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Hypergonadotropic hypogonadism presents in females with delayed or arrested puberty, primary or secondary amenorrhea due to gonadal dysfunction, and is further characterized by elevated gonadotropins and low sex steroids. Chromosomal aberrations and various specific gene defects can lead to hypergonadotropic hypogonadism. Responsible genes include those with roles in gonadal development or maintenance, sex steroid synthesis, or end-organ resistance to gonadotropins. Identification of novel causative genes in this disorder will contribute to our understanding of the regulation of human reproductive function. The aim of this study was to identify and report the gene responsible for autosomal-recessive hypergonadotropic hypogonadism in two unrelated families. Clinical evaluation and whole-exome sequencing were performed in two pairs of sisters with nonsyndromic hypergonadotropic hypogonadism from two unrelated families. Exome sequencing analysis revealed two different truncating mutations in the same gene: SOHLH1 c.705delT (p.Pro235fs*4) and SOHLH1 c.27C>G (p.Tyr9stop). Both mutations were unique to the families and segregation was consistent with Mendelian expectations for an autosomal-recessive mode of inheritance. Sohlh1 was known from previous mouse studies to be a transcriptional regulator that functions in the maintenance and survival of primordial ovarian follicles, but loss-of-function mutations in human females have not been reported. Our results provide evidence that homozygous-truncating mutations in SOHLH1 cause female nonsyndromic hypergonadotropic hypogonadism.


Yavuz Bayram, Suleyman Gulsuner, Tulay Guran, Ayhan Abaci, Gozde Yesil, Hilal Unal Gulsuner, Zeynep Atay, Sarah B Pierce, Tomasz Gambin, Ming Lee, Serap Turan, Ece Bober, Mehmed M Atik, Tom Walsh, Ender Karaca, Davut Pehlivan, Shalini N Jhangiani, Donna Muzny, Abdullah Bereket, Atilla Buyukgebiz, Eric Boerwinkle, Richard A Gibbs, Mary-Claire King, James R Lupski. Homozygous loss-of-function mutations in SOHLH1 in patients with nonsyndromic hypergonadotropic hypogonadism. The Journal of clinical endocrinology and metabolism. 2015 May;100(5):E808-14

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PMID: 25774885

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