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A non‐sense MCM9 mutation in a familial case of primary ovarian insufficiency
Author(s) -
Fauchereau F.,
Shalev S.,
Chervinsky E.,
BeckFruchter R.,
Legois B.,
Fellous M.,
Caburet S.,
Veitia R.A.
Publication year - 2016
Publication title -
clinical genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.543
H-Index - 102
eISSN - 1399-0004
pISSN - 0009-9163
DOI - 10.1111/cge.12736
Subject(s) - genetics , sanger sequencing , premature ovarian insufficiency , biology , exome sequencing , exon , consanguinity , mutation , genetic linkage , short stature , gene , loss function , phenotype , medicine , endocrinology
Primary ovarian insufficiency ( POI ) results in an early loss of ovarian function, and remains idiopathic in about 80% of cases. Here, we have performed a complete genetic study of a consanguineous family with two POI cases. Linkage analysis and homozygosity mapping identified 12 homozygous regions with linkage, totalling 84 Mb. Whole‐exome sequencing of the two patients and a non‐affected sister allowed us to detect a homozygous causal variant in the MCM9 gene. The variant c. 1483G >T [p. E495 *], confirmed using Sanger sequencing, introduced a premature stop codon in coding exon 8 and is expected to lead to the loss of a functional protein. MCM9 belongs to a complex required for DNA repair by homologous recombination, and its impairment in mouse is known to induce meiotic recombination defects and oocyte degeneration. A previous study recently described two consanguineous families in which homozygous mutations of MCM9 were responsible for POI and short stature. Interestingly, the affected sisters in the family described here had a normal height. Altogether, our results provide the confirmation of the implication of MCM9 variants in POI and expand their phenotypic spectrum.