Oligogenic basis of isolated gonadotropin-releasing hormone deficiency

Abstract

Between the genetic extremes of rare monogenic and common polygenic diseases lie diverse oligogenic disorders involving mutations in more than one locus in each affected individual. Elucidating the principles of oligogenic inheritance and mechanisms of genetic interactions could help unravel the newly appreciated role of rare sequence variants in polygenic disorders. With few exceptions, however, the precise genetic architecture of oligogenic diseases remains unknown. Isolated gonadotropin-releasing hormone (GnRH) deficiency caused by defective secretion or action of hypothalamic GnRH is a rare genetic disease that manifests as sexual immaturity and infertility. Recent reports of patients who harbor pathogenic rare variants in more than one gene have challenged the long-held view that the disorder is strictly monogenic, yet the frequency and extent of oligogenicity in isolated GnRH deficiency have not been investigated. By systematically defining genetic variants in large cohorts of well-phenotyped patients (n = 397), family members, and unaffected subjects (n = 179) for the majority of known disease genes, this study suggests a significant role of oligogenicity in this disease. Remarkably, oligogenicity in isolated GnRH deficiency was as frequent as homozygosity/compound heterozygosity at a single locus (2.5%). Among the 22% of patients with detectable rare protein-altering variants, the likelihood of oligogenicity was 11.3%. No oligogenicity was detected among controls (P < 0.05), even though deleterious variants were present. Viewing isolated GnRH deficiency as an oligogenic condition has implications for understanding the pathogenesis of its reproductive and nonreproductive phenotypes; deciphering the etiology of common GnRH-related disorders; and modeling the genetic architecture of other oligogenic and multifactorial diseases.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.

(A) Percentages of patients with monoallelic, biallelic, and digenic rare protein-altering variants in each gene. (B) Number of alleles with rare protein-altering variants in patients and controls.

Fig. 2.

Genetic interactions in isolated GnRH deficiency. The majority of oligogenic patients (lines) showed digenic biallelic inheritance, in which two genes are implicated, each one having an affected and a wild-type allele. Two patients (triangles) showed digenic triallelic inheritance, which involves both alleles of one gene (triangle base) and one allele of a second gene (triangle apex). The same types of inheritance were observed in patients with KS (solid symbols) or nIHH (empty symbols), suggesting that oligogenicity underlies both clinical forms of isolated GnRH deficiency. Circles denote patients who had single-gene variants and were homozygous or compound heterozygous.