%0 Journal Article %J Retina %D 2019 %T PHENOTYPIC VARIABILITY OF RECESSIVE RDH12-ASSOCIATED RETINAL DYSTROPHY. %A Zou, Xuan %A Fu, Qing %A Fang, Sha %A Li, Hui %A Ge, Zhongqi %A Yang, Lizhu %A Xu, Mingchu %A Sun, Zixi %A Li, Huajin %A Yumei Li %A Dong, Fangtian %A Rui Chen %A Sui, Ruifang %K Adolescent %K Adult %K Alcohol Oxidoreductases %K Biological Variation, Population %K Child %K Child, Preschool %K DNA Mutational Analysis %K Electroretinography %K Eye Diseases, Hereditary %K Female %K Genotype %K Humans %K Male %K Middle Aged %K Mutation %K Pedigree %K Phenotype %K Retinal Dystrophies %K Visual Acuity %K Young Adult %X

PURPOSE: To characterize the phenotypic variability and report the genetic defects in a cohort of Chinese patients with biallelic variants of the retinol dehydrogenase 12 (RDH12) gene.

METHODS: The study included 38 patients from 38 unrelated families with biallelic pathogenic RDH12 variants. Systematic next-generation sequencing data analysis, Sanger sequencing validation, and segregation analysis were used to identify the pathogenic mutations. Detailed ophthalmic examinations, including electroretinogram, fundus photography, fundus autofluorescence and optical coherence tomography, and statistical analysis were performed to evaluate phenotype variability.

RESULTS: Twenty-five different mutations of RDH12 were identified in the 38 families. Six of these variants were novel. Val146Asp was observed at the highest frequency (23.7%), and it was followed by Arg62Ter (14.5%) and Thr49Met (9.2%). Twenty-three probands were diagnosed with early-onset severe retinal dystrophy, 6 with Leber congenital amaurosis, 7 with autosomal recessive retinitis pigmentosa, and 2 with cone-rod dystrophy. Self-reported nyctalopia occurred in about a half of patients (55.3%) and was significantly more common among older patients (P < 0.01). Nyctalopia was not significantly associated with best-corrected visual acuity (P = 0.72), but older patients had significantly greater best-corrected visual acuity loss (P < 0.01). Only 15.8% of the patients had nystagmus, which was significantly more likely to occur among 36.8% of the patients with hyperopia >3D (P < 0.01) and/or in cases of reduced best-corrected visual acuity (P = 0.01), but was not associated with age (P = 0.87).

CONCLUSION: Several high-frequency RDH12 variants were identified in patients with inherited retinal dystrophies, most of which were missense mutations. Variable but characteristic phenotypes of a progressive nature was observed. Overall, the findings indicated that biallelic RDH12 mutations are a common cause of early-onset retinal dystrophy and a rare cause of cone-rod dystrophy.

%B Retina %V 39 %P 2040-2052 %8 2019 Oct %G eng %N 10 %1 https://www.ncbi.nlm.nih.gov/pubmed/30134391?dopt=Abstract %R 10.1097/IAE.0000000000002242 %0 Journal Article %J Am J Hum Genet %D 2017 %T Mutations in the Spliceosome Component CWC27 Cause Retinal Degeneration with or without Additional Developmental Anomalies. %A Xu, Mingchu %A Xie, Yajing Angela %A Abouzeid, Hana %A Gordon, Christopher T %A Fiorentino, Alessia %A Sun, Zixi %A Lehman, Anna %A Osman, Ihab S %A Dharmat, Rachayata %A Riveiro-Álvarez, Rosa %A Bapst-Wicht, Linda %A Babino, Darwin %A Arno, Gavin %A Busetto, Virginia %A Zhao, Li %A Li, Hui %A Lopez-Martinez, Miguel A %A Azevedo, Liliana F %A Hubert, Laurence %A Pontikos, Nikolas %A Eblimit, Aiden %A Lorda-Sanchez, Isabel %A Kheir, Valeria %A Plagnol, Vincent %A Oufadem, Myriam %A Soens, Zachry T %A Yang, Lizhu %A Bole-Feysot, Christine %A Pfundt, Rolph %A Allaman-Pillet, Nathalie %A Nitschké, Patrick %A Cheetham, Michael E %A Lyonnet, Stanislas %A Agrawal, Smriti A %A Li, Huajin %A Pinton, Gaëtan %A Michaelides, Michel %A Besmond, Claude %A Li, Yumei %A Yuan, Zhisheng %A von Lintig, Johannes %A Webster, Andrew R %A Le Hir, Hervé %A Stoilov, Peter %A Amiel, Jeanne %A Hardcastle, Alison J %A Ayuso, Carmen %A Sui, Ruifang %A Chen, Rui %A Allikmets, Rando %A Schorderet, Daniel F %K Abnormalities, Multiple %K Adolescent %K Animals %K Child %K Child, Preschool %K Cyclophilins %K Female %K Humans %K Male %K Mice %K Mutation %K Pedigree %K Peptidylprolyl Isomerase %K Retinal Degeneration %K Young Adult %X

Pre-mRNA splicing factors play a fundamental role in regulating transcript diversity both temporally and spatially. Genetic defects in several spliceosome components have been linked to a set of non-overlapping spliceosomopathy phenotypes in humans, among which skeletal developmental defects and non-syndromic retinitis pigmentosa (RP) are frequent findings. Here we report that defects in spliceosome-associated protein CWC27 are associated with a spectrum of disease phenotypes ranging from isolated RP to severe syndromic forms. By whole-exome sequencing, recessive protein-truncating mutations in CWC27 were found in seven unrelated families that show a range of clinical phenotypes, including retinal degeneration, brachydactyly, craniofacial abnormalities, short stature, and neurological defects. Remarkably, variable expressivity of the human phenotype can be recapitulated in Cwc27 mutant mouse models, with significant embryonic lethality and severe phenotypes in the complete knockout mice while mice with a partial loss-of-function allele mimic the isolated retinal degeneration phenotype. Our study describes a retinal dystrophy-related phenotype spectrum as well as its genetic etiology and highlights the complexity of the spliceosomal gene network.

%B Am J Hum Genet %V 100 %P 592-604 %8 2017 Apr 06 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/28285769?dopt=Abstract %R 10.1016/j.ajhg.2017.02.008