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

作者：Casey Jillian; McGettigan Paul; Brosnahan Donal; Curtis Emma; Treacy Eileen; Ennis Sean; Lynch Sally Ann^*

来源：European Journal of Medical Genetics, 2014, 57(2-3): 55-59.

DOI：10.1016/j.ejmg.2014.01.007

• Alstrom syndrome
• ALMS1
• Autosomal recessive dilated cardiomyopathy
• Cone-rod dystrophy
• Exome
• Genotype-phenotype correlations

We report on clinical and genetic studies in a non-consanguineous Irish sib-pair with infantile dilated cardiomyopathy and retinopathy. A diagnosis of Alstrom Syndrome (AS) was considered and diagnostic testing pursued. The Alstroms 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.

• 出版日期2014-2