Digenic mutations account for variable phenotypes in idiopathic hypogonadotropic hypogonadism

Area of Science:

• Genetics
• Endocrinology
• Developmental Biology

Background:

• Idiopathic hypogonadotropic hypogonadism (IHH) is a disorder of sexual maturation caused by gonadotropin-releasing hormone (GnRH) defects.
• Previously, single-gene defects were thought to cause IHH, but familial variability and incomplete penetrance suggested a more complex genetic model.

Observation:

• Two families with IHH (Kallmann syndrome and normosmic IHH) exhibited significant phenotypic variability.
• Pedigree 1 had a heterozygous FGFR1 mutation, and Pedigree 2 had a compound heterozygous GNRHR mutation.
• Further screening identified a second heterozygous NELF deletion in Pedigree 1 and an additional heterozygous FGFR1 mutation in Pedigree 2.

Findings:

• Interactions between mutations at different IHH loci were observed to modify phenotypes.
• The identified secondary mutations in NELF and FGFR1 accounted for the marked phenotypic variability within and across families.
• Two distinct genetic defects synergize to create a more severe IHH phenotype than either defect alone.

Implications:

• This multi-gene interaction model provides a potential explanation for the phenotypic heterogeneity observed in GnRH deficiency disorders.
• Understanding these complex genetic interactions is crucial for diagnosing and managing IHH and related developmental disorders.
• The findings highlight the importance of considering digenic inheritance in IHH pathogenesis and genetic counseling.