Alström syndrome: an example for efficient genetic testing in cilia-related disorders (ciliopathies)

Ciliary dysfunction has been shown to underlie a broad range of clinically and genetically heterogeneous phenotypes, the so-called ciliopathies. Literally all organs can be affected, frequent cilia-related manifestations are cystic kidney disease, retinal degeneration, deafness, skeletal disorders, and brain malformations, occurring either isolated or as part of syndromes. While there are some overlaps between different ciliopathies, genotype-phenotype correlations allow for time- and cost-efficient targeted testing approaches. We demonstrate this in two patients with Alström syndrome in whom we were able to identify loss-of-function mutations in the ALMS1 gene on chromosome 2p13. The phenotype in patients with Alström syndrome overlaps with that of Bardet-Biedl syndrome and typically shows retinal dystrophy, sensorineural hearing loss, obesity and endocrinological features, such as e. g., hypogonadism, diabetes mellitus, hypothyroidism, and hyperlipidemia. Other features that may point to the correct diagnosis are dilated cardiomyopathy and progressive pulmonary, hepatic and renal failure. Importantly, most patients have normal intelligence in contrast to patients with Bardet-Biedl syndrome who are often mentally retarded. Here we present our clinical and molecular data on Alström syndrome and an algorithm for efficient genetic testing approaches in a wide range of ciliopathies.

Cilia; ciliopathies; Alström syndrome; ALMS1; Bardet-Biedl syndrome (BBS)