Aim:Consanguineous marriages carry an increased risk of genetic conditions due to stretches of homozygosity in the genome and result in significant health and economic burden. Many of these conditions are difficult to diagnose despite comprehensive investigative methods. Next-generation sequencing offers the opportunity to better understand the genetic causes of neurogenetic disorders. The aim of this study is to obtain a comprehensive understanding of the genetic causes of childhood neurogenetic disorders in Turkey. The preliminary results of the ongoing study are presented.

Methods:Children with undiagnosed neurogenetic disorders born to consanguineous parents were recruited to the study. After deep phenotyping, whole exome sequencing(WES) was performed by Broad Institute MIT-Harvard. Variants were analyzed through RD-Connect and assessed for predicted deleterious effects by several bioinformatics algorithms.

Results:WES provided a molecular diagnosis for 21 families out of 31(67.74%)(Table1). Of the mutations, 52.38% were missense, 14.28% frameshift, 19.04% nonsense and 14.28% splice site. A novel candidate gene was discovered in one patient with leukodystrophy. New mutations were found in PRKCG and LAMB1 genes. Four patients(19.04%) had mutations in genes encoding mitochondrial proteins (NDUFS3,NDUFA12,COX6B1,TACO1). Two patients had a Turkish founder mutation in CLP1 gene and two patients had a possibly founder mutation in SAMHD1 gene.

Conclusion:Preliminary results of the study have already provided high diagnostic yield. Completion of the analyses of the aimed 250 families will provide important genomic data relevent to the Turkish population. Identifying genetic defects will lead to neurogenetic disease diagnosis and more effective targeted therapies in future. (This study is funded by TUBITAK-216S771).