New mutations in non-syndromic primary ovarian insufficiency patients identified via whole-exome sequencing

Abstract

This study was supported by the Universidad del Rosario and Colciencias (Grants CS/CIGGUR-ABN062-2016 and 672-2014). Colciencias supported Liliana Catherine Patiño´s work (Fellowship: 617, 2013). The authors declare no conflict of interest.

GENETICS IN ENDOCRINOLOGY: Genetic counseling for congenital hypogonadotropic hypogonadism and Kallmann syndrome: new challenges in the era of oligogenism and next-generation sequencing

“…The prevalence of rare variants will also depend on the choice of bioinformatic filter used to select them (178).…”

“…In clinical practice, the use of WES may lead to the detection of known mutations in a hereditary disease (recurrent mutations), new pathogenic variants in a previously validated gene, or potentially deleterious rare variants in new genes (162,178,(180)(181)(182). With WES, although several thousand genes are sequenced, bioinformatics analysis generally focuses on validated or candidate genes first, and then on genes coding for proteins involved in biological systems potentially relevant to the pathophysiology of the disease (178).…”

“…With WES, although several thousand genes are sequenced, bioinformatics analysis generally focuses on validated or candidate genes first, and then on genes coding for proteins involved in biological systems potentially relevant to the pathophysiology of the disease (178). But one of the main advantages of this method, without a priori assumptions, is that it can reveal mutations in unexpected genes, provided there are informative families (with large numbers of affected and unaffected members) available to ensure significant co-segregation between the rare variant(s) and the phenotype (180)(181)(182)(183).…”

“…Further, by analyzing tens or hundreds of genes is that the probability of finding several deleterious or potentially deleterious genetic variants in a given patient is significantly increased. This help to explain the progressive increase in rates of observed oligogenism rise in CHH/KS or in others reproductive disorders (20)(21)(22)177,178,184,186). Another recent breakthrough provided by WES is the demonstration that some complex or severe phenotypes can in fact result from a combination of several diseases in the same patient -so-called overlapping syndromes-caused by simultaneous mutations separately on several genes, being responsible for different diseases in a "blended" fashion (20-22, 151, 185,186).…”

A novel mutation in KHDRBS1 in a patient affected by primary ovarian insufficiency

“…Our group has published recently a description of the first investigation using WES with unrelated POI women. 5 Our attention in this study was focused on a specific subset of 420 coherent candidate genes, involving 69 Caucasian women. Due to the large amount of data, we used stringent bioinformatics filtering for selecting candidate sequence variants; however, no mutations were found in the KHDRBS1 gene.…”