Human Mutation最新文献

{"title":"ENPP1 deficiency: A clinical update on the relevance of individual variants using a locus-specific patient database.","authors":"Stephanie A Mercurio,&nbsp;Lauren M Chunn,&nbsp;Gus Khursigara,&nbsp;Catherine Nester,&nbsp;Kathleen Wray,&nbsp;Ulrike Botschen,&nbsp;Mark J Kiel,&nbsp;Frank Rutsch,&nbsp;Carlos R Ferreira","doi":"10.1002/humu.24477","DOIUrl":"https://doi.org/10.1002/humu.24477","url":null,"abstract":"<p><p>Loss-of-function variants in the ectonucleotide pyrophosphatase/phosphodiesterase family member 1 (ENPP1) cause ENPP1 Deficiency, a rare disorder characterized by pathological calcification, neointimal proliferation, and impaired bone mineralization. The consequence of ENPP1 Deficiency is a broad range of age dependent symptoms and morbidities including cardiovascular complications and 50% mortality in infants, autosomal recessive hypophosphatemic rickets type 2 (ARHR2) in children, and joint pain, osteomalacia and enthesopathies in adults. Recent research continues to add to the growing clinical presentation profile as well as expanding the role of ENPP1 itself. Here we review the current knowledge on the spectrum of clinical and genetic findings of ENPP1 Deficiency reported in patients diagnosed with GACI or ARHR2 phenotypes using a comprehensive database of known ENPP1 variants with associated clinical data. A total of 108 genotypes were identified from 154 patients. Of the 109 ENPP1 variants reviewed, 72.5% were demonstrably disease-causing, a threefold increase in pathogenic/likely pathogenic variants over other databases. There is substantial heterogeneity in disease severity, even among patients with the same variant. The approach to creating a continuously curated database of ENPP1 variants accessible to clinicians is necessary to increase the diagnostic yield of clinical genetic testing and accelerate diagnosis of ENPP1 Deficiency.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10557994","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":"Variant effect on splicing regulatory elements, branchpoint usage, and pseudoexonization: Strategies to enhance bioinformatic prediction using hereditary cancer genes as exemplars","authors":"Daffodil Canson,&nbsp;Dylan Glubb,&nbsp;Amanda B. Spurdle","doi":"10.1002/humu.24500","DOIUrl":"10.1002/humu.24500","url":null,"abstract":"<p>Human Mutation, 41, 1705–1721 (2020). https://doi.org/10.1002/humu.24074</p><p>Dylan Glubb co-supervised first author Daffodil Canson through an Honorary appointment at the University of Queensland and he should be recognized as affiliated to below affiliation [2] in the original paper.</p><p>²Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2022-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/humu.24500","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10328458","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":"Germline selection of PTPN11 (HGNC:9644) variants make a major contribution to both Noonan syndrome's high birth rate and the transmission of sporadic cancer variants resulting in fetal abnormality","authors":"Jordan Eboreime,&nbsp;Soo-Kyung Choi,&nbsp;Song-Ro Yoon,&nbsp;Anastasiia Sadybekov,&nbsp;Vsevolod Katritch,&nbsp;Peter Calabrese,&nbsp;Norman Arnheim","doi":"10.1002/humu.24493","DOIUrl":"10.1002/humu.24493","url":null,"abstract":"<p>Some spontaneous germline gain-of-function mutations promote spermatogonial stem cell clonal expansion and disproportionate variant sperm production leading to unexpectedly high transmission rates for some human genetic conditions. To measure the frequency and spatial distribution of de novo mutations we divided three testes into 192 pieces each and used error-corrected deep-sequencing on each piece. We focused on <i>PTPN11</i> (HGNC:9644) Exon 3 that contains 30 different <i>PTPN11</i> Noonan syndrome (NS) mutation sites. We found 14 of these variants formed clusters among the testes; one testis had 11 different variant clusters. The mutation frequencies of these different clusters were not correlated with their case-recurrence rates nor were case recurrence rates of <i>PTPN11</i> variants correlated with their tyrosine phosphatase levels thereby confusing <i>PTPN11</i>'s role in germline clonal expansion. Six of the <i>PTPN11</i> exon 3 de novo variants associated with somatic mutation-induced sporadic cancers (but not NS) also formed testis clusters. Further, three of these six variants were observed among fetuses that underwent prenatal ultrasound screening for NS-like features. Mathematical modeling showed that germline selection can explain both the mutation clusters and the high incidence of NS (1/1000–1/2500).</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2022-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10099774/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9351049","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":"Comprehensive analysis of the PRPF31 gene in retinitis pigmentosa patients: Four novel Alu-mediated copy number variations at the PRPF31 locus","authors":"Zhixuan Chen,&nbsp;Jieqiong Chen,&nbsp;Min Gao,&nbsp;Yang Liu,&nbsp;Yidong Wu,&nbsp;Yafang Wang,&nbsp;Yuanyuan Gong,&nbsp;Suqin Yu,&nbsp;Wenjia Liu,&nbsp;Xiaoling Wan,&nbsp;Xiaodong Sun","doi":"10.1002/humu.24494","DOIUrl":"10.1002/humu.24494","url":null,"abstract":"<p>Retinitis pigmentosa (RP) is a monogenic disease characterized by irreversible degeneration of the retina. <i>PRPF31</i>, the second most common causative gene of autosomal dominant RP, frequently harbors copy number variations (CNVs), but the underlying mechanism is unclear. In this study, we summarized the phenotypic and genotypic characteristics of 18 RP families (F01−F18) with variants in <i>PRPF31</i>. The prevalence of <i>PRPF31</i> variants in our cohort of Chinese RP families was 1.7% (18/1024). Seventeen different variants in <i>PRPF31</i> were detected, including eight novel variants. Notably, four novel CNVs encompassing <i>PRPF31</i>, with a proportion of 22.2% (4/18), were validated to harbor gross deletions involving <i>Alu</i>/<i>Alu</i>-mediated rearrangements (AAMRs) in the same orientation. Among a total of 12 CNVs of <i>PRPF31</i> with breakpoints mapped on nucleotide-resolution, 10 variants (83.3%) were presumably mediated by <i>Alu</i> elements. Furthermore, we described the correlation between the genotypes and phenotypes in <i>PRPF31</i>-related RP. Our findings expand the mutational spectrum of the <i>PRPF31</i> gene and provide strong evidence that <i>Alu</i> elements of <i>PRPF31</i> probably contribute to the susceptibility to genomic rearrangement in this locus.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2022-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9137403","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":"New clinical and molecular evidence linking mutations in ARSG to Usher syndrome type IV","authors":"Virginie G. Peter,&nbsp;Mathieu Quinodoz,&nbsp;Silvia Sadio,&nbsp;Sebastian Held,&nbsp;Márcia Rodrigues,&nbsp;Marta Soares,&nbsp;Ana Berta Sousa,&nbsp;Luisa Coutinho Santos,&nbsp;Markus Damme,&nbsp;Carlo Rivolta","doi":"10.1002/humu.24496","DOIUrl":"10.1002/humu.24496","url":null,"abstract":"<p>Human Mutation, 42, 261–271 (2021) https://doi.org/10.1002/humu.24150</p><p>The correct figure should show a white area in the center of the black field (indicating preserved vision), which is not the case in the published version of the article, and it is therefore incorrect from a scientific standpoint. The correct figure should be as follows:</p><p>Figure 1</p><p>The publisher apologizes for the error.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2022-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/humu.24496","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10327316","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":"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":null,"pages":null},"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":null,"pages":null},"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":null,"pages":null},"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":null,"pages":null},"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":null,"pages":null},"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}