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

Area of Science:

• Genetics
• Developmental Biology
• Pediatric Medicine

Background:

• Caudal regression syndrome (CRS), also known as sacral agenesis, is a rare congenital disorder affecting the caudal spine, spinal cord, hindgut, urogenital system, and lower limbs.
• CRS results from abnormal caudal mesoderm development, influenced by genetic and environmental factors, with maternal type 1 diabetes being a known risk factor.

Purpose of the Study:

• To identify genetic factors contributing to Caudal Regression Syndrome (CRS).
• To investigate de novo and inherited rare mutations and copy number variations (CNVs) in CRS patients.

Main Methods:

• Whole exome sequencing was performed on four Caucasian trios.
• Copy number variation (CNV) analyses were conducted to detect deletions and duplications.
• Candidate genes and mutations were identified through sequencing and CNV analysis.

Main Results:

• Candidate genes SPTBN5, MORN1, ZNF330, CLTCL1, and PDZD2 were implicated in CRS.
• De novo mutations were found in SPTBN5, MORN1, and ZNF330.
• Inherited mutations in PDZD2 and CLTCL1, as well as mutations in PTEN, GLTSCR2, and VANGL1, were identified.
• Two CNV deletions, one de novo and one homozygous, were detected in a CRS patient, overlapping with previously reported deletions.

Conclusions:

• Despite the genetic heterogeneity and phenotypic complexity of CRS, common genetic features were identified across patients.
• This pilot study highlights potential causative genes and genetic mechanisms underlying CRS.