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Yan Xu, Liping Guan, Xueshan Xiao, Jianguo Zhang, Shiqiang Li, Hui Jiang, Xiaoyun Jia, Ye Yin, Xiangming Guo, Qingjiong Zhang; ALMS1 truncation mutations identified by exome sequencing in 11 Chinese families with early-onset severe retinal degeneration. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):170.
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Homozygous or compound heterozygous truncation mutations in ALMS1, which are known to associate with Alström Syndrome, are the cause of initial diagnosis of early-onset severe retinal degeneration. The aim of this study was to identify recessive truncation mutations in ALMS1 in patients with retinal degeneration.
Clinical data and genomic DNA were collected for 455 Chinese families with retinal degeneration. Genomic DNA from probands was initially analyzed by whole exome sequencing. Candidate variants in ALMS1 were confirmed by Sanger sequencing. Potential pathogenic mutations were further validated mutations in available family members and 192 normal individuals.
In total, 15 mutations (14 truncation mutations and a missense; 10 were novel) were detected in 12 patients with early-onset severe retinal degeneration. Analysis of family members in nine of the 12 families demonstrated segregation of the disease with these mutations except for a compound heterozygous mutation consisting of a truncation mutation and a missense. One of these patients also suffered from congenital heart disease at the initial ophthalmic diagnosis. Many slight systemic manifestations, including mild hearing loss, obesity, expressive language delay, and band-like enamel hypoplasia, were found in available affected children in the following examination.
Causative mutations were detected in ALMS1 by exome sequencing in about 2.5% (11/455) of the studied families. This suggests that the patients with ALMS1 truncation mutations may initially be diagnosed with early-onset severe retinal degeneration because the abnormal ocular signs are the most obvious, and many of the systemic phenotypes are absent or mildly in infancy but develop throughout childhood and adolescence. These lines of evidence indicate that ALMS1 truncation mutations should be considered as a possible cause in patients initially diagnosed with early-onset severe retinal degeneration.
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