep-phenotyped the neurodevelopmental and behavioral features in four patients. Within our cohort, all exhibited developmental delays in motor skills and/or speech, with the average age of first words at 2 years and 6 months and independent walking at 3 years and 5 months. All four had learning disabilities and difficulties regulating emotions and behavior. Intellectual disability, ranging from borderline to moderate, was present in all four participants. Moreover, we reviewed the literature and identified 52 additional people with SGS, and summarized the features across both datasets. Mean age was 23 years (9-48 years). When combining our cohort and reported cases, we found that 80% (45/56) had developmental and/or cognitive impairment, with the remainder having normal intelligence. Our study elucidates the developmental, cognitive, and behavioral features in participants with SGS and contributes to a better understanding of this rare condition.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142726573","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The p.(Gly111Arg) ABCC8 Variant: A Founder Mutation Causing Congenital Hyperinsulinism in the Indian Agarwal Community.","authors":"Vandana Jain, Venkatesan Radha, Viswanathan Mohan, Matthew N Wakeling, Jasmin J Bennett, Sarah E Flanagan","doi":"10.1111/cge.14657","DOIUrl":"https://doi.org/10.1111/cge.14657","url":null,"abstract":"<p><p>Loss-of-function ABCC8 variants are the commonest cause of congenital hyperinsulinism. On a systematic search of our databases, the p.(Gly111Arg) ABCC8 variant was identified in 26 individuals, of which 23 were from the Indian Agarwal community. Haplotype analysis subsequently confirmed that p.(Gly111Arg) is a founder variant in the Agarwal population.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142726577","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Skipping of Exon 20 in EP300: A Novel Variant Linked to Rubinstein-Taybi Syndrome With Atypical and Severe Clinical Manifestations.","authors":"Lisa Pavinato, Silvia Carestiato, Slavica Trajkova, Lorena Sorasio, Giovanna Mantovani, Luisa De Sanctis, Jennifer Kerkhof, Haley, Jessica Rzasa, Emily Todd, Maria Balzo, Simona Cardaropoli, Alessandro Bruselles, Silvia De Rubeis, Joseph D Buxbaum, Marco Tartaglia, Bekim Sadikovic, Giovanni Battista Ferrero, Alfredo Brusco","doi":"10.1111/cge.14654","DOIUrl":"https://doi.org/10.1111/cge.14654","url":null,"abstract":"<p><p>Rubinstein-Taybi syndrome (RSTS) is a rare autosomal dominant neurodevelopmental disorder linked to haploinsufficiency of CREBBP (RSTS1) and EP300 (RSTS2) genes. Characteristic features often include distinctive facial traits, broad thumbs and toes, short stature, and various degrees of intellectual disability. The clinical presentation of RSTS is notably variable, making it challenging to establish a clear genotype-phenotype correlation, except for specific variants which cause the allelic Menke-Hennekam syndrome. Trio exome analysis, data collection via networking and GeneMatcher platforms, transcript processing analysis, and DNA methylation profiling were performed. We identified two unrelated patients with de novo variants in EP300 (NM_001429.4: c.3671+5G>C; c.3671+5_3671+8delGTAA) predicted to cause in-frame exon 20 skipping, confirmed in one patient. In silico 3D protein modeling suggested that exon 20 deletion (comprising 27 amino acids) likely alters the structural conformation between the RING_CBP-p300 and HAT-KAT11 domains. Clinically, both patients displayed severe RSTS2-like clinical features, including autism spectrum disorder, speech delay, hearing loss, microcephaly, developmental delay, and intellectual disability, alongside ocular, respiratory, and cardiovascular abnormalities. Additionally, one patient developed early-onset colorectal cancer. DNA methylation profiling in Subject #1 confirmed RSTS but did not align with the specific episignatures for RSTS1 or RSTS2. We propose that skipping of exon 20 in EP300 is associated with a distinct form of Rubinstein-Taybi syndrome featuring clinical characteristics not fully aligning with RSTS1 or RSTS2. Our findings increase the understanding of RSTS genetic and molecular basis and stress the need for further research to establish definitive genotype-phenotype correlations.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142738664","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}