LRAT

Inheritance Pattern: AR

Disease ID:MONDO:0013231

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0019118

Submitter: ClinGen

*LRAT* was first reported in relation to autosomal recessive early-onset retinal dystrophy (often described clinically as Leber congenital amaurosis / early-onset severe retinal dystrophy, with overlap into juvenile retinitis pigmentosa phenotypes) in 2001 (Thompson et al., PMID: 11381255). Per ClinGen disease-entity principles, reported LRAT-associated phenotypes fall on an early-onset retinal dystrophy spectrum (e.g., LCA/early-onset severe retinal dystrophy, autosomal recessive retinitis pigmentosa, and related entities such as retinitis punctata albescens). In this summary, these are considered part of a shared biallelic LRAT-related retinopathy spectrum given a consistent underlying pathway (visual-cycle deficiency) and overlapping core features (early-onset night blindness/visual impairment with progressive retinal degeneration). Human genetic evidence includes multiple unrelated affected individuals/families with biallelic LRAT variants reported across multiple publications since the original 2001 report, as well as subsequent case reports/series expanding the phenotype and variant spectrum (e.g., homozygous frameshift reported with retinitis punctata albescens; PMID: 22559933; and an intronic splice-altering variant supported by minigene assays in a consanguineous family with early-onset RP; PMID: 29973277). Reported pathogenic variant types include missense, frameshift, and splice-altering changes (PMIDs: 11381255, 17011878, 24265693, 28418496, 24625443, 30054919, 22570351, 22559933, 29973277). The mechanism of disease is most consistent with loss of function due to disruption of LRAT enzymatic activity in the visual cycle (supported by the nature of reported variant types and functional pathway relevance; PMIDs: 11381255, 22559933). Evidence supporting the gene–disease relationship includes biochemical studies showing that *LRAT* encodes lecithin retinol acyltransferase, a key enzyme in the retinoid (visual) cycle in the retinal pigment epithelium, required for generation/regeneration of visual chromophore. Disruption of this pathway is consistent with severe early-onset photoreceptor dysfunction and progressive retinal degeneration (PMID: 11381255). Disease-relevant model systems demonstrate that LRAT deficiency causes retinal dysfunction/degeneration and that restoring/bypassing LRAT function can improve retinal physiology. For example, *Lrat−/−* mouse studies show a phenotype consistent with human congenital/early-onset blindness and demonstrate rescue of retinal function via AAV-mediated gene therapy and pharmacologic bypass retinoids (PMID: 16250670). Additional animal model development and phenotyping (e.g., *Lrat−/−* rat) further support a consistent retinal degeneration phenotype (PMID: 34281288). In summary, there is Definitive evidence supporting the relationship between *LRAT* and *LRAT*-related retinopathy, based on multiple human case reports across time since 2001 and supportive experimental model/rescue data (PMIDs: 11381255, 17438524, 22559933, 29973277, 16250670, 34281288). This classification was approved by the ClinGen Retina Gene Curation Expert Panel on March 5th, 2026 (SOP Version 12).

Inheritance Pattern: AR

Disease ID:MONDO:0013231

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0019200

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0009549

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0013231

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0018998

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0018998

Submitter: PanelApp Australia