کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
5888784 1568127 2016 5 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Full Length ArticleAssessing the general population frequency of rare coding variants in the EXT1 and EXT2 genes previously implicated in hereditary multiple exostoses
موضوعات مرتبط
علوم زیستی و بیوفناوری بیوشیمی، ژنتیک و زیست شناسی مولکولی زیست شناسی تکاملی
پیش نمایش صفحه اول مقاله
Full Length ArticleAssessing the general population frequency of rare coding variants in the EXT1 and EXT2 genes previously implicated in hereditary multiple exostoses
چکیده انگلیسی


- Presumed pathogenic EXT1 and EXT2 variants were found in a large collection of exome sequences from the general population
- EXT1, but not EXT2, is under high selective constraint, potentially indicating differences in their respective functions
- Large-scale sequencing data can help prioritize potentially damaging mutations and characterize disease-causing genes

Hereditary multiple exostoses (HME) is a rare childhood-onset skeletal disease linked to mutations in exostosin glycosyltransferase 1 (EXT1) or 2 (EXT2). Patients are heterozygous for either an EXT1 or EXT2 mutation, and it is widely assumed that exostosis formation and associated defects, such as growth retardation and skeletal deformities, require loss-of-heterozygosity or a second hit in affected cells. However, the relevance and phenotypic impact of many presumed pathogenic EXT variants remain uncertain. We extracted all amino acid-altering (missense) and loss of function (LoF; nonsense, frameshift, or splice-site) variants from the Exome Aggregation Consortium (ExAC), a large population-based repository of exome sequence data from diverse ancestries that has screened out severe pediatric disease, to assess the overall mutation spectrum of predicted protein-damaging variants across these two genes in the general population. We then determined whether clinically-identified, presumably pathogenic variants implicated in HME exist among healthy individuals. We found six EXT1 and four EXT2 missense mutations in ExAC, suggesting that these mutations have either been misclassified as pathogenic or are not fully penetrant. Furthermore, EXT1 is heavily selectively constrained, while EXT2 is more tolerant to protein-damaging variants, especially at its C-terminus, possibly explaining the genotype-phenotype correlation that EXT1 variants usually result in more severe disease. In conclusion, population-based exome data is a useful filter for determining whether clinically detected variants are likely pathogenic, as well as revealing biological insight into rare disease genes such as EXT1 and EXT2.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Bone - Volume 92, November 2016, Pages 196-200
نویسندگان
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