| Autor: |
Azmanov DN; Laboratory for Molecular Genetics, Centre for Medical Research/Western Australian Institute for Medical Research, The University of Western Australia Perth, WA, Australia., Chamova T; Department of Neurology, Medical University Sofia, Bulgaria., Tankard R; Bioinformatics Division, The Walter and Eliza Hall Institute Melbourne, VIC, Australia., Gelev V; Faculty of Chemistry and Pharmacy, Sofia University Sofia, Bulgaria., Bynevelt M; Department of Surgery, School of Medicine, The University of Western Australia Perth, WA, Australia ; Neurological Intervention and Imaging Service (WA), Sir Charles Gairdner Hospital Perth, WA, Australia., Florez L; Laboratory for Molecular Genetics, Centre for Medical Research/Western Australian Institute for Medical Research, The University of Western Australia Perth, WA, Australia., Tzoneva D; Department of Anesthesiology and Intensive Care, University Hospital 'Alexandrovska' Sofia, Bulgaria., Zlatareva D; Department of Diagnostic Imaging, University Hospital 'Alexandrovska' Sofia, Bulgaria., Guergueltcheva V; Department of Neurology, Medical University Sofia, Bulgaria., Bahlo M; Bioinformatics Division, The Walter and Eliza Hall Institute Melbourne, VIC, Australia ; Department of Mathematics and Statistics, The University of Melbourne Melbourne, VIC, Australia., Tournev I; Department of Neurology, Medical University Sofia, Bulgaria ; Department of Cognitive Science and Psychology, New Bulgarian University Sofia, Bulgaria., Kalaydjieva L; Laboratory for Molecular Genetics, Centre for Medical Research/Western Australian Institute for Medical Research, The University of Western Australia Perth, WA, Australia. |
| Abstrakt: |
Exome sequencing was used as a diagnostic tool in a Roma/Gypsy family with three subjects (one deceased) affected by lissencephaly with cerebellar hypoplasia (LCH), a clinically and genetically heterogeneous diagnostic category. Data analysis identified high levels of unreported inbreeding, with multiple rare/novel "deleterious" variants occurring in the homozygous state in the affected individuals. Step-wise filtering was facilitated by the inclusion of parental samples in the analysis and the availability of ethnically matched control exome data. We identified a novel mutation, p.Asp487Tyr, in the VLDLR gene involved in the Reelin developmental pathway and associated with a rare form of LCH, the Dysequilibrium Syndrome. p.Asp487Tyr is the third reported missense mutation in this gene and the first example of a change affecting directly the functionally crucial β-propeller domain. An unexpected additional finding was a second unique mutation (p.Asn494His) with high scores of predicted pathogenicity in KCNV2, a gene implicated in a rare eye disorder, retinal cone dystrophy type 3B. This result raised diagnostic and counseling challenges that could be resolved through mutation screening of a large panel of healthy population controls. The strategy and findings of this study may inform the search for new disease mutations in the largest European genetic isolate. |
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