Syndromic Retinopathy

Gene: CLCN2

Green List (high evidence)

The homozygous R753X was detected in a Chinese individual from a consanguineous family with leukodystrophy with ataxia (LKPAT) (described in a previous paper) as well as severe bilateral retinal degeneration with loss of photoreceptor and RPE.

Four additional patients with LKPAT (described elsewhere) have been reported with homozygous variants and ocular features (Table 1).

Transfection to HEK293T cells showed that R753X reduced channel activity compared to wild-type.

Additionally, patient iPSC-derived RPE cells carrying the R753X exhibited dysfunctional ClC-2 chloride channels and outer segment phagocytosis. These functions were rescued following the repair of the CLCN2 mutation using the CRISPR-Cas9 system. NB: No significant difference was observed in the R753X mRNA expression levels between the control and patient hiPSC-RPE cells (suggesting NMD escape).
Sources: Literature

Created: 6 Apr 2023, 2:50 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Leukoencephalopathy with ataxia MIM# 615651

Publications

• 36964785

Green List (high evidence)

Association with hyperaldosteronism: Familial hyperaldosteronism type II is an autosomal dominant disorder characterized by hypertension due to increased aldosterone, often with hypokalemia. Patients usually present before age 20 years, although some may present in infancy. The disorder shows incomplete penetrance and variable expressivity; some patients may have normal blood pressure but have an increased aldosterone:renin ratio (ARR) on laboratory testing. At least 6 unrelated families reported. Note bi-allelic variants cause a different phenotype.

Association with leukodystrophy: At least six families reported, three with adult onset and three with childhood onset.

Created: 30 May 2021, 9:19 a.m. | Last Modified: 30 May 2021, 9:19 a.m.

Panel Version: 0.7719

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Leukoencephalopathy with ataxia, MIM# 615651; Hyperaldosteronism, familial, type II, MIM# 605635

Publications

• 29403011
• 29403012
• 23707145