ESPE Abstracts (2019) 92 P1-394

Next Generation Sequencing in GnRH Deficient Patients with Congenital Hypogonadotrophic Hypogonadism: Novel Findings in KAL1, SRA1, WDR11, FGFR1, CHD7 and PROP1 Genes

Vassos Neocleous 1,2, Pavlos Fanis1,2, Meropi Toumba3,1, Feride Cinarli1,2, Melpo Schiza1,2, Charilaos Stylianou4, George A Tanteles5,2, Anastasios Oulas6,2, George M Spyrou 6,2, Nicos Skordis7,1,8, Leonidas A Phylactou 1,2


1Department of Molecular Genetics, Function and Therapy, Nicosia, Cyprus. 2Cyprus School of Molecular Medicine, Nicosia, Cyprus. 3Pediatric Endocrine Clinic, IASIS Hospital, Paphos, Cyprus. 4Pediatric Endocrine Unit, Archbishop Makarios III Hospital, Nicosia, Cyprus. 5Clinical Genetics department, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus. 6Bioinformatics Group, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus. 7Division of Pediatric Endocrinology, Paedi Center for specialized Pediatrics, Nicosia, Cyprus. 8St George's, University of London Medical School at the University of Nicosia, Nicosia, Cyprus


Abstract: Objective: Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic disease caused by GnRH deficiency and characterized by absent or incomplete puberty with infertility. The identification of the genetic cause in this group of patients through the use of next generation sequencing (NGS) can assist to the clinical management.

Methods: Seven GnRH deficient nonrelated Cypriot probands were studied (six male and one female) so as to determine the frequency and distribution of GnRH deficiency mutations and their detailed reproductive phenotypes. All patients underwent whole exome sequencing (WES) by NGS and the returned data was filtered for genes with biological involvement in the GnRH neuronal system and CHH. The candidate mutations were confirmed by Sanger sequencing and in silico computational algorithms and structural analysis was performed for the predicted pathogenicity of the alterations at the protein level.

Results: Molecular analysis of the six male and one female GnRH deficient nonrelated Cypriot patients revealed novel mutations in previously reported genes with biological implication in the development of the disorder. Mutations in four nonrelated male patients included the novel X-linked recessive p.Qln82stop in KAL1, the novel WDR11 autosomal dominant p.Leu244Pro in an anosmic CHH/Kallmann Syndrome patient and the novel autosomal dominant p.Pro186Ala and p.Arg822Cys in the FGFR1 gene. An 18 yr old male was also identified to share the novel CHD7 autosomal dominant p.Arg2400Trp in compound heterozygosity with the novel PROP1 recessive p.Arg112Gln. Lastly, the novel p.Ile179Thr in the SRA1 gene was identified in a 19 yr male and a 30 yr female in the heterozygous and homozygous state, respectively.

Conclusion: This report embraces the description of novel mutations in a series of genes known to be implicated in the biological development of CHH. The identification of such genetic malformations can be very informative for the management and future planning of these patients.