Novel genes associated with isolated optic nerve hypoplasia in 6 family trios - a clinical and exome study

Purpose Optic nerve hypoplasia (ONH) is a rare blinding malformation,ONH is often syndromic with MRI pituitary anomalies. We explore genetic causes of isolated ONH Methods Probands (2F/4M) 0.5-6 yrs with normal pituitary MRI were enrolled after consent with Pediatric, dysmorphologic and ophthalmologic endocrine examinations SNP aCGH, WES & Sanger validation sequencing. Ophth. exam: VEP,ERG,fundoscopy, color & acuity testing. Male patients tested for HESX. DNA extracted from lymphoblastoid lines or blood. DNA sequenced 30X in > 92% on Illumina platform; QC used Sam, Picard, Bed tools, variant call GATK, annotation snpEff/snpSift; filter using Autosomal Dominant hypothesis, absence in 1k, 65k 19 genomes,Exac databases. Variants present in subjects but not parents were selected and tested using polyphen2, Sift and mutation taster. 2nd approach for variant filtering using ANOVAR yielded 197 variants with strong deleterious effect; variants present in at least 2 pedigrees were then prioritized Results Patients followed 2-15 yrs had normal intelligence, eye examination showed normal ERG with abnormal VEP, dyschromatopsia VA ~20/200. 3 had learning difficulties, One F severe dyspraxia, and one M GH, Cortisol testosterone deficit and micropenis. 3 had sleeping disorders treated with melatonin. No HESX mutations were identified. All parents were healthy but 3 fathers were unavailable for blood sampling.SNP array CGH revealed a paternally inherited single 410,4 kb deletion of the 2p26.1 VRK2 gene described in complex intellectual disability. 5 genes showed deleterious missense mutations identified and being confirmed by Sanger sequencing Conclusions A 2p16.1 inherited deletion variant of unknown significance was identified on array CGH. WES analysis identified 5 candidate genes confirmed by Sanger sequencing which will need confirmation in a different dataset