De novo mutations associated with sporadic cases of Caudal regresion syndrome

Abstract

Aim: The identification of de novo disease causing mutations in three Caucasian patients with sporadic Caudal Regression Syndrome (CRS). CRS is a rare and diverse congenital disorder which is characterised by different degrees of agenesis of the caudal spine. Known genetic mutations are only able to explain a fraction of cases and are not accounting for sporadic occurrences or the diversity of the disorder. Methods: Exome sequencing assay was conducted of the three sporadic cases and their biological parents. We targeted rare genetic variants as the underlying cause of CRS as well as de novo mutations. Further we investigated de novo indels, copy number variations (CNV) and compound heterozygosity. Identified mutations were ranked and filtered based on genomic, genetic and statistical features. Results: Sanger sequencing confirmed two different de novo mutations in two cases (detailed results will be presented). In addition, our analysis revealed several potentially causal compound heterozygous mutations which are also under investigation. Conclusion: CRS may be caused by de novo or compound heterozy mutations thus, i) the diversity of the disorder is mirrored in the underlying genetic architecture and its mutations; ii) ranking of compound heterozygous mutations enables identification of candidate genes.