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A case-control collapsing analysis identifies retinal dystrophy genes associated with ophthalmic disease in patients with no pathogenic ABCA4 variants.

ABSTRACT: PURPOSE:Variants in the ABCA4 gene are causal for a variety of retinal dystrophy phenotypes, including Stargardt disease (STGD1). However, 15% of patients who present with symptoms compatible with STGD1/ABCA4 disease do not have identifiable causal ABCA4 variants. We hypothesized that a case-control collapsing analysis in ABCA4-negative patients with compatible symptoms would provide an objective measure to identify additional disease genes. METHODS:We performed a genome-wide enrichment analysis of "qualifying variants"-ultrarare variants predicted to impact protein function-in protein-coding genes in 79 unrelated cases and 9028 unrelated controls. RESULTS:Despite modest sample size, two known retinal dystrophy genes, PRPH2 and CRX, achieved study-wide significance (p?

SUBMITTER: Wolock CJ

PROVIDER: S-EPMC6768764 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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A case-control collapsing analysis identifies retinal dystrophy genes associated with ophthalmic disease in patients with no pathogenic ABCA4 variants.

Wolock Charles J CJ Stong Nicholas N Ma Chu Jian CJ Nagasaki Takayuki T Lee Winston W Tsang Stephen H SH Kamalakaran Sitharthan S Goldstein David B DB Allikmets Rando R

Genetics in medicine : official journal of the American College of Medical Genetics 20190330 10

<h4>Purpose</h4>Variants in the ABCA4 gene are causal for a variety of retinal dystrophy phenotypes, including Stargardt disease (STGD1). However, 15% of patients who present with symptoms compatible with STGD1/ABCA4 disease do not have identifiable causal ABCA4 variants. We hypothesized that a case-control collapsing analysis in ABCA4-negative patients with compatible symptoms would provide an objective measure to identify additional disease genes.<h4>Methods</h4>We performed a genome-wide enri ...[more]

PMID: 30926958

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Project description:PNPLA6-related disorders include several phenotypes, such as Boucher-Neuhäuser syndrome, Gordon Holmes syndrome, spastic paraplegia, photoreceptor degeneration, Oliver-McFarlane syndrome and Laurence-Moon syndrome. In this study, detailed clinical evaluations and genetic testing were performed in five (4 Chinese and 1 Caucasian/Chinese) syndromic retinal dystrophy patients. Genotype-phenotype correlations were analyzed based on review of the literatures of previously published PNPLA6-related cases. The mean age of patients and at first visit were 20.8 years (11, 12, 25, 28, 28) and 14.2 years (4, 7, 11, 24, 25), respectively. They all presented with severe chorioretinal dystrophy and profoundly decreased vision. The best corrected visual acuity (BCVA) ranged from 20/200 to 20/2000. Systemic manifestations included cerebellar ataxia, hypogonadotropic hypogonadism and hair anomalies. Six novel and three reported pathogenic variants in PNPLA6 (NM_001166111) were identified. The genotypes of the five cases are: c.3134C > T (p.Ser1045Leu) and c.3846+1G > A, c.3547C > T (p.Arg1183Trp) and c.1841+3A > G, c.3436G > A (p.Ala1146Thr) and c.2212-10A > G, c.3436G > A (p.Ala1146Thr) and c.2266C > T (p.Gln756*), c.1238_1239insC (p.Leu414Serfs*28) and c.3130A > G (p.Thr1044Ala). RT-PCR confirmed that the splicing variants indeed led to abnormal splicing. Missense variants p.Thr1044Ala, p.Ser1045Leu, p.Ala1146Thr, p.Arg1183Trp and c.3846+1G > A are located in Patatin-like phospholipase (Pat) domain. In conclusion, we report the phenotypes in five patients with PNPLA6 associated syndromic retinal dystrophy with variable systemic involvement and typical choroideremia-like fundus changes. Ocular manifestations may be the first and the only findings for years. All of our patients carried one severe deleterious variant (stop-gain or splicing variant) and one milder variant (missense variant). Retinal involvement was significantly correlated with severe deleterious variants and variants in Pat domain.

Dataset Information

A case-control collapsing analysis identifies retinal dystrophy genes associated with ophthalmic disease in patients with no pathogenic ABCA4 variants.

Publications

A case-control collapsing analysis identifies retinal dystrophy genes associated with ophthalmic disease in patients with no pathogenic ABCA4 variants.

Similar Datasets

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