Monogenic hearing loss

Gene: NTN1

Comment on list classification: Promoting this gene to amber as there is 1 case plus some functional data supporting the association with hearing loss.

Created: 24 Sep 2025, 4:29 p.m. | Last Modified: 24 Sep 2025, 4:29 p.m.

Panel Version: 5.24

I don't know

Comment on list classification: There is one patient reported in literature with sensorineural hearing loss, heterozygous for a C-terminus missense variant in NTN1. At least 3 other patients, heterozygous for C-terminus NTN1 variants, had hearing impairment. Morpholino gene knockdown of ntn1a in zebrafish embryos resulted in sensory hair cell defects, supporting the gene's role in hearing. Based on the available evidence, NTN1 should be rated Amber for Monogenic hearing loss.

Created: 23 Sep 2025, 2:49 p.m. | Last Modified: 23 Sep 2025, 2:49 p.m.

Panel Version: 5.23

PMID: 39648562 (Toms et al., 2024) reports a patient with bilateral sensorineural hearing loss, 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 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.

Functional evidence:
In PMID: 39648562, morpholino knockdown of ntn1a in zebrafish (86% gene similarity to human ortholog) had ocular coloboma and sensory hair cell defects. At 5 dpf, hair cells of the lateral line neuromasts were found have abnormal morphology. There was also a significant reduction in the overall number of sensory hair cells present.

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 Monogenic hearing loss.

Created: 23 Sep 2025, 2:46 p.m. | Last Modified: 23 Sep 2025, 2:46 p.m.

Panel Version: 5.23

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
sensorineural hearing loss disorder, MONDO:0020678

Publications

• 28945198
• 39648562

Red List (low evidence)

NTN1 is not associated with a phenotype entry in OMIM.

Created: 9 Feb 2016, 10:07 a.m.

NTN1 is not associated with a phenotype entry in OMIM.

Created: 7 Feb 2016, 3:44 p.m.

Publications

• PMID:10485706
• 10958786
• 11048721
• 11239147
• 11239160
• 11986620
• 11986622
• 12352982
• 12827203
• 15343335
• 15494732
• 15494733
• 15494734
• 15510105
• 15520390
• 15758951
• 16809490
• 17908930
• 17916735
• 18353983
• 18585357
• 18776887
• 18796601
• 19349462
• 19589994
• 24876346
• 7604039
• 8895455
• 8978605
• 9796814
• 9950216