Retinal disorders

Gene: AIPL1

Green List (high evidence)

Comment on list classification: There is limited evidence for the association of AIPL1 and autosomal dominant cone-rod dystrophy. An overwhelming majority of reported patients harbour biallelic AIPL1 variants, with heterozygous carriers being unaffected. Variant p.Ala352_Pro355del in AIPL1 has the most supporting evidence for pathogenicity. However, the allele frequency in control populations is too high to cause dominant disease (MAF = 0.01129). In addition, the gene-disease relationship between AIPL1 and autosomal dominant retinal dystrophy has been classified as Disputed in ClinGen. Based on available evidence, the MOI should be changed to BIALLELIC.

Created: 19 Jan 2026, 12:32 p.m. | Last Modified: 19 Jan 2026, 12:34 p.m.

Panel Version: 8.78

Monoallelic cases:
https://doi.org/10.1016/j.humgen.2025.201413 Ghavidel et al., 2025
1 yo Iranian boy, heterozygous for AIPL1: c.834G>A, p.Trp278*. Consanguineous parents. Diagnosed with Leber's congenital amaurosis at 6 months old. Variant has max AF = 0.0004415 in gnomAD v4 (European pop) with 1 homozygote reported. Method: WES in proband, Sanger seq in family members.
The same mutation (p.W278X) was found in homozygosity in 5 Italian families and in compound het state with another AIPL1 mutation in 3 other families with recessive LCA (PMID: 21474771). Unlikely to be pathogenic dominant.

PMID: 10873396 Sohocki, et al., 2000
Identified 11 individuals with biallelic AIPL1 variants, as well as 2 apparently dominant pedigree, with affected individuals heterozygous (AIPL1):c.1053_1064del (p.Ala352_Pro355del). Heterozygous individuals presented with juvenile RP or dominant cone-rod dystrophy. Method: sequenced 6 exons of AIPL1 only. The pedigrees are small, dominant segregation not well established.
Mutation NM_014336.5(AIPL1):c.1053_1064del (p.Ala352_Pro355del) has MAF of 0.01129 (Ashkenazi Jewish population) in gnomAD v4.1.0, and 3 total homozygotes reported - too high to cause dominant disease.

Supporting functional evidence:
PMID: 33067476 Sacristan-Reviriego et al., 2020 - poses that this deletion has an alternative pathogenicity mechanism: PRD-mediated dominant negative effect causing cone-rod dystrophy
PMID: 25274777 Ku et al., 2015 - mouse model where p.A352_P355del human AIPL1 transgene was expressed in an Aipl1 null background. In single transgenic mice, the mutant transgene led to a cone-rod dystrophy phenotype, predominantly leading to a slow and progressive cone degeneration.

Biallelic cases:
PMID: 38880373 Zhang et al., 2024
Cohort of 51 Chinese patients with Leber congenital amaurosis (LCA) or early-onset severe retinal dystrophy (EOSRD); identified 28 disease-causing AIPL1 variants - biallelic cases only. Most common variant in the cohort was c.421C>T, p.Gln141* (18 patients homozygous, 6 heterozygous + another LoF variant).

PMID: 31576779 Wan et al., 2019
2 sibs with Leber congenital amaurosis, homozygous for AIPL1 p.Gln81* variant. Parents both heterozygous for the variant, unaffected.

PMID: 24426771 Li et al., 2014
Report of autosomal recessive retinal dystrophy in two consanguineous Pakistani families. Homozygous AIPL1: c.773G>C (p.Arg258Pro) variant detected in family 61032, and a homozygous AIPL1: c.465G>T (p.(H93_Q155del)) change in all affected members of family 61227. Heterozygous carriers had no signs of retinitis pigmentosa.

PMID: 21900377 Pennesi et al., 2011
Family 1: patient was found to have a homozygous Trp278 stop mutation in AIPL1; family 2: two siblings were compound heterozygous for AIPL1 (Leu17Pro and Lys214Asn). Variants confirmed in trans, het parents and sister unaffected. Sequenced 14 LCA-causing genes.

PMID: 15249368 Dharmaraj et al., 2004
Cohort of 303 LCA patients. Identified seventeen homozygotes and 9 compound heterozygotes. The ERG of a parent heterozygote carrier (het for W88X) revealed significantly reduced rod function, while ERGs for 6 other carrier parents were normal.

The gene-disease relationship between AIPL1 and autosomal dominant retinal dystrophy has been classified as Disputed in ClinGen (Retina GCEP, April 2025). AIPL1-related Leber congenital amaurosis (biallelic_autosomal) is ranked Definitive in Gene2Phenotype.

Created: 13 Jan 2026, 5:11 p.m. | Last Modified: 19 Jan 2026, 12:33 p.m.

Panel Version: 8.78

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Leber congenital amaurosis 4, OMIM:604393; Leber congenital amaurosis, MONDO:0018998

Publications

• 10873396
• 15249368
• 21474771
• 21900377
• 24426771
• 25274777
• 31576779
• 33067476
• 38880373

The mode of inheritance of this gene has been updated to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal' following NHS Genomic Medicine Service approval.

Created: 10 Oct 2023, 10:23 a.m. | Last Modified: 10 Oct 2023, 10:23 a.m.

Panel Version: 4.34

Mode of inheritance
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal

Comment on phenotypes: Previous phenotypes (overwritten): Achromatopsia, Cone, and Cone-rod Dystrophy; Cone-rod dystrophy (AD); Leber congenital amaurosis 4 (AR); Retinitis pigmentosa, juvenile (AD); Leber Congenital Amaurosis; Leber congenital amaurosis; Leber congenital amaurosis 4, 604393; Retinitis pigmentosa, juvenile, 604393; Cone-rod dystrophy, 604393; Eye Disorders; Retinitis Pigmentosa, Dominant; Retinitis Pigmentosa, Recessive; Retinitis pigmentosa

Created: 22 Nov 2022, 3:09 p.m. | Last Modified: 22 Nov 2022, 3:09 p.m.

Panel Version: 2.301

Comment on mode of inheritance: MOI should be updated from 'biallelic' to 'both mono- and biallelic (but biallelic mutations cause a more SEVERE disease form) at the next GMS panel update.

This gene is typically associated with recessive inheritance of a Leber congenital amaurosis (LCA) phenotype. However, some patients with heterozygous variants have also been identified, usually presenting less severe phenotypes within the retinal dystrophy spectrum such as retinitis pigmentosa and rod-cone dystrophy/dysfunction - although heterozygous variants act with reduced penetrance (PMID: 10873396; 15249368; 21900377; 33067476)

Both MOIs are also listed in OMIM.

Created: 22 Nov 2022, 3:04 p.m. | Last Modified: 22 Nov 2022, 3:04 p.m.

Panel Version: 2.299

Mode of inheritance
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal

Green List (high evidence)

Green List (high evidence)

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Leber congenital amaurosis 4

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

This gene is on the Manchester Genetic Retinal Degeneration Conditions panel (covers known genes for isolated progessive retinal degeneration, Leber congenital amaurosis, macular dystrophy, achromatopsia, congenital stationary night blindness as well as the two most common causes of syndromic blindess Usher and Bardet-Biedl syndromes and additional syndromes including Joubert, Senior-Loken, and Cohen syndrome.

Created: 2 Jun 2016, 8:03 a.m.

UKGTN source has Cone-rod dystrophy and Retinitis pigmentosa, juvenile as autosomal dominant mode of inheritance, Leber congenital amaurosis 4 as autosomal recessive mode of inheritance.

Created: 26 Apr 2016, 12:38 p.m.

Comment on mode of inheritance: Confirmed on G2P and OMIM.

Created: 15 Mar 2016, 10:43 a.m.