Identification of Multiple Gene Mutations Accounts for a new Genetic Architecture of Primary Ovarian Insufficiency

Abstract

Genetic anomalies in women with POI are more frequent than previously believed. Digenic findings in several cases suggest that POI is not a purely monogenic disorder and points to a role of digenicity. The genotype-phenotype correlations in some kindreds suggest that a synergistic effect of several mutations may underlie the POI phenotype.

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

“…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).…”

“…As discussed above, the term oligogenic transmission implies that the phenotype only emerges, or is only significantly magnified, when more than one CHH/KS gene is mutated (174)(175)(176)(177). In other words, before diagnosing oligogenism, it is necessary to show that the phenotype and/or expression of associated signs cosegregate(s) with a greater oligogenic load than other members of the same family who are either unaffected or have only an attenuated form.…”

Molecular Aspects and Clinical Relevance of GDF9 and BMP15 in Ovarian Function

“…For example, BMP15 variants of R68W, R138H, L148P (Rossetti et al, 2009), R76C, and R206H (Inagaki & Shimasaki, 2010) located in the proregion lead to a reduced production of mature BMP15 in an in vitro assay, showing that reduced biological effects may be due to an impaired processing or a decreased precursor stability (Inagaki & Shimasaki, 2010; Rossetti et al, 2009). Ins263L might not have a functional abnormality since it is present also in control women and might represent, together with N103S, a polymorphism with no functional significance (Bouilly et al, 2016; Di Pasquale et al, 2006; Dixit et al, 2006; Laissue et al, 2006; Rossetti et al, 2009; Tiotiu et al, 2010; Wang et al, 2010). …”

“…Women with nonsyndromic POI showed heterozygous mutations not only in BMP15 or GDF9 but also in other key genes of ovarian function, such as NOBOX, FOXL2, SOHLH1, FIGLA, GALT, STAG3, HFM1, SYCE1, MCM8, MCM9, SCM1β, REC8, LHX8, and many more, involved in cell functions such as regulation of transcription, meiosis, and DNA repair (Bouali et al, 2016; Bouilly et al, 2016; Qin et al, 2015). A recent study on whole-exome sequencing of Chinese POI patients showed a novel homozygous truncating variant in the NOBOX gene (chr7:144098161delC) that impaired severely the transcriptional activation of the GDF9 gene in functional analyses, suggesting that a loss-of-function effect on NOBOX transcriptional activity could be associated with POI via reduced GDF9 (Li et al, 2017).…”

R-spondin2, a novel target of NOBOX: identification of variants in a cohort of women with primary ovarian insufficiency

“…Genetic component such as X-chromosome abnormalities, deletions, FMR1 premutations, BMP15 variants, were identified as the first genetic causes of the pathophysiology [4]. To date, about 30 autosomal genes were identified as involved in the pathogenesis of POI, and more recently a digenic form has been observed in large cohort of POI women [5]. For instance, recent publications reported mutations in genes involved in meiosis like STAG3 [6], HFM1 [7] or SYCE1 [8] and in transcription factors including FIGLA [9] or SOHLH2 [10].…”