Next generation sequencing in women affected by nonsyndromic premature ovarian failure displays new potential causative genes and mutations

We found that ADAMTS19 and BMPR2 mutations might be related to premature ovarian failure (POF) pathogenesis. We proposed that heterozygous LHCGR mutations might contribute, with variants in further POF genes, toward premature menopause.


Dora Janeth Fonseca, Ph.D., Liliana Catherine Patiño, M.Sc., Yohjana Carolina Suárez, M.Sc., Asid de Jesús Rodríguez, M.Sc., Heidi Eliana Mateus, M.D., M.Sc., Karen Marcela Jiménez, M.Sc., Oscar Ortega-Recalde, M.D., M.Sc., Ivonne Díaz-Yamal, M.D., Paul Laissue, M.D., Ph.D.

Volume 104, Issue 1, Pages 154–162



To identify new molecular actors involved in nonsyndromic premature ovarian failure (POF) etiology.


This is a retrospective case-control cohort study.


University research group and IVF medical center.


Twelve women affected by nonsyndromic POF. The control group included 176 women whose menopause had occurred after age 50 and had no antecedents regarding gynecological disease. A further 345 women from the same ethnic origin (general population group) were also recruited to assess allele frequency for potentially deleterious sequence variants.


Next generation sequencing (NGS), Sanger sequencing, and bioinformatics analysis.

Main Outcome Measure(s):

The complete coding regions of 70 candidate genes were massively sequenced, via NGS, in POF patients. Bioinformatics and genetics were used to confirm NGS results and to identify potential sequence variants related to the disease pathogenesis.


We have identified mutations in two novel genes, ADAMTS19 and BMPR2, that are potentially related to POF origin. LHCGR mutations, which might have contributed to the phenotype, were also detected.


We thus recommend NGS as a powerful tool for identifying new molecular actors in POF and for future diagnostic/prognostic purposes.

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