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Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) comprises a continuum of reproductive disorders arising from defects in the specification, migration and/or function of GnRH neurons. The anosmic form, Kallmann syndrome, is characterized by hypogonadotropic hypogonadism and anosmia. Recent genetic studies have identified TCF12 as a novel IGD locus in patients with Kallmann syndrome (PMID:32620954).
A systematic interrogation of 13 unrelated families (12 autosomal dominant, one autosomal recessive) with anosmic IGD revealed heterozygous loss-of-function variants in TCF12, including frameshift, nonsense and splice-site mutations. These alterations were absent from population databases and co-segregated with disease in multiple pedigrees (PMID:32620954).
The variant spectrum comprises predominantly truncating mutations: for example, c.1763del (p.Glu588fs) disrupting the bHLH domain in affected individuals. Splice-site variants such as c.1115-1G>A further support a haploinsufficiency mechanism. No recurrent or founder alleles have been reported to date.
Inheritance is principally autosomal dominant, with clear segregation of TCF12 variants in affected relatives across most kindreds. One family exhibited biallelic inheritance, suggesting phenotypic variability under complete loss-of-function in rare contexts.
Functional modeling in zebrafish showed that tcf12 knock-out larvae have disrupted GnRH neuronal patterning and concomitant downregulation of tcf3a/b and stub1, both network partners of TCF12. Restoration of stub1 mRNA rescued GnRH neuron development in vivo, confirming the pathogenic mechanism of TCF12 haploinsufficiency (PMID:32620954).
Together, genetic and experimental evidence robustly support a haploinsufficiency model for TCF12 in Kallmann syndrome. Incorporation of TCF12 into diagnostic panels for IGD will enhance molecular diagnosis, enable tailored genetic counseling, and guide future therapeutic research.
Gene–Disease AssociationStrong13 unrelated families (12 AD, 1 AR) with TCF12 loss-of-function variants and in vivo functional rescue in zebrafish ([PMID:32620954]) Genetic EvidenceStrong13 probands with heterozygous truncating and splice-site variants segregating with Kallmann syndrome ([PMID:32620954]) Functional EvidenceModerateZebrafish tcf12 knock-out mimics GnRH neuron defects and is rescued by stub1 mRNA ([PMID:32620954]) |