Background: Primary ovarian failure (POF) is a major cause of female infertility. POF is characterized by amenorrhea, hypo-estrogenism, and elevated gonadotrophin levels. In POF disorder, several genetic alterations have been described, however in most of the patients the etiology of this disorder remains unknown.
Objective and hypotheses: To identify new genes implicated in the development of POF using whole-exome sequencing (WES).
Method: Four subjects with FOP of two families were studied. In family 1, DNA of two affected daughters and their mother were available. In the second family two affected sisters, their parents, and one unaffected sister were analyzed. Family 2 is consanguineous (parents are second cousins), suggesting a recessive mode of inheritance. Exons and splice sites were captured with the Agilent SureSelectXT Human Exon V5 Kit and 2×100 bp paired-end. WES was performed on an Illumina HiSeq2500. The mean coverage of the captured regions was >50× in all samples. WES was performed in all described members and genetic variant was confirmed with Sanger sequencing.
Results: One novel homozygous missense variant (c.149A>G) in POLR3H, the gene encoding polymerase (RNA) III (DNA directed) polypeptide H, was identified in all four affected women from both families. The parents were heterozygous for this variant and the unaffected sister did not carry the variant, consistent with perfect segregation with autosomal recessive mode of inheritance. POLR3H variant is not present the publicly available databases 1000Genomes, 6500ESP, and ExAC. Finally, the c.149A>G variant is predicted to be deleterious according to in silico analysis.
Conclusion: Our findings identified a previoulsy undescribed homozygous variant in POLR3H associated with primary ovarian failure in two unrelated families. These results suggest the involvement of POLR3H gene in the etiology of primary ovarian failure.
01 - 03 Oct 2015
European Society for Paediatric Endocrinology