Severe early-childhood-onset retinal dystrophy: genes and variants

Genes linked to Severe early-childhood-onset retinal dystrophy

• ABCA4: Retinal-specific phospholipid-transporting ATPase ABCA4

  It flips retinal-derived lipid adducts across photoreceptor disc membranes so they can be cleared during the visual cycle. Biallelic loss-of-function variants cause Stargardt disease and can also produce cone-rod dystrophy or retinitis pigmentosa.

  148 disease-causing and 63 uncertain variants in ABCA4 are linked to Severe early-childhood-onset retinal dystrophy.

• CRB1: Protein crumbs homolog 1

  It helps maintain apical polarity and structural organization of photoreceptors and Muller glia in the retina. Biallelic pathogenic variants cause inherited retinal dystrophies including Leber congenital amaurosis and retinitis pigmentosa.

  0 disease-causing and 0 uncertain variants in CRB1 are linked to Severe early-childhood-onset retinal dystrophy.

Weakly linked (only a few uncertain records): CLN3, BBS1 and RHO.

Where Severe early-childhood-onset retinal dystrophy variants cluster

• ABCA4 ABC transporter 1 (positions 929–1160): 26 of 148 disease-causing changes, 1.7× more than its size predicts.
• ABCA4 Transmembrane (positions 1832–1852): 5 of 148 disease-causing changes, 3.7× more than its size predicts.
• ABCA4 ABC transporter 2 (positions 1938–2170): 23 of 148 disease-causing changes, 1.5× more than its size predicts.
• ABCA4 Extracellular (positions 1853–1873): 4 of 148 disease-causing changes, 2.9× more than its size predicts.
• ABCA4 Transmembrane (positions 22–42): 3 of 148 disease-causing changes, 2.2× more than its size predicts.

Known disease-causing variants in Severe early-childhood-onset retinal dystrophy

Showing 60 of 148.

Uncertain variants in Severe early-childhood-onset retinal dystrophy that look disease-causing

Which prediction tools work for Severe early-childhood-onset retinal dystrophy

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• REVEL: 97 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 97 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MetaLR: 94 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 92 out of 100
• CADD: 91 out of 100
• PolyPhen-2: 90 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• phyloP: 89 out of 100

Same protein, different disease

• ABCA4-related retinopathy is also caused by ABCA4 variants; they fall partly in the same places as the Severe early-childhood-onset retinal dystrophy variants (60 disease-causing).
• Retinitis pigmentosa is also caused by ABCA4 variants; they fall partly in the same places as the Severe early-childhood-onset retinal dystrophy variants (58 disease-causing).
• Stargardt disease is also caused by ABCA4 variants; they fall mostly in different places as the Severe early-childhood-onset retinal dystrophy variants (41 disease-causing).
• Cone-rod dystrophy is also caused by ABCA4 variants; they fall partly in the same places as the Severe early-childhood-onset retinal dystrophy variants (29 disease-causing).
• Retinal disorder is also caused by ABCA4 variants; they fall in the same places as the Severe early-childhood-onset retinal dystrophy variants (7 disease-causing).

Diseases related to Severe early-childhood-onset retinal dystrophy

• Retinitis pigmentosa, also linked to ABCA4 and CRB1
• Leber congenital amaurosis, also linked to ABCA4 and CRB1
• Cone-rod dystrophy, also linked to ABCA4 and CRB1
• Autosomal recessive retinitis pigmentosa, also linked to ABCA4 and CRB1
• ABCA4-related retinopathy, also linked to ABCA4
• Stargardt disease, also linked to ABCA4
• Age related macular degeneration 9, also linked to ABCA4
• Retinal disorder, also linked to ABCA4
• Pigmented paravenous retinochoroidal atrophy, also linked to CRB1
• Optic atrophy, also linked to ABCA4
• Congenital stationary night blindness autosomal dominant 3, also linked to ABCA4
• Isolated macular dystrophy, also linked to ABCA4

Frequently asked questions

Which genes are linked to Severe early-childhood-onset retinal dystrophy?

In CATVariant, Severe early-childhood-onset retinal dystrophy is linked to 2 analyzed proteins: ABCA4 (Retinal-specific phospholipid-transporting ATPase ABCA4) and CRB1 (Protein crumbs homolog 1).

How many genetic variants are linked to Severe early-childhood-onset retinal dystrophy?

397 variants: 148 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 64 are of uncertain significance or have conflicting reports.

Which uncertain variants in Severe early-childhood-onset retinal dystrophy look disease-causing?

3 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example ABCA4 G991R, ABCA4 T959S and ABCA4 R1705W. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Severe early-childhood-onset retinal dystrophy?

Among tools not trained on clinical labels, SIFT separates this disease's known disease-causing variants from harmless ones best (AUROC 0.92, based on 135 disease-causing and 60 harmless variants).

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

Download every variant as CSV · Browse all diseases · Methods · About the Center