Abstract
BackgroundCaudal 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.MethodWhole exome sequencing and copy number variation (CNV) analyses were conducted on 4 Caucasian trios to identify de novo and inherited rare mutations.ResultsIn this pilot study, exome sequencing and copy number variation (CNV) analyses implicate a number of candidate genes, including SPTBN5, 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). Importantly, predicted damaging mutations in PTEN (heterozygous), in its direct regulator GLTSCR2 (compound heterozygous) and in VANGL1 (heterozygous) were identified. These genes had previously been linked with the CRS phenotype.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.ConclusionDespite the genetic diversity and the complexity of the phenotype, this pilot study identified genetic features common across CRS patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s12881-016-0359-2) contains supplementary material, which is available to authorized users.
Highlights
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
De novo mutations were found in SPTBN5, MORN1 and ZNF330 and inherited predicted damaging mutations in PDZD2 and CLTCL1
Two copy number variation (CNV) deletions, one de novo and one homozygous, were detected in one of our CRS patients. These deletions overlapped with CNVs previously reported in patients with similar phenotype
Summary
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. Caudal Regression Syndrome (CRS; Caudal Dysgenesis Syndrome, Caudal Dysplasia Sequence, Congenital Sacral Agenesis; OMIM 600145) is a rare (1 in 7,500– 100,000 births [1, 2]) congenital disorder characterized by varying degrees of spinal column agenesis Associated with it are anomalies of central nervous, genito-urinary, cardiac, respiratory and gastro-intestinal systems [3]. Fewer or even no cells will be available to form the notochord at a given abnormal segmental level. The consequences of such segmental notochordal paucity are manifold and affect the development of the spinal column and spinal cord as well as other organs that rely on the notochord as their inductor. If the prospective notochord is depleted a wide array of segmental vertebral malformations may develop
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