Retinal disorders

Gene: VWA8

Green List (high evidence)

Comment on list classification: There are now 2 unrelated probands reported in literature with monoallelic nonsense variants in VWA8 and retinitis pigmentosa. A mouse model presented in PMID: 42120427 (Kong et al., 2026) is supportive of this disease association. Homozygous knockout mice had a more severe retinal phenotype than heterozygous mutants (though biallelic cases not yet reported in human). There is one pedigree reported with a bialellic VWA8 missense variant segregating with a complex neurodevelopmental disorder without retinal disease - potentially resulting from a different disease mechanism. Based on available evidence, this gene can be promoted to Green on Retinal disorders with MOI set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted.

Created: 14 Aug 2026, 10:22 a.m. | Last Modified: 14 Aug 2026, 10:22 a.m.

Panel Version: 9.19

PMID: 40638000 Chacon-Camacho et al., 2025
Report of a Mexican patient suffering from retinitis pigmentosa. Classical features of retinal dystrophy were identified, including nyctalopia, peripheral visual field loss, as well as vascular attenuation, and bone spicules on fundus examination. Genetic analysis identified a novel pathogenic c.3069C>G (p.Tyr1023Ter) heterozygous VWA8 variant - 2 hets reported in gnomAD v4.1.1.

PMID: 34660594 Umair et al., 2021
Report of a large consanguineous family of Saudi origin with a complex developmental syndrome: global developmental delay, microcephaly, scoliosis, limbs, and cardiovascular malformations. Affected individuals were homozygous for the VWA8: c.947A>G; p.(Asp316Gly) variant - reported in 29 het individuals in gnomAD v4.1.1 (no homozygotes). Seq method: WES + Sanger confirmation in the parents and sibs.
Functional evidence: zebrafish morpholino approach showed delayed development at an early stage, lack of movement, light sensitivity, severe skeletal deformity such as scoliosis, and facial dysmorphism in vwa8-knockdown fish

PMID: 42120427 Kong et al., 2026 - Functional evidence - same research group as first patient report in PMID: 37012052
Authors constructed CRISPR Cas9 gene knockout mice with Vwa8 and identified Vwa8 wild-type, heterozygous (Vwa8+/-), and homozygous (Vwa8-/-) mice. Compared to the wild-type mice, the expression of the Hexokinase 2 (HK2) and Pyruvate kinase muscle (PKM) mitochondrial enzymes was reduced in mitochondria isolated from the retinal tissue of the Vwa8+/- and Vwa8-/- mice.
The Vwa8+/- mice showed partial retina pigmentation compared to the wild-type mice, whereas the Vwa8-/- mice had more significant abnormal pigmentation of the fundus. Electroretinogram (ERG) analysis revealed a significant reduction in b-wave amplitudes under photopic conditions in 10-month-old Vwa8+/- mice when compared to wild-type controls, while it was more severe in Vwa8-/- mice with only minimal electrical responses to light stimulation.

Created: 14 Aug 2026, 9:59 a.m. | Last Modified: 14 Aug 2026, 10:16 a.m.

Panel Version: 9.17

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
?Retinitis pigmentosa 97, OMIM:620422; retinitis pigmentosa 97, MONDO:0957314

Publications

• 34660594
• 40638000
• 42120427

Comment on list classification: New gene added by Hannah Knight. A single family (PMID: 37012052) with 11 individuals all presenting initial symptoms of visual defects which later progressed to macular changes, including macular degeneration and dystrophy. Two variants (c.3070G>A;c.4558C>T (p.Gly1024Arg; p.Arg1520Ter)) on the same allele of the VWA8 gene were found to segregate with disease. Expression studies showed reduced protein expression. Zebrafish knockdown model displayed a similar phenotype to that of humans.

Although there is only one family reported to date, multi-generational segregation with disease and concordant phenotype in a knockdown zebrafish model supports pathogenicity and therefore rating Amber with a 'watchlist' tag.

Created: 3 Jan 2024, 3:13 p.m. | Last Modified: 3 Jan 2024, 3:13 p.m.

Panel Version: 4.50

I don't know

PMID: 37012052 (2023) identified VWA8 as a novel cause of adRP in a four generation family with 11 affected family members.
6 of the affected members appear to have been tested and confirmed to carry the variant, while 5 unaffected members appear to have been confirmed NOT to
Sources: Literature

Created: 16 Nov 2023, 4:21 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
?Retinitis pigmentosa 97

Publications

• 37012052