The role of small in-frame insertions/deletions in inherited eye disorders and how structural modelling can help estimate their pathogenicity

• Published in: Orphanet journal of rare diseases Vol. 11; no. 1; p. 125
• Main Authors: Sergouniotis, Panagiotis I., Barton, Stephanie J., Waller, Sarah, Perveen, Rahat, Ellingford, Jamie M., Campbell, Christopher, Hall, Georgina, Gillespie, Rachel L., Bhaskar, Sanjeev S., Ramsden, Simon C., Black, Graeme C., Lovell, Simon C.
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 14.09.2016; BioMed Central
• Subjects: Accreditation; Cataract - genetics; Cataracts; Computational Biology; Consent; Crystallography; Diagnostic tests; Ethics; Eye diseases; Eye Diseases - genetics; Funding; Gene expression; Genetic aspects; Genetic variation; Genomes; Humans; INDEL Mutation - genetics; Laboratories; Medical research; Methods; Microscopy; NMR; Nuclear magnetic resonance; Proteins; Quality; Rare diseases; Reading Frames - genetics; Retinal Dystrophies - genetics; United Kingdom > UK; Inherited eye disease; Childhood cataract; Retinal dystrophy; In-frame insertions/deletions; Homology modeling
• ISSN: 1750-1172; 1750-1172
• DOI: 10.1186/s13023-016-0505-0

Although the majority of small in-frame insertions/deletions (indels) has no/little affect on protein function, a small subset of these changes has been causally associated with genetic disorders. Notably, the molecular mechanisms and frequency by which they give rise to disease phenotypes remain largely unknown. The aim of this study is to provide insights into the role of in-frame indels (≤21 nucleotides) in two genetically heterogeneous eye disorders. One hundred eighty-one probands with childhood cataracts and 486 probands with retinal dystrophy underwent multigene panel testing in a clinical diagnostic laboratory. In-frame indels were collected and evaluated both clinically and in silico. Variants that could be modeled in the context of protein structure were identified and analysed using integrative structural modeling. Overall, 55 small in-frame indels were detected in 112 of 667 probands (16.8 %); 17 of these changes were novel to this study and 18 variants were reported clinically. A reliable model of the corresponding protein sequence could be generated for 8 variants. Structural modeling indicated a diverse range of molecular mechanisms of disease including disruption of secondary and tertiary protein structure and alteration of protein-DNA binding sites. In childhood cataract and retinal dystrophy subjects, one small in-frame indel is clinically reported in every ~37 individuals tested. The clinical utility of computational tools evaluating these changes increases when the full complexity of the involved molecular mechanisms is embraced.