TY - JOUR T1 - Sacral agenesis:A Whole Exome Sequencing and Copy Number Study JF - bioRxiv DO - 10.1101/058578 SP - 058578 AU - Robert M. Porsch AU - Elisa Merello AU - Patrizia De Marco AU - Guo Cheng AU - Laura Rodriguez AU - Paul K. Tam AU - Stacey S. Cherny AU - Pak C. Sham AU - Valeria Carpa AU - Maria-Mercé Garcia-Barcelo AU - Desmond D. Campbell Y1 - 2016/01/01 UR - http://biorxiv.org/content/early/2016/06/13/058578.abstract N2 - 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-insulin-dependent diabetes mellitus.Results In this pilot study, exome sequencing and copy number variation (CNV) analyses of 5 CRS trios implicate diabetes related genes, including MORN1, ZNF330, CLTCL1 and PDZD2. De novo mutations were identified in SPTBN5, MORN1 and ZNF330 and inherited damaging mutations in PDZD2 (homozygous) and CLTCL1 (compound heterozygous). In addition, a compound heterozygous mutation in GLTSCR2, a direct regulator of the CRS-related gene PTEN, was identified.Pathway based tests suggested the involvement of both pancreatic cancer (p < 1 × 10−4), and an immunity-related (p < 1 × 10−4) KEGG pathways.Two CNV deletions, one de novo (3q13.13) and one homozygous (8p23.2), 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 including mutations in genes associated with diabetes. ER -