GnRH Deficient Patients With Congenital Hypogonadotropic Hypogonadism: Novel Genetic Findings in ANOS1, RNF216, WDR11, FGFR1, CHD7 , and POLR3A Genes in a Case Series and Review of the Literature

Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic disease caused by Gonadotropin-Releasing Hormone (GnRH) deficiency. So far a limited number of variants in several genes have been associated with the pathogenesis of the disease. In this original research and review manuscript the ret...

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Published in:	Frontiers in endocrinology (Lausanne) 2020-08, Vol.11, p.626-626
Main Authors:	Neocleous, Vassos, Fanis, Pavlos, Toumba, Meropi, Tanteles, George A, Schiza, Melpo, Cinarli, Feride, Nicolaides, Nicolas C, Oulas, Anastasis, Spyrou, George M, Mantzoros, Christos S, Vlachakis, Dimitrios, Skordis, Nicos, Phylactou, Leonidas A
Format:	Article
Language:	eng
Subjects:	Adolescent Adult Aged Analysis digenic inheritance DNA Helicases - genetics DNA-Binding Proteins - genetics Endocrinology Extracellular Matrix Proteins - genetics Female Genes Genetic disorders Genetic research GnRH Gonadotropin-Releasing Hormone - deficiency High-Throughput Nucleotide Sequencing Humans Hypogonadism Hypogonadism - genetics hypogonadotropic hypogonadism Male Membrane Proteins - genetics Mutation Nerve Tissue Proteins - genetics next generation sequencing Pedigree Pituitary hormones Proto-Oncogene Proteins - genetics Receptor, Fibroblast Growth Factor, Type 1 - genetics Retrospective Studies RNA Polymerase III - genetics Ubiquitin-Protein Ligases - genetics Young Adult
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Summary:	Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic disease caused by Gonadotropin-Releasing Hormone (GnRH) deficiency. So far a limited number of variants in several genes have been associated with the pathogenesis of the disease. In this original research and review manuscript the retrospective analysis of known variants in ( , and genes is described, along with novel variants identified in patients with CHH by the present study. Seven GnRH deficient unrelated Cypriot patients underwent whole exome sequencing (WES) by Next Generation Sequencing (NGS). The identified novel variants were initially examined by computational algorithms and structural analysis of their predicted pathogenicity at the protein level was confirmed. In four non-related GnRH males, a novel X-linked pathogenic variant in gene, two novel autosomal dominant (AD) probably pathogenic variants in and genes and one rare AD probably pathogenic variant in gene were identified. A rare autosomal recessive (AR) variant in the gene was identified in homozygosity in a female patient, whilst two other male patients were also, respectively, found to carry novel or previously reported rare pathogenic variants in more than one genes; / and . This report embraces the description of novel and previously reported rare pathogenic variants in a series of genes known to be implicated in the biological development of CHH. Notably, patients with CHH can harbor pathogenic rare variants in more than one gene which raises the hypothesis of locus-locus interactions providing evidence for digenic inheritance. The identification of such aberrations by NGS can be very informative for the management and future planning of these patients.
ISSN:	1664-2392 1664-2392