Expanding the Spectrum of Founder Mutations Causing Isolated Gonadotropin-Releasing Hormone Deficiency

Abstract

Context: Loss of function (LoF) mutations in more than 20 genes are now known to cause isolated GnRH deficiency (IGD) in humans. Most causal IGD mutations are typically private, ie, limited to a single individual/pedigree. However, somewhat paradoxically, four IGD genes (GNRH1, TAC3, PROKR2, and GNRHR) have been shown to harbor LoF founder mutations that are shared by multiple unrelated individuals. It is not known whether similar founder mutations occur in other IGD genes.

Objective: The objective of the study was to determine whether shared deleterious mutations in IGD-associated genes represent founder alleles.

Setting: This study was an international collaboration among academic medical centers.

Methods: IGD patients with shared mutations, defined as those documented in three or more unrelated probands in 14 IGD-associated genes, were identified from various academic institutions, the Human Gene Mutation Database, and literature reports by other international investigators. Haplotypes of single-nucleotide polymorphisms and short tandem repeats surrounding the mutations were constructed to assess genetic ancestry.

Results: A total of eight founder mutations in five genes, GNRHR (Q106R, R262Q, R139H), TACR3 (W275X), PROKR2 (R85H), FGFR1 (R250Q, G687R), and HS6ST1 (R382W) were identified. Most founder alleles were present at low frequency in the general population. The estimated age of these mutant alleles ranged from 1925 to 5600 years and corresponded to the time of rapid human population expansion.

Conclusions: We have expanded the spectrum of founder alleles associated with IGD to a total of eight founder mutations. In contrast to the approximately 9000-year-old PROKR2 founder allele that may confer a heterozygote advantage, the rest of the founder alleles are relatively more recent in origin, in keeping with the timing of recent human population expansion and any selective heterozygote advantage of these alleles requires further evaluation.

Figure 1.

Haplotypes of probands with GNRHR R262Q. For each STR marker, the number of dinucleotide repeats is shown. Seven probands (numbers 1–3, 6, 7, 11, and 12) had the shared haplotype deduced from fully phased samples. Most probands were Caucasians except proband number 2 (Mexican) and proband number 3 (South Asian). Two probands (numbers 3 and 7) had hypothalamic amenorrhea, whereas the remaining probands had Kallmann syndrome or normosmic idiopathic hypogonadotropic hypogonadism. Blue horizontal lines display the individual haplotypes, with pink horizontal lines showing the haplotype regions identical with each other. The minimum common haplotype shared by all probands is marked with vertical dotted lines. Subject 7 was homozygous for this mutation and his two haplotypes are labeled a and b.

Figure 2.

Haplotypes of probands with GNRHR R139H. In 10 probands (numbers 1, 3, 6–10, 12, 13, and 15), full phasing with both parents samples were possible and they shared common haplotypes. All probands were Caucasians, and eight of them (proband numbers 6–10, 12, 13, and 15) were from Poland. Blue horizontal lines display the individual haplotypes, with pink horizontal lines showing the haplotype regions identical with each other. The common minimum haplotype shared by all probands is marked with vertical dotted lines. In each of the probands homozygous for the mutation (subjects 8, 9, 12, 13, and 15), their two respective haplotypes are labeled a and b.

Figure 3.

A world map indicating the geographic location of the patients with the founder mutations.