Differentiating Alström from Bardet-Biedl syndrome (BBS) using systematic ciliopathy genes sequencing

Abstract

Introduction: Early onset retinal degeneration associated with obesity can present a diagnostic challenge in paediatric ophthalmology practice. Clinical overlap between Bardet-Biedl syndrome (BBS) and Alström syndrome has been described, although the two entities are genetically distinct. To date, 16 genes are known to be associated with BBS (BBS1-16) and only one gene has been identified for Alström syndrome (ALMS1).

Materials and Methods: In collaboration with the French National Center for Sequencing (CNS, Evry), all coding exons and flanking introns were sequenced for 27 ciliopathy genes (BBS1-12, MGC1203, TTC21b, AHI1, NPHP2-8 (NPHP6=BBS14), MKS1(BBS13), MKS3, C2ORF86, SDCCAG8, ALMS1) in 96 patients referred with a clinical diagnosis of BBS. ALMS1 gene analysis included sequencing of all coding exons.

Results: BBS known gene mutations were found in 44 patients (36 with two mutations and 8 heterozygous). ALMS1 mutations were found in four cases. The rate of ALMS1 mutations among patients suspected of having BBS was 4.2%.

Discussion: Clinically, all four patients presented early-onset severe retinal degeneration with congenital nystagmus associated with obesity. The difficult early differential diagnosis between the two syndromes is outlined. One mutation had already been reported (c.11310delAGAG/p.R3770fsX) and three were novel (c.2293C>T/p.Q765X, c.6823insA/p.R2275fsX, c.9046delA/p.N3016fsX).

Conclusions: Ciliopathy genes sequencing can be very helpful in providing a timely diagnosis in this group of patients, hence appropriate genetic counselling for families and adequate medical follow-up for affected children.

Keywords::

• Alström syndrome
• Bardet-Biedl syndrome
• ALMS1 gene
• retinal ciliopathy

ACKNOWLEDGMENTS

We would like to express our gratitude to Dr J. Roume, unité de génétique médicale, centre hospitalier intercommunal, Poissy, France, Dr C. Francannet, fédération de génétique humaine, service de génétique médicale, CHU Clermont-Ferrand, Clermont-Ferrand, France, and Dr S. Daoud, laboratoire Ayouche, Agadir, Maroc for referring patients.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.