Limb disorders

Gene: NTN1

Red List (low evidence)

Comment on list classification: There is one patient reported in literature with a limb disorder (right hand polydactyly), heterozygous for a C-terminus missense variant in NTN1. At least 3 other patients, heterozygous for C-terminus NTN1 variants, had no polydcatyly. Based on the available evidence, NTN1 should be rated Red for Limb disorders.

Created: 23 Sep 2025, 12:27 p.m. | Last Modified: 23 Sep 2025, 12:27 p.m.

Panel Version: 7.10

PMID: 39648562 (Toms et al., 2024) reports a patient with right hand polydactyly, heterozygous for a de novo variant in NTN1: NM_004822.3:c.1483T>A p.(Tyr495Asn). Sequencing method: WGS.The patient (Female, 30 years old, White British) also had chorioretinal coloboma and microphthalmia, and bilateral sensorineural hearing loss. The C-terminus variant is not found in gnomAD v4.1.0; in silico prediction tools: Revel score = 0.5 (Uncertain), AlphaMissense score = 0.806 (Deleterious Supporting); predicted NMD escape (https://www.deciphergenomics.org/gene/NTN1/overview/protein-genomic-info)

Confoundingly, patients with congenital mirror movements from 3 families reported in PMID: 28945198 (Meneret et al., 2017) who also harboured heterozygous NTN1 variants at the C-terminal end (p.Cys601Arg, p.Ile518del, p.Cys601Ser) had normal eyesight, no oculomotor abnormalities, and no hearing impairment.

This gene appears to be intolerant to LoF variants (NTN1 pLI score = 1). NTN1 is associated with Mirror movements 4, OMIM:618264 (OMIM entry accessed 10th Sep 2025).

Based on the available evidence, this gene can only be rated Red for Limb disorders.
Sources: Literature

Created: 23 Sep 2025, 12:12 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
polydactyly, MONDO:0021003

Publications

• 28945198
• 39648562