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Whole genome sequencing identifies a novel ALMS1 gene mutation in two Chinese siblings with Alstrom syndrome.

ABSTRACT: Alström syndrome is a rare multi-systemic disorder with a broad spectrum of symptoms. This syndrome is characterized by childhood retinal degeneration; sensorineural hearing loss; obesity; type 2 diabetes mellitus; cardiomyopathy; systemic fibrosis; and pulmonary, hepatic, and renal failure.A Chinese quartet family with two siblings predominantly affected by cone-rod dystrophy and short stature were recruited. The craniofacial dysmorphism and on-set age-of-cone-rod dystrophy in the proband showed a minor intrafamilial variability. Whole genome sequencing was performed to provide the full spectrum of the two siblings' genetic variations. In this study, we present the patients' clinical features and our interpretation of the whole genome sequencing data. After examining the data, we focus on two compound heterozygous mutations, (c.3902C?>?A, p.S1301X; c.6436C?>?T, p.R2146X) in ALMS1, which are shared by two siblings.We reported a novel ALMS1 mutation. Whole genome sequencing is a powerful tool to provide the full spectrum of genetic variations for heterogeneous disorders such as Alström syndrome.

SUBMITTER: Yang L

PROVIDER: S-EPMC5518093 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Whole genome sequencing identifies a novel ALMS1 gene mutation in two Chinese siblings with Alström syndrome.

Yang Lin L Li Zixiu Z Mei Mei M Fan Xiaomei X Zhan Guodong G Wang Huijun H Huang Guoying G Wang Mingbang M Tian Weidong W Zhou Wenhao W

BMC medical genetics 20170719 1

<h4>Background</h4>Alström syndrome is a rare multi-systemic disorder with a broad spectrum of symptoms. This syndrome is characterized by childhood retinal degeneration; sensorineural hearing loss; obesity; type 2 diabetes mellitus; cardiomyopathy; systemic fibrosis; and pulmonary, hepatic, and renal failure.<h4>Case presentation</h4>A Chinese quartet family with two siblings predominantly affected by cone-rod dystrophy and short stature were recruited. The craniofacial dysmorphism and on-set a ...[more]

PMID: 28724398

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Project description:PurposeAlström syndrome (AS) is a rare monogenic autosomal recessively inherited disorder characterized by cone rod dystrophy and multiple organ dysfunction. Mutations in the Alström syndrome 1 (ALMS1) gene have been found to be causative for AS. The purpose of this study was to identify ALMS1 mutations and to assess the clinical features of Chinese patients with AS.MethodsDetailed ocular and laboratory examinations were performed. Peripheral blood samples were collected from patients and their parents. Genomic DNA was extracted with a Qiagen kit. Exons and exon/intron junctions of ALMS1 were amplified with polymerase chain reaction (PCR) and screened for mutations with Sanger sequencing. The results were compared with the ALMS1 transcript to exclude polymorphisms and confirm pathogenic mutations.ResultsSeven patients from five unrelated non-consanguineous families were diagnosed with AS. All patients had cone rod dystrophy with impaired visual acuity, photophobia, and nystagmus. Other clinical features, including sensorineural hearing loss, truncal obesity, insulin resistance, type 2 diabetes mellitus, renal and hepatic dysfunction, hyperlipidemia, hypothyroidism, mental retardation, acanthosis nigricans, and scoliosis, were present. Sequencing revealed two novel mutations, p.N3150Kfs2X and p.V3154Xfs, in patient 1; one novel mutation, p.N3672Ifs11X, and one previously reported nonsense mutation, p.R3703X, in patient 2; novel mutations p.S2479X and p.R3611Efs7X in patient 3; one novel homozygous mutation, p.S695X, in patients 4 and 5; and two novel mutations, p.H688HfsX and p.Q3147Qfs2X, in patients 6 and 7. These mutations were not present in 100 unrelated healthy Chinese control subjects. The patients' parents were heterozygous carriers of the mutant allele.ConclusionsSeven Chinese patients with AS showed typical ophthalmic features and multiple organ dysfunction. Novel loss of function mutations in the ALMS1 gene are the underlying genetic defects.

Dataset Information

Whole genome sequencing identifies a novel ALMS1 gene mutation in two Chinese siblings with Alstrom syndrome.

Publications

Whole genome sequencing identifies a novel ALMS1 gene mutation in two Chinese siblings with Alström syndrome.

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