Structural eye disease

Gene: NTN1

Comment on list classification: Updating the rating to amber. One case with a relevant phenotype plus some functional data from zebrafish. Note that there are cases reported with missense variants in the C-terminus of this gene, that do not exhibit the eye phenotype.

Created: 22 Sep 2025, 12:42 p.m. | Last Modified: 22 Sep 2025, 12:42 p.m.

Panel Version: 4.24

I don't know

Comment on list classification: There is one patient reported in literature with structural eye disease (coloboma and microphthalmia), heterozygous for a C-terminus missense variant in NTN1. At least 3 other patients, heterozygous for C-terminus NTN1 variants, had no ocular abnormalities. Gene knockouts in zebrafish and mouse embryos resulted in ocular coloboma phenotype, supporting the gene's role in eye development. Based on the available evidence, NTN1 should be rated Amber for Structural eye disease.

Created: 10 Sep 2025, 10:52 a.m. | Last Modified: 10 Sep 2025, 10:52 a.m.

Panel Version: 4.20

As reviewed by Hannah Knight, PMID: 39648562 (Toms et al., 2024) reports a patient with chorioretinal coloboma and microphthalmia, 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 bilateral sensorineural hearing loss and right hand polydactyly. 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.

Mouse, chick, and zebrafish models provide good evidence for NTN1's function in optic fissure fusion:
In PMID: 39648562, morpholino knockdown of ntn1a in zebrafish (86% gene similarity to human ortholog) had ocular coloboma and sensory hair cell defects.
PMID: 31162046 (Hardy et al.,2019): Gene knockdown in zebrafish, using sgRNA targeting the first exon of ntn1. Homozygous knockouts were phenotypic; meanwhile heterozygous fish had no ocular abnormalities. Ntn1-/- mice also displayed highly penetrant ocular coloboma (10/11). Transcriptomic profiling in chick embryos showed that NTN1 is expressed in the chick optic fissure closure.

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 Amber for Structural eye disease.

Created: 10 Sep 2025, 10:38 a.m. | Last Modified: 22 Sep 2025, 12:56 p.m.

Panel Version: 4.27

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
microphthalmia, isolated, with coloboma, MONDO:0000170

Publications

• 39648562
• 31162046

I don't know

PMID: 39648562 reported a patient with chorioretinal coloboma and microphthalmia who carried a heterozygous NTN1 variant, c.1483T>A p.(Tyr495Asn). Patient also had bilateral sensorineural hearing loss which was investigated by examining the sensory hair cells of ntn1a morphant zebrafish, suggesting a role for netrin‐1 in hair cell development.

NTN1 was previously identified as a mediator of optic fissure closure from transcriptome analyses of chick and zebrafish and was shown to cause ocular coloboma when knocked out in both mouse and zebrafish.
Sources: Literature

Created: 13 Aug 2025, 11:07 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Chorioretinal Coloboma; Sensorineural Hearing Loss; Polydactyly

Publications

• PMID: 39648562