kallmann syndrome

exome sequencing

sex development

multiple endocrine neoplasia

gh deficiency

pathogenic variants

sanger sequencing

variants

genet pubmed scopus

mutation

European Journal of Endocrinology

Context 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. Objective 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. Results 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. Conclusions 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.

New genetic findings in a large cohort of congenital hypogonadotropic hypogonadism