Challenges of diagnostic exome sequencing in an inbred founder population.
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.
Laboratory for Molecular Genetics, Centre for Medical Research/Western Australian Institute for Medical Research, The University of Western Australia Perth, WA, Australia.
Dimitar N
DN
Azmanov
Department of Neurology, Medical University Sofia, Bulgaria.
Teodora
T
Chamova
Bioinformatics Division, The Walter and Eliza Hall Institute Melbourne, VIC, Australia.
Rick
R
Tankard
Faculty of Chemistry and Pharmacy, Sofia University Sofia, Bulgaria.
Vladimir
V
Gelev
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.
Michael
M
Bynevelt
Laboratory for Molecular Genetics, Centre for Medical Research/Western Australian Institute for Medical Research, The University of Western Australia Perth, WA, Australia.
Laura
L
Florez
Department of Anesthesiology and Intensive Care, University Hospital "Alexandrovska" Sofia, Bulgaria.
Dochka
D
Tzoneva
Department of Diagnostic Imaging, University Hospital "Alexandrovska" Sofia, Bulgaria.
Dora
D
Zlatareva
Department of Neurology, Medical University Sofia, Bulgaria.
Velina
V
Guergueltcheva
Bioinformatics Division, The Walter and Eliza Hall Institute Melbourne, VIC, Australia ; Department of Mathematics and Statistics, The University of Melbourne Melbourne, VIC, Australia.
Melanie
M
Bahlo
Department of Neurology, Medical University Sofia, Bulgaria ; Department of Cognitive Science and Psychology, New Bulgarian University Sofia, Bulgaria.
Ivailo
I
Tournev
Laboratory for Molecular Genetics, Centre for Medical Research/Western Australian Institute for Medical Research, The University of Western Australia Perth, WA, Australia.
Luba
L
Kalaydjieva
Diagnostic exome sequencing; Roma/Gypsies; VLDLR; dysequilibrium syndrome; founder mutations