TY - JOUR
T1 - Sacral agenesis
T2 - A pilot whole exome sequencing and copy number study
AU - Porsch, Robert M.
AU - Merello, Elisa
AU - De Marco, Patrizia
AU - Cheng, Guo
AU - Rodriguez, Laura
AU - So, Manting
AU - Sham, Pak C.
AU - Tam, Paul K.
AU - Capra, Valeria
AU - Cherny, Stacey S.
AU - Garcia-Barcelo, Maria Mercè
AU - Campbell, Desmond D.
PY - 2016/12/22
Y1 - 2016/12/22
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 type 1 diabetes. Method: Whole exome sequencing and copy number variation (CNV) analyses were conducted on 4 Caucasian trios to identify de novo and inherited rare mutations. Results: In 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. Conclusion: Despite the genetic diversity and the complexity of the phenotype, this pilot study identified genetic features common across CRS patients.
AB - 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. Method: Whole exome sequencing and copy number variation (CNV) analyses were conducted on 4 Caucasian trios to identify de novo and inherited rare mutations. Results: In 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. Conclusion: Despite the genetic diversity and the complexity of the phenotype, this pilot study identified genetic features common across CRS patients.
KW - Caudal regression
KW - Copy-number variation
KW - Sacral agenesis
KW - Whole exome sequencing
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U2 - 10.1186/s12881-016-0359-2
DO - 10.1186/s12881-016-0359-2
M3 - Article
AN - SCOPUS:85006877762
VL - 17
JO - BMC Medical Genetics
JF - BMC Medical Genetics
SN - 1471-2350
IS - 1
M1 - 98
ER -