Hypogonadotropic hypogonadism (GMS)

Gene: ARHGAP35

Green List (high evidence)

The rating of this gene has been updated to green and the mode of inheritance set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.

Created: 6 Dec 2024, 8:12 a.m. | Last Modified: 6 Dec 2024, 8:13 a.m.

Panel Version: 3.22

Comment on list classification: There is sufficient evidence available for promoting this gene to green rating in the next GMS review.

Created: 31 Oct 2023, 2:16 p.m. | Last Modified: 31 Oct 2023, 2:16 p.m.

Panel Version: 3.9

16 patients from 13 different families were reported with idiopathic hypogonadotropic hypogonadism (9 with IHH and 7 with Kallmann syndrome (IHH + anosmia)) and with monoallelic ARHGAP35 variants. Rare protein-truncating variants and missense variants were found in the RhoGAP domain of ARHGAP35 gene.

Zebrafish modeling using gnrh3:egfp phenotype assessment showed that mutant larvae with deficient arhgap35a (predominant ARHGAP35 paralog in zebrafish brain), displayed decreased GnRH3-GFP+ neuronal area, a readout for IHH. In vitro GAP activity studies showed that 1 rare missense variant (Arg1284Trp) had decreased GAP activity.

This gene has not yet been associated with this phenotype either in OMIM or in Gene2Phenotype. However, this gene has been associated with ARHGAP35-related developmental disorder in DD panel of G2P (with 'definitive' rating).
Sources: Literature

Created: 31 Oct 2023, 2:14 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
hypogonadotropic hypogonadism, MONDO:0018555

Publications

• 36178483