Abstract
Purpose:
The co-occurrence of familial exudative vitreoretinopathy (FEVR), or retinal folds/retinal dysplasia, associated with microcephaly has been reported multiple times in the literature. The purpose of this study was to investigate a consanguineous family segregating this phenotype, along with a cohort of sporadic cases, to determine the underlying genetic defect.
Methods:
Patients and family members underwent standard ophthalmic examination. The coding sequence and flanking splice sites of the known FEVR genes (NDP, FZD4, LRP5, TSPAN12) were PCR amplified and directly sequenced. For consanguineous cases, DNA was subjected to whole genome SNP genotyping (Affymetrix) and autozygosity mapping was performed using IBDfinder (http://dna.leeds.ac.uk/ibdfinder/). Whole exome sequencing (Agilent and Illumina) was performed on key individuals.
Results:
The majority of patients had a diagnosis of FEVR and microcephaly, although ophthalmic examination of the consanguineous familial cases revealed the presence of aniridia in addition to the posterior eye defects. Genetic screening of the known FEVR genes revealed no mutations. Regions of homozygosity were identified in consanguineous patients but no one region was present in all cases. Whole exome sequencing excluded the presence of recessive mutations in genes known to underlie primary microcephaly or microcephaly associated with ocular defects including KIF11 and CDK19. Eleven candidate homozygous and compound heterozygous variants shared by the familial cases are now being investigated further.
Conclusions:
Autozygosity mapping and whole exome sequencing highlighted a number of potential variants underlying FEVR and microcephaly. Due to the complexity of the phenotype in these patients, the cause could be a contiguous gene defect so low-coverage whole genome sequencing is currently ongoing to investigate copy number variations.