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The ligand gene KISS1 is implicated in autosomal recessive hypogonadotropic hypogonadism. In a consanguineous kindred, a homozygous inactivating KISS1 variant, c.339C>G (p.Asn113Lys), was identified in multiple affected siblings who failed to progress through puberty and exhibited low gonadotropin levels, confirming kisspeptin’s essential role in GnRH neuron activation ([PMID:22335740]).
Functional studies in Kiss1 knockout mice recapitulate pubertal arrest and infertility, and exogenous kisspeptin restores GnRH secretion, supporting a loss-of-function mechanism ([PMID:17519946]). No additional pathogenic KISS1 variants have been reported in isolated hypogonadotropic hypogonadism cohorts, underscoring the rarity of this aetiology.
Key Take-home: Homozygous inactivating KISS1 variants cause rare autosomal recessive hypogonadotropic hypogonadism and should be considered in genetic evaluation of GnRH deficiency.
Gene–Disease AssociationLimitedOne homozygous inactivating variant segregating in a single consanguineous family Genetic EvidenceLimitedSingle family with homozygous c.339C>G (p.Asn113Lys) variant in KISS1 associated with HH Functional EvidenceLimitedKnockout mouse models and receptor signalling studies support loss-of-function but no variant-specific assays |