Clinical Genetics最新文献

{"title":"Bi-allelic variants in MYH3 cause recessively-inherited arthrogryposis","authors":"Burcin Morali,&nbsp;Valancy Miranda,&nbsp;John Raelson,&nbsp;Guy Grimard,&nbsp;Peter Glavas,&nbsp;François Audibert,&nbsp;Nicolas A. Dumont,&nbsp;Julia Barone,&nbsp;Michael Bamshad,&nbsp;Emmanuelle Lemyre,&nbsp;Philippe M. Campeau","doi":"10.1111/cge.14570","DOIUrl":"10.1111/cge.14570","url":null,"abstract":"<p>Arthrogryposis is a clinical feature defined by congenital joint contractures in two or more different body areas which occurs in between 1/3000 and 1/5000 live births. Variants in multiple genes have been associated with distal arthrogryposis syndromes. Heterozygous variants in <i>MYH3</i> have been identified to cause the dominantly-inherited distal arthrogryposis conditions, Freeman–Sheldon syndrome, Sheldon–Hall syndrome, and multiple pterygium syndrome. In contrast, <i>MYH3</i> variants underlie both dominantly and recessively inherited Contractures, Pterygia, and Spondylocarpotarsal Fusion syndromes (CPSFS) which are characterized by extensive bony abnormalities in addition to congenital contractures. Here we report two affected sibs with distal arthrogryposis born to unaffected, distantly related parents. Sequencing revealed that both sibs were homozygous for two ultra-rare <i>MYH3</i> variants, c.3445G&gt;A (p.Glu1149Lys) and c.4760T&gt;C (p.Leu1587Pro). Sequencing and deletion/duplication analysis of 169 other arthrogryposis genes yielded no other compelling candidate variants. This is the first report of biallelic variants in <i>MYH3</i> being implicated in a distal arthrogryposis phenotype without the additional features of CPSFS. Thus, akin to CPSFS, both dominant and recessively inherited distal arthrogryposis can be caused by variants in <i>MYH3</i>.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":"106 4","pages":"483-487"},"PeriodicalIF":2.9,"publicationDate":"2024-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cge.14570","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141295670","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel molecular, structural and clinical findings in an Italian cohort of congenital cataract","authors":"Mauro Lecca,&nbsp;Lucia Mauri,&nbsp;Simone Gana,&nbsp;Alessandra Del Longo,&nbsp;Federica Morelli,&nbsp;Roberta Nicotra,&nbsp;Massimo Plumari,&nbsp;Jessica Galli,&nbsp;Fabio Sirchia,&nbsp;Enza Maria Valente,&nbsp;Ugo Cavallari,&nbsp;Marco Mazza,&nbsp;Sabrina Signorini,&nbsp;Edoardo Errichiello","doi":"10.1111/cge.14568","DOIUrl":"10.1111/cge.14568","url":null,"abstract":"<p>The current genetic diagnostic workup of congenital cataract (CC) is mainly based on NGS panels, whereas exome sequencing (ES) has occasionally been employed. In this multicentre study, we investigated by ES the detection yield, mutational spectrum and genotype–phenotype correlations in a CC cohort recruited between 2020 and mid-2022. The cohort consisted of 67 affected individuals from 51 unrelated families and included both non-syndromic (75%) and syndromic (25%) phenotypes, with extra-CC ocular/visual features present in both groups (48% and 76%, respectively). The functional effect of variants was predicted by 3D modelling and hydropathy properties changes. Variant clustering was used for the in-depth assessment of genotype–phenotype correlations. A diagnostic (pathogenic or likely pathogenic) variant was identified in 19 out of 51 probands/families (~37%). In a further 14 probands/families a candidate variant was identified: in 12 families a VUS was detected, of which 9 were considered plausibly pathogenic (i.e., 4 or 5 points according to ACMG criteria), while in 2 probands ES identified a single variant in an autosomal recessive gene associated with CC. Eighteen probands/families, manifesting primarily non-syndromic CC (15/18, 83%), remained unsolved. The identified variants (8 P, 12 LP, 10 VUS-PP, and 5 VUS), half of which were unreported in the literature, affected five functional categories of genes involved in transcription/splicing, lens formation/homeostasis (i.e., crystallin genes), membrane signalling, cell–cell interaction, and immune response. A phenotype-specific variant clustering was observed in four genes (<i>KIF1A, MAF</i>, <i>PAX6</i>, <i>SPTAN1</i>), whereas variable expressivity and potential phenotypic expansion in two (<i>BCOR</i>, <i>NHS</i>) and five genes (<i>CWC27</i>, <i>KIF1A</i>, <i>IFIH1, PAX6</i>, <i>SPTAN1</i>), respectively. Finally, ES allowed to detect variants in six genes not commonly included in commercial CC panels. These findings broaden the genotype–phenotype correlations in one of the largest CC cohorts tested by ES, providing novel insights into the underlying pathogenetic mechanisms and emphasising the power of ES as first-tier test.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":"106 4","pages":"403-412"},"PeriodicalIF":2.9,"publicationDate":"2024-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cge.14568","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141260917","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The impact of the European Society of Cardiology guidelines and whole exome sequencing on genetic testing in hereditary cardiac diseases","authors":"Catia Mio,&nbsp;Jessica Zucco,&nbsp;Dora Fabbro,&nbsp;Elisa Bregant,&nbsp;Federica Baldan,&nbsp;Lorenzo Allegri,&nbsp;Angela Valentina D'Elia,&nbsp;Valentino Collini,&nbsp;Massimo Imazio,&nbsp;Giuseppe Damante,&nbsp;Flavio Faletra","doi":"10.1111/cge.14569","DOIUrl":"10.1111/cge.14569","url":null,"abstract":"<p>In the last decade, an incredible improvement has been made in elucidating the genetic bases of cardiomyopathies. Here we report the impact of either the European Society of Cardiology (ESC) guidelines or the use of whole exome sequencing (WES) in terms of a number of variants of uncertain significance (VUS) and missed diagnoses in a series of 260 patients affected by inherited cardiac disorders. Samples were analyzed using a targeted gene panel of 128 cardiac-related genes and/or WES in a subset of patients, with a three-tier approach. Analyzing (i) only a subset of genes related to the clinical presentation, strictly following the ESC guidelines, 20.77% positive test were assessed. The incremental diagnostic rate for (ii) the whole gene panel, and (iii) the WES was 4.71% and 11.67%, respectively. The diverse analytical approaches increased the number of VUSs and incidental findings. Indeed, the use of WES highlights that there is a small percentage of syndromic conditions that standard analysis would not have detected. Moreover, the use of targeted sequencing coupled with “narrow” analytical approach prevents the detection of variants in actionable genes that could allow for preventive treatment. Our data suggest that genetic testing might aid clinicians in the diagnosis of inheritable cardiac disorders.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":"106 4","pages":"394-402"},"PeriodicalIF":2.9,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cge.14569","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141260973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"B-cell immune deficiency in twin sisters expands the phenotype of MOPDI","authors":"Lucas W. Gauthier,&nbsp;Morgane Gossez,&nbsp;Christophe Malcus,&nbsp;Sébastien Viel,&nbsp;Guillaume Monneret,&nbsp;Remy Bordonné,&nbsp;Linda Pons,&nbsp;Sara Cabet,&nbsp;Marion Delous,&nbsp;Sylvie Mazoyer,&nbsp;Audrey Putoux,&nbsp;Patrick Edery","doi":"10.1111/cge.14571","DOIUrl":"10.1111/cge.14571","url":null,"abstract":"<p>Microcephalic osteodysplastic primordial dwarfism type I (MOPDI) is a very rare and severe autosomal recessive disorder characterized by marked intrauterine growth retardation, skeletal dysplasia, microcephaly and brain malformations. MOPDI is caused by biallelic mutations in <i>RNU4ATAC</i>, a non-coding gene involved in U12-type splicing of 1% of the introns in the genome, which are recognized by their specific splicing consensus sequences. Here, we describe a unique observation of immunodeficiency in twin sisters with mild MOPDI, who harbor a novel n.108_126del mutation, encompassing part of the U4atac snRNA 3′ stem-loop and Sm protein binding site, and the previously reported n.111G&gt;A mutation. Interestingly, both twin sisters show mild B-cell anomalies, including low naive B-cell counts and increased memory B-cell and plasmablasts counts, suggesting partial and transitory blockage of B-cell maturation and/or excessive activation of naive B-cells. Hence, the localization of a mutation in stem II of U4atac snRNA, as observed in another <i>RNU4ATAC</i>-opathy with immunodeficiency, that is, Roifman syndrome (RFMN), is not required for the occurrence of an immune deficiency. Finally, we emphasize the importance of considering immunodeficiency in MOPDI management to reduce the risk of serious infectious episodes.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":"106 4","pages":"476-482"},"PeriodicalIF":2.9,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cge.14571","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141260915","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SERPINA11 related novel serpinopathy – A perinatal lethal disorder","authors":"Shagun Aggarwal,&nbsp;Venugopal Satidevi Vineeth,&nbsp;Shrutika S. Padwal,&nbsp;Sameer Ahmed Bhat,&nbsp;Arpita Singh,&nbsp;Aditya Kulkarni,&nbsp;Mallikarjun Patil,&nbsp;Karthik Tallapaka,&nbsp;Divya Pasumarthi,&nbsp;Vijayasree Venkatapuram,&nbsp;Pragna Lakshmi Thotakura,&nbsp;Ashwin Dalal,&nbsp;Rashna Bhandari","doi":"10.1111/cge.14564","DOIUrl":"10.1111/cge.14564","url":null,"abstract":"<p><i>SERPINA11</i> is a hitherto poorly characterised gene belonging to Clade A of the SERPIN superfamily, with unknown expression pattern and functional significance. We report a perinatal lethal phenotype in two foetuses from the same family associated with a biallelic loss of function variant in <i>SERPINA11</i>, and provide functional evidence to support its candidature as a Mendelian disorder. The <i>SERPINA11</i> variant-associated foetal phenotype is characterised by gross and histopathological features of extracellular matrix disruption. Western blot and immunofluorescence analyses revealed SERPINA11 expression in multiple mouse tissues, with pronounced expression in the bronchiolar epithelium. We observed a significant decrease in SERPINA11 immunofluorescence in the affected foetal lung compared with a healthy gestation-matched foetus. Protein expression data from HEK293T cell lines following site-directed mutagenesis support the loss of function nature of the variant. Transcriptome analysis from the affected foetal liver indicated the possibility of reduced <i>SERPINA11</i> transcript abundance. This novel serpinopathy appears to be a consequence of the loss of inhibition of serine proteases involved in extracellular matrix remodelling, revealing SERPINA11 as a protease inhibitor critical for embryonic development.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":"106 3","pages":"367-373"},"PeriodicalIF":2.9,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141237511","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 significance of carrying MEFV variants in symptomatic and asymptomatic individuals","authors":"Eldad Ben-Chetrit,&nbsp;Isabelle Touitou","doi":"10.1111/cge.14566","DOIUrl":"10.1111/cge.14566","url":null,"abstract":"<p>Familial Mediterranean fever (FMF) is an autoinflammatory disease characterized by recurrent attacks of fever, serositis (peritonitis, pleuritis, or synovitis), and erysipelas-like erythema. Genetic variants in the <i>MEFV</i> gene are associated with this disease. Familial Mediterranean fever is considered an autosomal recessive disease. However, in Middle Eastern countries, a third of the patients expressing FMF manifestations, carry a single mutation only. Moreover, some cases of pure dominant inheritance linked to specific single <i>MEFV</i> variants have also been described. This complex inheritance of <i>MEFV</i>-associated inflammatory diseases poses a serious challenge when interpreting the results of genetic testing in patients having recurrent fever syndromes. In addition, in certain situations, asymptomatic individuals may be incidentally found to carry <i>MEFV</i> variants. These cases pose the question of their exact diagnosis and whether they should be treated. Previous studies have focused on genetic results interpretations among symptomatic patients. In the current article, we would like to elaborate on the genetic interpretation in cases of symptomatic individuals suspected to have FMF and on asymptomatic individuals carrying <i>MEFV</i> variants. We aim to assist physicians unfamiliar with FMF to cope with genetic results interpretation when facing symptomatic and asymptomatic individuals carrying <i>MEFV</i> variants and suggest a management plan accordingly.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":"106 3","pages":"217-223"},"PeriodicalIF":2.9,"publicationDate":"2024-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cge.14566","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141179229","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel biallelic PISD missense variants cause spondyloepimetaphyseal dysplasia with disproportionate short stature and fragmented mitochondrial morphology","authors":"Line Aagaard Nolting,&nbsp;Tess Holling,&nbsp;Gen Nishimura,&nbsp;Jakob Ek,&nbsp;Mads Bak,&nbsp;Merete Ljungberg,&nbsp;Kerstin Kutsche,&nbsp;Hanne Hove","doi":"10.1111/cge.14549","DOIUrl":"10.1111/cge.14549","url":null,"abstract":"<p>Biallelic variants in <i>PISD</i> cause a phenotypic spectrum ranging from short stature with spondyloepimetaphyseal dysplasia (SEMD) to a multisystem disorder affecting eyes, ears, bones, and brain. <i>PISD</i> encodes the mitochondrial-localized enzyme phosphatidylserine decarboxylase. The PISD precursor is self-cleaved to generate a heteromeric mature enzyme that converts phosphatidylserine to the phospholipid phosphatidylethanolamine. We describe a 17-year-old male patient, born to unrelated healthy parents, with disproportionate short stature and SEMD, featuring platyspondyly, prominent epiphyses, and metaphyseal dysplasia. Trio genome sequencing revealed compound heterozygous <i>PISD</i> variants c.569C&gt;T; p.(Ser190Leu) and c.799C&gt;T; p.(His267Tyr) in the patient. Investigation of fibroblasts showed similar levels of the PISD precursor protein in both patient and control cells. However, patient cells had a significantly higher proportion of fragmented mitochondria compared to control cells cultured under basal condition and after treatment with 2-deoxyglucose that represses glycolysis and stimulates respiration. Structural data from the PISD orthologue in <i>Escherichia coli</i> suggest that the amino acid substitutions Ser190Leu and His267Tyr likely impair PISD's autoprocessing activity and/or phosphatidylethanolamine biosynthesis. Based on the data, we propose that the novel <i>PISD</i> p.(Ser190Leu) and p.(His267Tyr) variants likely act as hypomorphs and underlie the pure skeletal phenotype in the patient.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":"106 3","pages":"360-366"},"PeriodicalIF":2.9,"publicationDate":"2024-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cge.14549","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141154418","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biallelic FANCA variants detected in sisters with isolated premature ovarian insufficiency","authors":"Elena J. Tucker,&nbsp;Michael F. Sharp,&nbsp;Anna Lokchine,&nbsp;Katrina M. Bell,&nbsp;Catherine S. Palmer,&nbsp;Brianna L. Kline,&nbsp;Gorjana Robevska,&nbsp;Jocelyn van den Bergen,&nbsp;Jérôme Dulon,&nbsp;Diana Stojanovski,&nbsp;Katie L. Ayers,&nbsp;Philippe Touraine,&nbsp;Wayne Crismani,&nbsp;Sylvie Jaillard,&nbsp;Andrew H. Sinclair","doi":"10.1111/cge.14543","DOIUrl":"10.1111/cge.14543","url":null,"abstract":"<p>Premature ovarian insufficiency is a common form of female infertility affecting up to 4% of women and characterised by amenorrhea with elevated gonadotropin before the age of 40. Oocytes require controlled DNA breakage and repair for homologous recombination and the maintenance of oocyte integrity. Biallelic disruption of the DNA damage repair gene, <i>Fanconi anemia complementation group A</i> (<i>FANCA)</i>, is a common cause of Fanconi anaemia, a syndrome characterised by bone marrow failure, cancer predisposition, physical anomalies and POI. There is ongoing dispute about the role of heterozygous <i>FANCA</i> variants in POI pathogenesis, with insufficient evidence supporting causation. Here, we have identified biallelic <i>FANCA</i> variants in French sisters presenting with POI, including a novel missense variant of uncertain significance and a likely pathogenic deletion that initially evaded detection. Functional studies indicated no discernible effect on DNA damage sensitivity in patient lymphoblasts. These novel <i>FANCA</i> variants add evidence that heterozygous loss of one allele is insufficient to cause DNA damage sensitivity and POI. We propose that intragenic deletions, that are relatively common in <i>FANCA</i>, may be missed without careful analysis, and could explain the presumed causation of heterozygous variants. Accurate variant curation is critical to optimise patient care and outcomes.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":"106 3","pages":"321-335"},"PeriodicalIF":2.9,"publicationDate":"2024-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cge.14543","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141080748","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Copy number variants at 4q31.3 affecting the regulatory region of FBXW7 associated with neurodevelopmental delay","authors":"Wei Zhou,&nbsp;Chunli Wang,&nbsp;Luhan Fu,&nbsp;Wei Shi,&nbsp;Aihua Zhang,&nbsp;Zhanjun Jia,&nbsp;Xiaoke Zhao,&nbsp;Dalin Fu,&nbsp;Bixia Zheng","doi":"10.1111/cge.14548","DOIUrl":"10.1111/cge.14548","url":null,"abstract":"<p>Emerging research has demonstrated that genomic alterations disrupting topologically associated domains (TADs) and chromatin interactions underlie the pathogenic mechanisms of specific copy number variants (CNVs) in neurodevelopmental disorders. We report two patients with a de novo deletion and a duplication in chromosome 4q31, potentially causing FBX-related neurodevelopmental syndrome by affecting the regulatory region of <i>FBXW7</i>. High-throughput chromosome conformation capture (Hi-C) analysis using available capture data in neural progenitor cells revealed the rewiring of the TAD boundary close to <i>FBXW7</i>. Both patients exhibited facial dysmorphisms, cardiac and limb abnormalities, and neurodevelopmental delays, showing significant clinical overlap with previously reported FBXW7-related features. We also included an additional 10 patients with CNVs in the 4q31 region from the literature and the DECIPHER database for Hi-C analysis, which confirmed that disruption of the regulatory region of FBXW7 likely contributes to the developmental defects observed in these patients.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":"106 3","pages":"354-359"},"PeriodicalIF":2.9,"publicationDate":"2024-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141080810","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":"Clinical and genetic investigation of 14 families with various forms of short stature syndromes","authors":"Fati Ullah Khan,&nbsp;Hammal Khan,&nbsp;Kifayat Ullah,&nbsp;Shoaib Nawaz,&nbsp; Abdullah,&nbsp;Muhammad Javed Khan,&nbsp;Sohail Ahmed,&nbsp;Muhammad Ilyas,&nbsp;Amjad Ali,&nbsp;Imran Ullah,&nbsp;Aamir Sohail,&nbsp;Shabir Hussain,&nbsp;Farooq Ahmad,&nbsp; Faisal,&nbsp;Raza Sufyan,&nbsp;Amir Hayat,&nbsp;Tooba Hanif,&nbsp;Fatima Bibi,&nbsp;Maria Hayat,&nbsp;Rehmat Ullah,&nbsp;Inam Ullah Khan,&nbsp;Raja Hussain Ali,&nbsp;Muhammad Sharif Hasni,&nbsp;Hamid Ali,&nbsp;Muhammad Bilal,&nbsp;Susana Peralta,&nbsp;Rebecca Buchert,&nbsp;Zamrud Zehri,&nbsp;Gul Hassan,&nbsp;Khurrum Liaqat,&nbsp;Muhammad Zahid,&nbsp;Khadim Shah,&nbsp;Outi Mikitie,&nbsp;Tobias B. Haack,&nbsp;Weizhen Ji,&nbsp;Saquib A. Lakhani,&nbsp;Muhammad Ansar,&nbsp;Wasim Ahmad","doi":"10.1111/cge.14550","DOIUrl":"10.1111/cge.14550","url":null,"abstract":"<p>Skeletal dysplasias are a heterogeneous group of disorders presenting mild to lethal defects. Several factors, such as genetic, prenatal, and postnatal environmental may contribute to reduced growth. Fourteen families of Pakistani origin, presenting the syndromic form of short stature either in the autosomal recessive or autosomal dominant manner were clinically and genetically investigated to uncover the underlying genetic etiology. Homozygosity mapping, whole exome sequencing, and Sanger sequencing were used to search for the disease-causing gene variants. In total, we have identified 13 sequence variants in 10 different genes. The variants in the <i>HSPG2</i> and <i>XRCC4</i> genes were not reported previously in the Pakistani population. This study will expand the mutation spectrum of the identified genes and will help in improved diagnosis of the syndromic form of short stature in the local population.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":"106 3","pages":"347-353"},"PeriodicalIF":2.9,"publicationDate":"2024-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141075539","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}