CCDC141 mutations in idiopathic hypogonadotropic hypogonadism

PubMedID: 28324054Context: Gonadotropin-releasing hormone neurons originate outside the central nervous systemin the olfactory placode and migrate into the central nervous system, becoming integral components of the hypothalamic-pituitary-gonadal axis. Failure of thismigration can lead to idiopathic hypogonadotropic hypogonadism (IHH)/Kallmann syndrome (KS). We have previously shown that CCDC141 knockdown leads to impaired migration of GnRH neurons but not of olfactory receptor neurons. Objective: The aim of this study was to further describe the phenotype and prevalence of CCDC141 mutations in IHH/KS. Design: Using autozygosity mapping, candidate gene screening, whole-exome sequencing, and Sanger sequencing, those individuals carrying deleterious CDCD141 variants and their phenotypes were determined in a cohort of 120 IHH/KS families. Patients and Interventions: No interventions were made. Results: Our studies revealed nine affected individuals from four independent families in which IHH/ KS is associated with inactivating CCDC141 variants, revealing a prevalence of 3.3%. Affected individuals (with the exception of those fromfamily 1 who concomitantly have FEZF1mutations) have normal olfactory function and anatomically normal olfactory bulbs. Four affected individuals show evidence of clinical reversibility. In three of the families, there was at least one more potentially deleterious variant in other known puberty genes with evidence of allelic heterogeneity within respective pedigrees. Conclusions: These studies confirm that inactivating CCDC141 variants cause normosmic IHH but not KS. This is consistent with our previous in vitro experiments showing exclusively impaired embryonic migration of GnRH neurons upon CCDC141 knockdown. These studies expand the clinical and genetic spectrum of IHH and also attest to the complexity of phenotype and genotype in IHH. Copyright © 2017 Endocrine Society.National Institutes of Health National Institute of Neurological Disorders and Stroke: NS002824-25/26 4579 National Council for Scientific Research: 113S962This work was supported by the Scientific and Technological Research Council of Turkey project number 113S962, the Cukurova University scientific research project number 4579, and the Intramural Research Program of the National Institutes of Health, National Institute of Neurologic Disorders and Stroke Grant NS002824-25/26 (to B.I.H. and S.W.). Disclosure Summary: The authors have nothing t

Inactivating Mutations in CCDC141 Causing Idiopathic Hypogonadotrophic Hypogonadism/Kallmann Syndrome

WOS: 000384166800138

Mutations in SGPL1, the Gene Encoding Sphingosine-1-Phosphate Lyase, Cause a Novel Form of Primary Adrenal Insufficiency with Steroid Resistant Nephrotic Syndrome

Meeting Abstrac

Exome Sequencing of a Primary Ovarian Insufficiency Cohort Reveals Common Molecular Etiologies for a Spectrum of Disease

Context: Primary ovarian insufficiency (POI) encompasses a spectrum of premature menopause, including both primary and secondary amenorrhea. For 75% to 90% of individuals with hyper-gonadotropic hypogonadism presenting as POI, the molecular etiology is unknown. Common etiologies include chromosomal abnormalities, environmental factors, and congenital disorders affecting ovarian development and function, as well as syndromic and nonsyndromic single gene disorders suggesting POI represents a complex trait.Objective: To characterize the contribution of known disease genes to POI and identify molecular etiologies and biological underpinnings of POI.Design, Setting, and Participants: We applied exome sequencing (ES) and family-based genomics to 42 affected female individuals from 36 unrelated Turkish families, including 31 with reported parental consanguinity.Results: This analysis identified likely damaging, potentially contributing variants and molecular diagnoses in 16 families (44%), including 11 families with likely damaging variants in known genes and five families with predicted deleterious variants in disease genes (IGSF10, MND1, MRPS22, and SOHLH1) not previously associated with POI. Of the 16 families, 2 (13%) had evidence for potentially pathogenic variants at more than one locus. Absence of heterozygosity consistent with identity-by-descent mediated recessive disease burden contributes to molecular diagnosis in 15 of 16 (94%) families. GeneMatcher allowed identification of additional families from diverse genetic backgrounds.Conclusions: ES analysis of a POI cohort further characterized locus heterogeneity, reaffirmed the association of genes integral to meiotic recombination, demonstrated the likely contribution of genes involved in hypothalamic development, and documented multilocus pathogenic variation suggesting the potential for oligogenic inheritance contributing to the development of POI