Value of whole exome sequencing for syndromic retinal dystrophy diagnosis in young patients

Several retinal dystrophies are associated with syndromic features including such conditions as Bardet-Biedl and Joubert syndromes. Cohen syndrome is an autosomal recessive disorder associated with multiple clinical manifestations including developmental delay, acquired microcephaly, myopia, pigmentary retinopathy, joint hypermobility, truncal obesity, friendly disposition and intermittent neutropenia. In young patients, diagnosis is difficult, because several of the characteristic features may not be present until school age or later years and the intermittent neutropenia is not always detectable. Design: This was a prospective study using whole exome sequencing in syndromic retinal dystrophy. It was undertaken in a hospital and research institute setting. Participants: Participants in this study were members of a consanguineous Australian family of Lebanese ethnicity with two siblings with retinal dystrophy, microcephaly and developmental delay. Methods: Detailed clinical evaluation was undertaken. Whole exome capture and sequencing of patient genomic DNA samples was followed by sequence alignment, variant detection, comparison and prioritization. Main Outcome Measures: Pathogenic variant identification in the disease-causing gene in affected individuals. Results: We identified a novel homozygous deletion leading to a frameshift mutation in VPS13B, c.11327del, p.(Asn3776Thrfs*102), the disease gene associated with Cohen syndrome. Conclusions: This report emphasizes the value of a broad-based whole exome sequencing approach in disease gene identification in the syndromic retinal dystrophies, where all disease characteristics may not be present in young patients to allow a clinical diagnosis. This facilitates improved prognostic and genetic information for patients and families.