| Author/Editor | 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. | |
| Title | The role of small in-frame insertions/deletions in inherited eye disorders and how structural modelling can help estimate their pathogenicity | |
| Type | članek | |
| Vol. and No. | Letnik 11, št. 1 | |
| Publication year | 2016 | |
| Volume | str. 1-8 | |
| ISSN | 1750-1172 - Orphanet journal of rare diseases | |
| Language | eng | |
| Abstract | Background:Although the majority of small in-frame insertions/deletions (indels) has no/little affect on proteinfunction, a small subset of these changes has been causally associated with genetic disorders. Notably, themolecular 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.Results:One hundred eighty-one probands with childhood cataracts and 486 probands with retinal dystrophyunderwent multigene panel testing in a clinical diagnostic laboratory. In-frame indels were collected and evaluatedboth clinically andin silico. Variants that could be modeled in the context of protein structure were identified andanalysed 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 thecorresponding protein sequence could be generated for 8 variants. Structural modeling indicated a diverse range ofmolecular mechanisms of disease including disruption of secondary and tertiary protein structure and alteration ofprotein-DNA binding sites.Conclusions:In childhood cataract and retinal dystrophy subjects, one small in-frame indel is clinically reported inevery ~37 individuals tested. The clinical utility of computational tools evaluating these changes increases when the fullcomplexity of the involved molecular mechanisms is embraced. | |
| Keywords | inherited eye disease retinal dystrophy childhood cataract dedna očesna bolezen distrofija mrežnice očesna mrena |