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HESX1 is a paired-like homeobox transcription factor critical for forebrain and pituitary development. In a cohort of 217 well-characterized idiopathic hypogonadotropic hypogonadism/Kallmann syndrome (KS) patients, sequencing of HESX1 revealed three novel heterozygous missense variants—c.18G>T (p.Gln6His), c.124C>T (p.His42Tyr), and c.223G>T (p.Val75Leu)—in 3 of 217 KS males (1.4%) (PMID:23465708). Both p.Gln6His and p.His42Tyr were predicted to be deleterious by SIFT, and no additional mutations in established IHH/KS genes were detected, supporting a possible contributory role of HESX1 in the KS phenotype.
Although these variants are absent from control populations and predicted damaging, they occur de novo or without reported segregation in affected families, and no functional assays specific to KS have been reported. Thus, current evidence supports a limited association between HESX1 heterozygous variants and Kallmann syndrome. Additional familial segregation, functional validation in olfactory-GnRH neuronal models, and recurrence data are needed to strengthen clinical validity.
Key Take-home: HESX1 heterozygous missense variants are rare findings in KS and currently represent limited genetic evidence for clinical testing in Kallmann syndrome diagnostics.
Gene–Disease AssociationLimitedThree heterozygous HESX1 missense variants identified in unrelated KS probands without familial segregation evidence Genetic EvidenceLimited3/217 KS probands with heterozygous missense variants in HESX1 predicted deleterious ([PMID:23465708]) Functional EvidenceNo EvidenceNo functional studies assessing HESX1 variants in a Kallmann syndrome context have been reported |