Oligogenic basis of isolated gonadotropin-releasing hormone deficiency.
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.
Sykiotis
Gerasimos P
GP
Harvard Reproductive Endocrine Sciences Center and the Reproductive Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
Plummer
Lacey
L
Hughes
Virginia A
VA
Au
Margaret
M
Durrani
Sadia
S
Nayak-Young
Sadhana
S
Dwyer
Andrew A
AA
Quinton
Richard
R
Hall
Janet E
JE
Gusella
James F
JF
Seminara
Stephanie B
SB
Crowley
William F
WF
Pitteloud
Nelly
N
D016022:Case-Control Studies; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D016326:Extracellular Matrix Proteins / Q000235:genetics; D005260:Female; D051524:Fibroblast Growth Factor 8 / Q000235:genetics; D005768:Gastrointestinal Hormones / Q000235:genetics; D053263:Gene Regulatory Networks; D014644:Genetic Variation; D007987:Gonadotropin-Releasing Hormone / Q000172:deficiency*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007006:Hypogonadism / Q000235:genetics*; D017436:Kallmann Syndrome / Q000235:genetics; D008297:Male; D008957:Models, Genetic; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics; D009479:Neuropeptides / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000235:genetics; D000074502:Receptors, Kisspeptin-1; D011966:Receptors, LHRH / Q000235:genetics; D018000:Receptors, Peptide / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics
C076266:ANOS1 protein, human; D016326:Extracellular Matrix Proteins; C496456:FGF8 protein, human; C484844:GNRHR protein, human; D005768:Gastrointestinal Hormones; C118688:KISS1R protein, human; C411985:NSMF protein, human; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; C423608:PROK2 protein, human; C470838:PROKR2 protein, human; D043562:Receptors, G-Protein-Coupled; D000074502:Receptors, Kisspeptin-1; D011966:Receptors, LHRH; D018000:Receptors, Peptide; D014157:Transcription Factors; D051524:Fibroblast Growth Factor 8; D007987:Gonadotropin-Releasing Hormone; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1