Human Mutation最新文献

{"title":"Genetic characterization of 1210 Japanese pedigrees with inherited retinal diseases by whole-exome sequencing","authors":"Akiko Suga,&nbsp;Kazutoshi Yoshitake,&nbsp;Naoko Minematsu,&nbsp;Kazushige Tsunoda,&nbsp;Kaoru Fujinami,&nbsp;Yozo Miyake,&nbsp;Kazuki Kuniyoshi,&nbsp;Takaaki Hayashi,&nbsp;Kei Mizobuchi,&nbsp;Shinji Ueno,&nbsp;Hiroko Terasaki,&nbsp;Taro Kominami,&nbsp;Nobuhisa Nao-I,&nbsp;Go Mawatari,&nbsp;Atsushi Mizota,&nbsp;Kei Shinoda,&nbsp;Mineo Kondo,&nbsp;Kumiko Kato,&nbsp;Tetsuju Sekiryu,&nbsp;Makoto Nakamura,&nbsp;Sentaro Kusuhara,&nbsp;Hiroyuki Yamamoto,&nbsp;Shuji Yamamoto,&nbsp;Kiyofumi Mochizuki,&nbsp;Hiroyuki Kondo,&nbsp;Itsuka Matsushita,&nbsp;Shuhei Kameya,&nbsp;Takeo Fukuchi,&nbsp;Tetsuhisa Hatase,&nbsp;Masayuki Horiguchi,&nbsp;Yoshiaki Shimada,&nbsp;Atsuhiro Tanikawa,&nbsp;Shuichi Yamamoto,&nbsp;Gen Miura,&nbsp;Nana Ito,&nbsp;Akira Murakami,&nbsp;Takuro Fujimaki,&nbsp;Yoshihiro Hotta,&nbsp;Koji Tanaka,&nbsp;Takeshi Iwata","doi":"10.1002/humu.24492","DOIUrl":"10.1002/humu.24492","url":null,"abstract":"<p>Inherited retinal diseases (IRDs) comprise a phenotypically and genetically heterogeneous group of ocular disorders that cause visual loss via progressive retinal degeneration. Here, we report the genetic characterization of 1210 IRD pedigrees enrolled through the Japan Eye Genetic Consortium and analyzed by whole exome sequencing. The most common phenotype was retinitis pigmentosa (RP, 43%), followed by macular dystrophy/cone- or cone-rod dystrophy (MD/CORD, 13%). In total, 67 causal genes were identified in 37% (448/1210) of the pedigrees. The first and second most frequently mutated genes were <i>EYS</i> and <i>RP1</i>, associated primarily with autosomal recessive (ar) RP, and RP and arMD/CORD, respectively. Examinations of variant frequency in total and by phenotype showed high accountability of a frequent <i>EYS</i> missense variant (c.2528G&gt;A). In addition to the two known <i>EYS</i> founder mutations (c.4957dupA and c.8805C&gt;G) of arRP, we observed a frequent <i>RP1</i> variant (c.5797C&gt;T) in patients with arMD/CORD.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"43 12","pages":"2251-2264"},"PeriodicalIF":3.9,"publicationDate":"2022-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10626803","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":"SPiP: Splicing Prediction Pipeline, a machine learning tool for massive detection of exonic and intronic variant effects on mRNA splicing","authors":"Raphaël Leman,&nbsp;Béatrice Parfait,&nbsp;Dominique Vidaud,&nbsp;Emmanuelle Girodon,&nbsp;Laurence Pacot,&nbsp;Gérald Le Gac,&nbsp;Chandran Ka,&nbsp;Claude Ferec,&nbsp;Yann Fichou,&nbsp;Céline Quesnelle,&nbsp;Camille Aucouturier,&nbsp;Etienne Muller,&nbsp;Dominique Vaur,&nbsp;Laurent Castera,&nbsp;Flavie Boulouard,&nbsp;Agathe Ricou,&nbsp;Hélène Tubeuf,&nbsp;Omar Soukarieh,&nbsp;Pascaline Gaildrat,&nbsp;Florence Riant,&nbsp;Marine Guillaud-Bataille,&nbsp;Sandrine M. Caputo,&nbsp;Virginie Caux-Moncoutier,&nbsp;Nadia Boutry-Kryza,&nbsp;Françoise Bonnet-Dorion,&nbsp;Ines Schultz,&nbsp;Maria Rossing,&nbsp;Olivier Quenez,&nbsp;Louis Goldenberg,&nbsp;Valentin Harter,&nbsp;Michael T. Parsons,&nbsp;Amanda B. Spurdle,&nbsp;Thierry Frébourg,&nbsp;Alexandra Martins,&nbsp;Claude Houdayer,&nbsp;Sophie Krieger","doi":"10.1002/humu.24491","DOIUrl":"10.1002/humu.24491","url":null,"abstract":"<p>Modeling splicing is essential for tackling the challenge of variant interpretation as each nucleotide variation can be pathogenic by affecting pre-mRNA splicing via disruption/creation of splicing motifs such as 5′/3′ splice sites, branch sites, or splicing regulatory elements. Unfortunately, most in silico tools focus on a specific type of splicing motif, which is why we developed the Splicing Prediction Pipeline (SPiP) to perform, in one single bioinformatic analysis based on a machine learning approach, a comprehensive assessment of the variant effect on different splicing motifs. We gathered a curated set of 4616 variants scattered all along the sequence of 227 genes, with their corresponding splicing studies. The Bayesian analysis provided us with the number of control variants, that is, variants without impact on splicing, to mimic the deluge of variants from high-throughput sequencing data. Results show that SPiP can deal with the diversity of splicing alterations, with 83.13% sensitivity and 99% specificity to detect spliceogenic variants. Overall performance as measured by area under the receiving operator curve was 0.986, better than SpliceAI and SQUIRLS (0.965 and 0.766) for the same data set. SPiP lends itself to a unique suite for comprehensive prediction of spliceogenicity in the genomic medicine era. SPiP is available at: https://sourceforge.net/projects/splicing-prediction-pipeline/</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"43 12","pages":"2308-2323"},"PeriodicalIF":3.9,"publicationDate":"2022-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/humu.24491","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10571527","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":"TFIIH stabilization recovers the DNA repair and transcription dysfunctions in thermo-sensitive trichothiodystrophy","authors":"Manuela Lanzafame,&nbsp;Tiziana Nardo,&nbsp;Roberta Ricotti,&nbsp;Chiara Pantaleoni,&nbsp;Stefano D'Arrigo,&nbsp;Franco Stanzial,&nbsp;Francesco Benedicenti,&nbsp;Mary A. Thomas,&nbsp;Miria Stefanini,&nbsp;Donata Orioli,&nbsp;Elena Botta","doi":"10.1002/humu.24488","DOIUrl":"10.1002/humu.24488","url":null,"abstract":"<p>Trichothiodystrophy (TTD) is a rare hereditary disease whose prominent feature is brittle hair. Additional clinical signs are physical and neurodevelopmental abnormalities and in about half of the cases hypersensitivity to UV radiation. The photosensitive form of TTD (PS-TTD) is most commonly caused by mutations in the <i>ERCC2/XPD</i> gene encoding a subunit of the transcription/DNA repair complex TFIIH. Here we report novel <i>ERCC2/XPD</i> mutations affecting proper protein folding, which generate thermo-labile forms of XPD associated with thermo-sensitive phenotypes characterized by reversible aggravation of TTD clinical signs during episodes of fever. In patient cells, the newly identified XPD variants result in thermo-instability of the whole TFIIH complex and consequent temperature-dependent defects in DNA repair and transcription. Improving the protein folding process by exposing patient cells to low temperature or to the chemical chaperone glycerol allowed rescue of TFIIH thermo-instability and a concomitant recovery of the complex activities. Besides providing a rationale for the peculiar thermo-sensitive clinical features of these new cases, the present findings demonstrate how variations in the cellular concentration of mutated TFIIH impact the cellular functions of the complex and underlie how both quantitative and qualitative TFIIH alterations contribute to TTD clinical features.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"43 12","pages":"2222-2233"},"PeriodicalIF":3.9,"publicationDate":"2022-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10569708","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":"Using single molecule Molecular Inversion Probes as a cost-effective, high-throughput sequencing approach to target all genes and loci associated with macular diseases","authors":"Rebekkah J. Hitti-Malin,&nbsp;Claire-Marie Dhaenens,&nbsp;Daan M. Panneman,&nbsp;Zelia Corradi,&nbsp;Mubeen Khan,&nbsp;Anneke I. den Hollander,&nbsp;G. Jane Farrar,&nbsp;Christian Gilissen,&nbsp;Alexander Hoischen,&nbsp;Maartje van de Vorst,&nbsp;Femke Bults,&nbsp;Erica G. M. Boonen,&nbsp;Patrick Saunders,&nbsp;MD Study Group,&nbsp;Susanne Roosing,&nbsp;Frans P. M. Cremers","doi":"10.1002/humu.24489","DOIUrl":"10.1002/humu.24489","url":null,"abstract":"<p>Macular degenerations (MDs) are a subgroup of retinal disorders characterized by central vision loss. Knowledge is still lacking on the extent of genetic and nongenetic factors influencing inherited MD (iMD) and age-related MD (AMD) expression. Single molecule Molecular Inversion Probes (smMIPs) have proven effective in sequencing the <i>ABCA4</i> gene in patients with Stargardt disease to identify associated coding and noncoding variation, however many MD patients still remain genetically unexplained. We hypothesized that the missing heritability of MDs may be revealed by smMIPs-based sequencing of all MD-associated genes and risk factors. Using 17,394 smMIPs, we sequenced the coding regions of 105 iMD and AMD-associated genes and noncoding or regulatory loci, known pseudo-exons, and the mitochondrial genome in two test cohorts that were previously screened for variants in <i>ABCA4</i>. Following detailed sequencing analysis of 110 probands, a diagnostic yield of 38% was observed. This established an ‘‘MD-smMIPs panel,” enabling a genotype-first approach in a high-throughput and cost-effective manner, whilst achieving uniform and high coverage across targets. Further analysis will identify known and novel variants in MD-associated genes to offer an accurate clinical diagnosis to patients. Furthermore, this will reveal new genetic associations for MD and potential genetic overlaps between iMD and AMD.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"43 12","pages":"2234-2250"},"PeriodicalIF":3.9,"publicationDate":"2022-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/c6/70/HUMU-43-2234.PMC10092144.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9290067","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":"High-yield identification of pathogenic NF1 variants by skin fibroblast transcriptome screening after apparently normal diagnostic DNA testing","authors":"Hannie C. W. Douben,&nbsp;Mark Nellist,&nbsp;Leontine van Unen,&nbsp;Peter Elfferich,&nbsp;Esmee Kasteleijn,&nbsp;Marianne Hoogeveen-Westerveld,&nbsp;Jesse Louwen,&nbsp;Monique van Veghel-Plandsoen,&nbsp;Walter de Valk,&nbsp;Jasper J. Saris,&nbsp;Femke Hendriks,&nbsp;Esther Korpershoek,&nbsp;Lies H. Hoefsloot,&nbsp;Margreethe van Vliet,&nbsp;Yolande van Bever,&nbsp;Ingrid van de Laar,&nbsp;Emmelien Aten,&nbsp;Augusta M. A. Lachmeijer,&nbsp;Walter Taal,&nbsp;Lisa van den Bersselaar,&nbsp;Juliette Schuurmans,&nbsp;Rianne Oostenbrink,&nbsp;Rick van Minkelen,&nbsp;Yvette van Ierland,&nbsp;Tjakko J. van Ham","doi":"10.1002/humu.24487","DOIUrl":"10.1002/humu.24487","url":null,"abstract":"<p>Neurofibromatosis type 1 (NF1) is caused by inactivating mutations in <i>NF1</i>. Due to the size, complexity, and high mutation rate at the <i>NF1</i> locus, the identification of causative variants can be challenging. To obtain a molecular diagnosis in 15 individuals meeting diagnostic criteria for NF1, we performed transcriptome analysis (RNA-seq) on RNA obtained from cultured skin fibroblasts. In each case, routine molecular DNA diagnostics had failed to identify a disease-causing variant in <i>NF1</i>. A pathogenic variant or abnormal mRNA splicing was identified in 13 cases: 6 deep intronic variants and 2 transposon insertions causing noncanonical splicing, 3 postzygotic changes, 1 branch point mutation and, in 1 case, abnormal splicing for which the responsible DNA change remains to be identified. These findings helped resolve the molecular findings for an additional 17 individuals in multiple families with NF1, demonstrating the utility of skin-fibroblast-based transcriptome analysis for molecular diagnostics. RNA-seq improves mutation detection in NF1 and provides a powerful complementary approach to DNA-based methods. Importantly, our approach is applicable to other genetic disorders, particularly those caused by a wide variety of variants in a limited number of genes and specifically for individuals in whom routine molecular DNA diagnostics did not identify the causative variant.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"43 12","pages":"2130-2140"},"PeriodicalIF":3.9,"publicationDate":"2022-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/5b/07/HUMU-43-2130.PMC10099955.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9290065","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":"Revealing the functions of clonal driver gene mutations in patients based on evolutionary dependencies","authors":"Yujia Lan,&nbsp;Wei Liu,&nbsp;Xiaobo Hou,&nbsp;Shuai Wang,&nbsp;Hao Wang,&nbsp;Menglan Deng,&nbsp;Guiyu Wang,&nbsp;Yanyan Ping,&nbsp;Xinxin Zhang","doi":"10.1002/humu.24484","DOIUrl":"10.1002/humu.24484","url":null,"abstract":"<p>The clonal mutations in driver genes enable cells to gradually acquire growth advantage in tumor development. Therefore, revealing the functions of clonal driver gene mutations is important. Here, we proposed the method FCMP that considered evolutionary dependencies to analyze the functions of clonal driver gene mutations in a single patient. Applying our method to five cancer types from The Cancer Genome Atlas, we identified specific functions and common functions of clonal driver gene mutations. We found that the clonal driver gene mutations in the same patient played multiple functions. We also found that clonal mutations in the same driver gene performed different functions in different patients. These findings suggested that the clonal driver gene mutations showed strong tumor heterogeneity. In the pan-cancer analysis, the immune-related functions for clonal driver gene mutations were shared by multiple cancer types. In addition, clonal mutations in some driver genes predicted the survival of patients in cancers.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"43 12","pages":"2187-2204"},"PeriodicalIF":3.9,"publicationDate":"2022-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10569688","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":"MicroRNA binding site variation is enriched in psychiatric disorders","authors":"Michael P. Geaghan,&nbsp;William R. Reay,&nbsp;Murray J. Cairns","doi":"10.1002/humu.24481","DOIUrl":"10.1002/humu.24481","url":null,"abstract":"<p>Psychiatric disorders have a polygenic architecture, often associated with dozens or hundreds of independent genomic loci. Most associated loci impact noncoding regions of the genome, suggesting that the majority of disease heritability originates from the disruption of regulatory sequences. While most research has focused on variants that modify regulatory DNA elements, those affecting <i>cis</i>-acting RNA sequences, such as miRNA binding sites, are also likely to have a significant impact. We intersected genome-wide association study (GWAS) summary statistics with the dbMTS database of predictions for miRNA binding site variants (MBSVs). We compared the distributions of MBSV association statistics to non-MBSVs within brain-expressed 3′UTR regions. We aggregated GWAS <i>p</i> values at the gene, pathway, and miRNA family levels to investigate cellular functions and miRNA families strongly associated with each trait. We performed these analyses in several psychiatric disorders as well as nonpsychiatric traits for comparison. We observed significant enrichment of MBSVs in schizophrenia, depression, bipolar disorder, and anorexia nervosa, particularly in genes targeted by several miRNA families, including miR-335-5p, miR-21-5p/590-5p, miR-361-5p, and miR-557, and a nominally significant association between miR-323b-3p MBSVs and schizophrenia risk. We identified evidence for the association between MBSVs in synaptic gene sets in schizophrenia and bipolar disorder. We also observed a significant association of MBSVs in other complex traits including type 2 diabetes. These observations support the role of miRNA in the pathophysiology of psychiatric disorders and suggest that MBSVs are an important class of regulatory variants that have functional implications for many disorders, as well as other complex human traits.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"43 12","pages":"2153-2169"},"PeriodicalIF":3.9,"publicationDate":"2022-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/humu.24481","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10569685","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":"Front Cover, Volume 43, Issue 11","authors":"Stuart A. Scott,&nbsp;Kai Wang,&nbsp;Nancy B. Spinner","doi":"10.1002/humu.24485","DOIUrl":"10.1002/humu.24485","url":null,"abstract":"<p><b>Front Cover</b>: Image design credit: Shiva Ganesan, Laura K. Conlin, and Ramakrishnan Rajagopalan. The cover image is based on the Editorial Introduction <i>Human Mutation special issue on innovations in genomic diagnostics</i> by Stuart A. Scott et al., https://doi.org/10.1002/humu.24474.\u0000\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"43 11","pages":"i"},"PeriodicalIF":3.9,"publicationDate":"2022-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/humu.24485","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45378894","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":"Specifications of the ACMG/AMP variant curation guidelines for myocilin: Recommendations from the clingen glaucoma expert panel","authors":"Kathryn P. Burdon,&nbsp;Patricia Graham,&nbsp;Johanna Hadler,&nbsp;John D. Hulleman,&nbsp;Francesca Pasutto,&nbsp;Erin A. Boese,&nbsp;Jamie E. Craig,&nbsp;John H. Fingert,&nbsp;Alex W. Hewitt,&nbsp;Owen M. Siggs,&nbsp;Kristina Whisenhunt,&nbsp;Terri L. Young,&nbsp;David A. Mackey,&nbsp;Andrew Dubowsky,&nbsp;Emmanuelle Souzeau","doi":"10.1002/humu.24482","DOIUrl":"10.1002/humu.24482","url":null,"abstract":"<p>The standardization of variant curation criteria is essential for accurate interpretation of genetic results and clinical care of patients. The variant curation guidelines developed by the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) in 2015 are widely used but are not gene specific. To address this issue, the Clinical Genome Resource (ClinGen) Variant Curation Expert Panels (VCEP) have been tasked with developing gene-specific variant curation guidelines. The Glaucoma VCEP was created to develop rule specifications for genes associated with primary glaucoma, including <i>myocilin</i> (<i>MYOC</i>), the most common cause of Mendelian glaucoma. Of the 28 ACMG/AMP criteria, the Glaucoma VCEP adapted 15 rules to <i>MYOC</i> and determined 13 rules not applicable. Key specifications included determining minor allele frequency thresholds, developing an approach to counting probands and segregations, and reviewing functional assays. The rules were piloted on 81 variants and led to a change in classification in 40% of those that were classified in ClinVar, with functional evidence influencing the classification of 18 variants. The standardized variant curation guidelines for <i>MYOC</i> provide a framework for the consistent application of the rules between laboratories, to improve <i>MYOC</i> genetic testing in the management of glaucoma.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"43 12","pages":"2170-2186"},"PeriodicalIF":3.9,"publicationDate":"2022-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9771967/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10569686","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":"Biallelic ADAMTSL4 variants in a Chinese cohort of congenital ectopia lentis: Implications for genotype–phenotype relationships","authors":"Ze-Xu Chen,&nbsp;Wan-Nan Jia,&nbsp;Yang Sun,&nbsp;Tian-Hui Chen,&nbsp;Zhen-Nan Zhao,&nbsp;Li-Na Lan,&nbsp;Yan Liu,&nbsp;Ling-Hao Song,&nbsp;Yong-Xiang Jiang","doi":"10.1002/humu.24483","DOIUrl":"10.1002/humu.24483","url":null,"abstract":"<p><i>ADAMTSL4</i> variants are one of the common causes of congenital ectopia lentis (EL), reported ocular comorbidities of which include iris anomalies, cataract, and glaucoma. However, a genotype–phenotype correlation has not been established. Potentially pathogenic <i>ADAMTSL4</i> variants were screened from a Chinese cohort of congenital EL using panel-based next-generation sequencing followed by multiple bioinformatics analyses. The genotype–phenotype correlation was assessed via a systematic review of <i>ADAMTSL4</i> variants within our data and those from the literature. A total of 12 variants of <i>ADAMTSL</i>4, including seven frameshift variants, one nonsense variant, two splicing variants, and two missense variants, were found in nine probands. Combing genetic and clinical information from 72 probands in the literature revealed 37 <i>ADAMTSL4</i> variants known to cause EL, and the ethnic difference was prominent. The lens was inclined to dislocate inferior temporally (22, 27.16%), while the pupil was always located oppositely (9, 81.82%). Several anterior segments anomalies were identified, including ectopia pupillae (15, 18.52%), persistent pupillary membrane (9, 11.10%), poor pupil dilation (4, 30.8%), cataract (13, 24.10%), and glaucoma (8, 13.33%). Genotype–phenotype analysis revealed that truncation variants had higher risks of combined iris anomalies, including either ectopia pupillae or a persistent pupillary membrane (<i>p</i> =  0.007). The data from this study not only extend our knowledge of the <i>ADAMTSL4</i> variant spectrum but also suggest that deleterious variants of <i>ADAMTSL4</i> might be associated with severe ocular phenotypes.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"43 12","pages":"2141-2152"},"PeriodicalIF":3.9,"publicationDate":"2022-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10575933","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}