Abstracts

Rationale: The etiology of Landau-Kleffner syndrome (LKS) is still unknown but two earlier reports of siblings affected by LKS suggest a possible genetic role. Whole exome sequencing technology offers a promising approach to identify genetic causes of LKS. Methods: We performed whole exome sequencing in two siblings affected with classical LKS, including EEG pattern of CSWS and response to steroids. Briefly, Agilent V4 (51 MB) human exome enrichment kit was used to extract the exome library and sequencing was performed using Illumina HiSeq2000. Since both siblings were affected by LKS, we focused only on the variants segregating in an autosomal recessive manner (both homozygous and compound heterozygous). Novel, nonsynonymous variants with a minor allele frequency less than 1% (frequencies obtained from exome variant server) present in both siblings were considered as potential disease-associated variants. Sanger sequencing was subsequently used to validate the identified variants.Results: We identified compound heterozygous variants in 2 genes (Table): CUL7 (Figure A) and TBCD (Figure B). There were no homozygous variants that satisfied these criteria. Conclusions: Our findings suggest the role of CUL7 and TBCD in the etiology of LKS. Mutations in CUL7 are associated with autosomal recessive 3-M syndrome and disordered signaling of growth factors. Although these siblings did not have the classical features of 3-M syndrome, the height of one sibling was higher for her age (97 percentile) suggesting a possible abnormality in growth factor signaling. Similarly, TBCD is expressed in many regions of the brain and could potentially play a role in development of LKS. Oligogenic inheritance pattern and genetic pleiotropy could be the underlying mechanisms behind our observed findings.