DHH – 46,XY Complete Gonadal Dysgenesis

Desert Hedgehog (DHH) is essential for testicular differentiation via autocrine/paracrine Hedgehog signalling. Autosomal recessive pathogenic variants in DHH have been linked to 46,XY complete gonadal dysgenesis (CGD; 46,XY sex reversal) often accompanied by peripheral neuropathy.

Recessive inheritance is demonstrated by a consanguineous family in which two sisters (46,XY and 46,XX) homozygous for a truncating variant c.554C>A (p.Ser185Ter) presented with gonadal dysgenesis and peripheral neuropathy (PMID:29471294). Additional homozygous or compound heterozygous loss-of-function alleles—c.528C>G (p.Tyr176Ter) in two unrelated GD patients (PMID:30298535), c.271_273del (p.Glu91del) (PMID:21816240), p.Leu162Pro (PMID:23786321), and c.863C>T (p.Pro288Arg) (PMID:33594065)—have been reported in at least nine probands from six unrelated pedigrees.

The variant spectrum includes six protein-truncating mutations (nonsense, frameshift, small deletion) and multiple missense substitutions within the C-terminal auto-processing domain. These variants lead to complete or partial loss of DHh-N cleavage, abrogating Hedgehog ligand maturation.

Functional assays, including in vitro cleavage and cell co-culture signalling studies, show that frameshift and truncating variants (p.Asn337fs, p.Tyr176Ter) abolish DHh auto-processing, whereas missense variants like p.Glu212Lys retain only ~50% activity (PMID:30298535). Structural modelling of p.Glu91del and p.Leu162Pro predicts disrupted conformation impairing receptor binding (PMID:21816240, PMID:23786321).

Heterozygous DHH variants from DSD cohorts did not impair signalling or cause CGD, supporting a recessive mechanism and excluding dominant-negative effects (PMID:31018998).

Together, genetic and experimental data robustly support an autosomal recessive, loss-of-function mechanism in DHH for 46,XY CGD. DHH genetic testing should be included in diagnostic panels for 46,XY gonadal dysgenesis.

Key take-home: Biallelic DHH loss-of-function variants are a strong cause of autosomal recessive 46,XY complete gonadal dysgenesis with clinical utility in genetic diagnosis.

References

• Hormone research in paediatrics • 2018 • Novel Familial Variant of the Desert Hedgehog Gene: Clinical Findings in Two Sisters with 46,XY Gonadal Dysgenesis or 46,XX Karyotype and Literature Review. PMID:29471294
• Human mutation • 2018 • In vitro functional characterization of the novel DHH mutations p.(Asn337Lysfs*24) and p.(Glu212Lys) associated with gonadal dysgenesis. PMID:30298535
• European journal of medical genetics • 2011 • Novel homozygous mutations in Desert hedgehog gene in patients with 46,XY complete gonadal dysgenesis and prediction of its structural and functional implications by computational methods. PMID:21816240
• DNA and cell biology • 2013 • In vitro and molecular modeling analysis of two mutant desert hedgehog proteins associated with 46,XY gonadal dysgenesis. PMID:23786321
• NPJ genomic medicine • 2021 • Whole exome sequencing uncovered highly penetrant recessive mutations for a spectrum of rare genetic pediatric diseases in Bangladesh. PMID:33594065
• Journal of medical genetics • 2019 • Functional analysis of novel desert hedgehog gene variants improves the clinical interpretation of genomic data and provides a more accurate diagnosis for patients with 46,XY differences of sex development. PMID:31018998

Evidence Based Scoring (AI generated)