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Lorena Guimaraes Lima Amato, Luciana Ribeiro Montenegro, Antonio Marcondes Lerario, Alexander Augusto Lima Jorge, Gil Guerra Junior, Caroline Schnoll, Alessandra Covallero Renck, Ericka Barbosa Trarbach, Elaine Maria Frade Costa, Berenice Bilharinho Mendonca, Ana Claudia Latronico, Leticia Ferreira Gontijo Silveira, New genetic findings in a large cohort of congenital hypogonadotropic hypogonadism, European Journal of Endocrinology, Volume 181, Issue 2, Aug 2019, Pages 103–119, https://doi.org/10.1530/EJE-18-0764
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Abstract
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.
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.