Atypical Alstrom syndrome with novel ALMS1 mutations precluded by current diagnostic criteria

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Title: Atypical Alstrom syndrome with novel ALMS1 mutations precluded by current diagnostic criteria
Authors: Casey, Jillian
McGettigan, Paul A.
Brosnahan, Donal
et al.
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Date: Feb-2014
Online since: 2014-07-04T15:11:41Z
Abstract: We report on clinical and genetic studies in a non-consanguineous Irish sib-pair with infantile dilated cardiomyopathy and retinopathy. A diagnosis of Alström Syndrome (AS) was considered and diagnostic testing pursued. The Alströms gene (ALMS1) is very large (23 exons) and diagnostic testing of mutational hotspots (exon 6, 8 and 10) was negative. Furthermore the siblings were tall and did not have the typical phenotype of nystagmus, photophobia, obesity or hearing loss and so the AS diagnosis was removed. We then sought to identify the causative gene in this family using whole exome sequencing. Unexpectedly, the exome analysis identified novel compound heterozygous ALMS1 mutations in exon 5 (c.777delT:p.D260fs*26) and exon 20 (c.12145_12146insC:p.S4049fs*36) that segregated with the phenotype. Although the siblings show some clinical overlap with AS, their phenotype is not classical. It is plausible that their atypical presentation may be due to the location of the ALMS1 mutations outside the usual mutational hotspots. Our findings show how atypical cases of AS may be missed under the current diagnostic guidelines and support consideration of complete ALMS1 sequencing in children with two or more features, even if all of the core clinical features of AS are not present.
Funding Details: Health Research Board
Type of material: Journal Article
Publisher: Elsevier
Journal: European Journal of Medical Genetics
Volume: 57
Issue: 2-3
Start page: 55
End page: 59
Copyright (published version): 2014 Elsevier
Keywords: ALMS1Autosomal recessive dilated cardiomyopathyCone-rod dystrophyExomeGenotype-phenotype correlationsAlström syndrome
DOI: 10.1016/j.ejmg.2014.01.007
Language: en
Status of Item: Peer reviewed
Appears in Collections:Biomolecular and Biomedical Science Research Collection

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