Novel genetic causes for cerebral visual impairment.
Cerebral visual impairment (CVI) is a major cause of low vision in children due to impairment in projection and/or interpretation of the visual input in the brain. Although acquired causes for CVI are well known, genetic causes underlying CVI are largely unidentified. DNAs of 25 patients with CVI and intellectual disability, but without acquired (eg, perinatal) damage, were investigated by whole-exome sequencing. The data were analyzed for de novo, autosomal-recessive, and X-linked variants, and subsequently classified into known, candidate, or unlikely to be associated with CVI. This classification was based on the Online Mendelian Inheritance in Man database, literature reports, variant characteristics, and functional relevance of the gene. After classification, variants in four genes known to be associated with CVI (AHDC1, NGLY1, NR2F1, PGAP1) in 5 patients (20%) were identified, establishing a conclusive genetic diagnosis for CVI. In addition, in 11 patients (44%) with CVI, variants in one or more candidate genes were identified (ACP6, AMOT, ARHGEF10L, ATP6V1A, DCAF6, DLG4, GABRB2, GRIN1, GRIN2B, KCNQ3, KCTD19, RERE, SLC1A1, SLC25A16, SLC35A2, SOX5, UFSP2, UHMK1, ZFP30). Our findings show that diverse genetic causes underlie CVI, some of which will provide insight into the biology underlying this disease process.
Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.|Bartiméus Institute for the Visually Impaired, Zeist, The Netherlands.|Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.|Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands.
Daniëlle G M
DG
Bosch
Bartiméus Institute for the Visually Impaired, Zeist, The Netherlands.|Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands.
F Nienke
FN
Boonstra
Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
Nicole
N
de Leeuw
Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
Rolph
R
Pfundt
Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
Willy M
WM
Nillesen
Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.|Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.|Hubrecht Institute-KNAW, University Medical Centre Utrecht, CancerGenomics.nl, Utrecht, The Netherlands.
Joep
J
de Ligt
Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.|Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
Christian
http://orcid.org/0000-0003-1693-9699
C
Gilissen
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
Shalini
S
Jhangiani
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.|Texas Children's Hospital, Houston, TX, USA.|Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
James R
JR
Lupski
Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.|Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
Frans P M
FP
Cremers
Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.|Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands.
Bert B A
BB
de Vries
D000293:Adolescent; D019575:Blindness, Cortical / Q000175:diagnosis / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D056426:Genetic Loci; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult