Hypogonadotropic hypogonadism (GMS)

Gene: NDNF

I don't know

PMID: 31883645
3 PTC (1 NMD, 2 PTV) and 1 missense
- missense is common in gnomAD and appears not to have functional impact
- 2/3 PTCs have non-segregation ?? incomplete penetrance postulated
- the remaining PTC has insufficient segregation demonstrated.

Created: 1 Nov 2023, 3:01 a.m. | Last Modified: 1 Nov 2023, 3:01 a.m.

Panel Version: 3.9

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Hypogonadotropic hypogonadism 25 with anosmia MIM#618841

Publications

• 31883645

Comment on list classification: Gene was re-reviewed in light of an Amber review by Zornitza Stark (Australian Genomics) on a Green gene. At least five unrelated cases have been reported, as well as mouse and zebrafish studies showing Ndnf deficiency leads to anomalies in GnRH neuron migration. Pedigree analysis does indicate variable expressivity and incomplete penetrance, although this is relatively common in dominant forms of HH. Furthermore, inclusion of NDNF on this panel has already been reviewed and approved by the NHS specialist group and therefore the Green rating is being maintained.

Created: 17 Apr 2024, 9:27 a.m. | Last Modified: 17 Apr 2024, 9:27 a.m.

Panel Version: 3.18

PMID: 36245975 (2022) - another male patient with idiopathic hypogonadotropin hypogonadism identified harbouring a paternally inherited NDNF variant (c.1439T>A, p.Ile480Asn)

Created: 17 Apr 2024, 9:17 a.m. | Last Modified: 17 Apr 2024, 9:17 a.m.

Panel Version: 3.15

Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).

Created: 20 Oct 2020, 3:06 p.m. | Last Modified: 20 Oct 2020, 3:06 p.m.

Panel Version: 1.10

The rating of this gene has been updated following NHS Genomic Medicine Service approval.

Created: 3 Mar 2022, 2:06 p.m. | Last Modified: 3 Mar 2022, 2:06 p.m.

Panel Version: 1.50

Comment on list classification: Gene added by expert reviewer (Simon Thomas (Wessex)) with suggested Green rating.

The gene is associated with a relevent disease in OMIM and is probably associated with a relevent disease in Gene2Phentoype. There are 3 unrelated cases. Therefore, there is enough evidence to support this gene-disease phenotype.

Created: 5 May 2020, 3:36 p.m. | Last Modified: 5 May 2020, 3:36 p.m.

Panel Version: 1.8

Green List (high evidence)

Messina et al (Am J Hum Genet Jan 2020) screened NDNF (Neuron-Derived Neurotrophic Factor) because, in common with several IHH genes, it contains a fibronectin-3 (FN3) domain.
Three heterozygous protein-truncating variants and one heterozygous missense variant were identified in a cohort of 240 unrelated IHH patients. The authors also provided supporting evidence from animal models.
Sources: Literature

Created: 10 Jan 2020, 12:51 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Congenital hypogonadotropic hypogonadism (CHH)

Publications

• PMID: 31883645

Variants in this GENE are reported as part of current diagnostic practice