New genetic findings in a large cohort of congenital hypogonadotropic hypogonadism

in European Journal of Endocrinology
Correspondence should be addressed to A C Latronico or L F G Silveira; Email: or
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Congenital hypogonadotropic hypogonadism (CHH) is a rare condition caused by GnRH deficiency. Several genes have been associated with the pathogenesis of CHH, but most cases still remain without a molecular diagnosis. The advent of next-generation sequencing (NGS) has allowed the simultaneous genotyping of several regions, faster, making possible the extension of the genetic knowledge of CHH.


Genetic characterization of a large cohort of Brazilian CHH patients.

Design and patients

A cohort of 130 unrelated patients (91 males, 39 females) with CHH (75 normosmic CHH, 55 Kallmann syndrome) was studied using a panel containing 36 CHH-associated genes.


Potential pathogenic or probably pathogenic variants were identified in 43 (33%) CHH patients. The genes ANOS1, FGFR1 and GNRHR were the most frequently affected. A novel homozygous splice site mutation was identified in the GNRH1 gene and a deletion of the entire coding sequence was identified in SOX10. Deleterious variants in the IGSF10 gene were identified in two patients with reversible normosmic CHH. Notably, 6.9% of the patients had rare variants in more than one gene. Rare variants were also identified in SPRY4, IL17RD, FGF17, IGSF1 and FLRT3 genes.


This is a large study of the molecular genetics of CHH providing new genetic findings for this complex and heterogeneous genetic condition. NGS has been shown to be a fast, reliable and effective tool in the molecular diagnosis of congenital CHH and being able to targeting clinical genetic testing in the future.

Downloadable materials

  • Supplemental table 1: Prevalence of genetic defects in CHH patients previously studied by Sanger sequencing in our cohort.
  • Supplemental table 2. Clinical and genetic features of 130 patients evaluated by gene panel.


     European Society of Endocrinology

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    Rare variant identified by NGS in 130 patients with CHH.

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    Flowchart for the selection of candidate variants.

  • View in gallery

    (A) Family heredogram of patient with a GNRH1 mutation (squares indicate male family members, circles female family members, black symbols clinically affected patient – index, white circles phenotypically normal). (B) Amplification and automatic sequencing of cDNA fragment (556 bp) of GNRH1. (C) Schematic structure of GNRH1 with the localization of four homozygous mutations (three previously described).


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