title: Atypical Alstrom syndrome with novel ALMS1 mutations precluded by current diagnostic criteria.
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.
authors: National Children's Research Centre, Our Lady's Children's Hospital, Crumlin, Dublin 12, Ireland; Academic Centre on Rare Diseases, School of Medicine and Medical Science, University College Dublin, Belfield, Dublin 4, Ireland.
authors: Jillian
authors: J
authors: Casey
authors: Academic Centre on Rare Diseases, School of Medicine and Medical Science, University College Dublin, Belfield, Dublin 4, Ireland; UCD School of Agriculture, Food Science and Veterinary Medicine, University College Dublin, Dublin 4, Ireland.
authors: Paul
authors: P
authors: McGettigan
authors: Ophthalmology Department, Our Lady's Children's Hospital, Crumlin, Dublin 12, Ireland.
authors: Donal
authors: D
authors: Brosnahan
authors: Community Child Health/Neurology, The Adelaide and Meath Hospital, Tallaght, Dublin 24, Ireland.
authors: Emma
authors: E
authors: Curtis
authors: National Centre for Inherited Metabolic Disorders, Temple Street Children's University Hospital, Dublin 1, Ireland.
authors: Eileen
authors: E
authors: Treacy
authors: Academic Centre on Rare Diseases, School of Medicine and Medical Science, University College Dublin, Belfield, Dublin 4, Ireland; National Centre for Medical Genetics, Our Lady's Children's Hospital, Crumlin, Dublin 12, Ireland.
authors: Sean
authors: S
authors: Ennis
authors: Academic Centre on Rare Diseases, School of Medicine and Medical Science, University College Dublin, Belfield, Dublin 4, Ireland; National Centre for Medical Genetics, Our Lady's Children's Hospital, Crumlin, Dublin 12, Ireland; Genetics Department, Children's University Hospital, Temple Street, Dublin 1, Ireland. Electronic address: sallyann.lynch@olchc.ie.
authors: Sally Ann
authors: SA
authors: Lynch
mesh_terms: D056769:Alstrom Syndrome / Q000175:diagnosis* / Q000235:genetics*; D002311:Cardiomyopathy, Dilated / Q000175:diagnosis / Q000235:genetics; D018797:Cell Cycle Proteins; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005091:Exons; D005260:Female; D023061:Gene Order; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D010375:Pedigree; D011506:Proteins / Q000235:genetics*; D012174:Retinitis Pigmentosa / Q000175:diagnosis / Q000235:genetics
chemical_list: C490729:ALMS1 protein, human; D018797:Cell Cycle Proteins; D011506:Proteins
keywords: ALMS1; Alström syndrome; Autosomal recessive dilated cardiomyopathy; Cone–rod dystrophy; Exome; Genotype–phenotype correlations