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Classification of rare missense substitutions, using risk surfaces, with genetic- and molecular-epidemiology applications.

ABSTRACT: Many individually rare missense substitutions are encountered during deep resequencing of candidate susceptibility genes and clinical mutation screening of known susceptibility genes. BRCA1 and BRCA2 are among the most resequenced of all genes, and clinical mutation screening of these genes provides an extensive data set for analysis of rare missense substitutions. Align-GVGD is a mathematically simple missense substitution analysis algorithm, based on the Grantham difference, which has already contributed to classification of missense substitutions in BRCA1, BRCA2, and CHEK2. However, the distribution of genetic risk as a function of Align-GVGD's output variables Grantham variation (GV) and Grantham deviation (GD) has not been well characterized. Here, we used data from the Myriad Genetic Laboratories database of nearly 70,000 full-sequence tests plus two risk estimates, one approximating the odds ratio and the other reflecting strength of selection, to display the distribution of risk in the GV-GD plane as a series of surfaces. We abstracted contours from the surfaces and used the contours to define a sequence of missense substitution grades ordered from greatest risk to least risk. The grades were validated internally using a third, personal and family history-based, measure of risk. The Align-GVGD grades defined here are applicable to both the genetic epidemiology problem of classifying rare missense substitutions observed in known susceptibility genes and the molecular epidemiology problem of analyzing rare missense substitutions observed during case-control mutation screening studies of candidate susceptibility genes.

SUBMITTER: Tavtigian SV

PROVIDER: S-EPMC3938023 | biostudies-literature | 2008 Nov

REPOSITORIES: biostudies-literature

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Classification of rare missense substitutions, using risk surfaces, with genetic- and molecular-epidemiology applications.

Tavtigian Sean V SV Byrnes Graham B GB Goldgar David E DE Thomas Alun A

Human mutation 20081101 11

Many individually rare missense substitutions are encountered during deep resequencing of candidate susceptibility genes and clinical mutation screening of known susceptibility genes. BRCA1 and BRCA2 are among the most resequenced of all genes, and clinical mutation screening of these genes provides an extensive data set for analysis of rare missense substitutions. Align-GVGD is a mathematically simple missense substitution analysis algorithm, based on the Grantham difference, which has already ...[more]

PMID: 18951461

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Project description:BackgroundVisual system homeobox gene (VSX1) plays a major role in the early development of craniofacial and ocular tissues including cone opsin gene in the human retina. To date, few disease-causing mutations of VSX1 have been linked to familial and sporadic keratoconus (KC) in humans. In this study, we describe the clinical features and screening for VSX1 gene in families with KC from India.MethodsClinical data and genomic DNA were collected from patients with clinically diagnosed KC and their family members. The study was conducted on 20 subjects of eight families from India. The coding exons of VSX1 gene were amplified using PCR and amplicons were analyzed by direct sequencing. Predictive effect of the mutations was performed using Polyphen-2, SIFT and mutation assessor algorithms. Additionally, haplotypes of VSX1 gene were constructed for affected and unaffected individuals using SNPs.ResultsIn the coding region of VSX1, one novel missense heterozygous change (p.Leu268His) was identified in five KC patients from two unrelated families. Another family of three members had a novel heterozygous change (p.Ser251Thr). These variants co-segregated with the disease phenotype in all affected individuals but not in the unaffected family members and 105 normal controls. In silico analysis suggested that p.Leu268His could have a deleterious effect on the protein coded by VSX1, while p.Ser251Thr has a neutral effect on the functional properties of VSX1. Haplotype examination revealed common SNPs around the missense change (p.Leu268His) in two unrelated KC families.ConclusionsIn this study, we add p.Leu268His, a novel missense variation in the coding region of VSX1 to the existing repertoire of VSX1 coding variations observed in Indian patients with the characteristic phenotype of KC. The variant p.Ser251Thr might be a benign polymorphism, but further biophysical studies are necessary to evaluate its molecular mechanism. The shared haplotype by two families with the same variant suggests the possibility of a founder effect, which requires further elucidation. We suggest that p.Leu268His might be involved in the pathogenesis of KC, which may help in the genetic counselling of patients and their family.

Dataset Information

Classification of rare missense substitutions, using risk surfaces, with genetic- and molecular-epidemiology applications.

Publications

Classification of rare missense substitutions, using risk surfaces, with genetic- and molecular-epidemiology applications.

Similar Datasets

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