Sacral agenesis: A pilot whole exome sequencing and copy number study

Background Caudal regression syndrome (CRS) or sacral agenesis is a rare congenital disorder characterized by a constellation of congenital caudal anomalies affecting the caudal spine and spinal cord, the hindgut, the urogenital system, and the lower limbs. CRS is a complex condition, attributed to an abnormal development of the caudal mesoderm, likely caused by the effect of interacting genetic and environmental factors. A well-known risk factor is maternal type 1 diabetes. Results In this pilot study, exome sequencing and copy number variation (CNV) analyses of 4 CRS trios implicate a number of candidate genes, including MORN1 , ZNF330 , CLTCL1 and PDZD2 . De novo mutations were found in SPTBN5 , MORN1 and ZNF330 and inherited predicted damaging mutations in PDZD2 (homozygous) and CLTCL1 (compound heterozygous) as well as in CRS-related genes PTEN (heterozygous) and VANGL1 (heterozygous). In addition, a compound heterozygous mutation in GLTSCR2 , a direct regulator of PTEN was identified. Two CNV deletions, one de novo (chr3q13.13) and one homozygous (chr8p23.2), were detected in one of our CRS patients. These deletions overlapped with CNVs previously reported in patients with similar phenotype. Conclusion Despite the genetic diversity and the complexity of the phenotype, this pilot study identified genetic features common across CRS patients.