Sacral Agenesis With Vertebral Anomalies

A number sign (#) is used with this entry because of evidence that sacral agenesis with vertebral anomalies (SAVA) is caused by homozygous mutation in the T gene (601397) on chromosome 6q27.

Clinical Features

Postma et al. (2014) reported 4 children from 3 consanguineous families with abnormalities of the spine, including sacral agenesis, abnormal ossification of all vertebral bodies, and a persistent notochordal canal during development. Sacral agenesis and a persistent notochord were detected prenatally in 3 of the patients. During ultrasound follow-up, the tubular notochord structure became progressively less visible and was gradually replaced by vertebral bodies. Two sibs died in the neonatal period. MRI of 1 of these infants showed sacral and left renal agenesis, persistent cloaca with anal atresia, and vertical clefting of the vertebral bodies. One affected child in a second family was developing well at 22 months' follow-up, but additional clinical details were not provided. CT scans in this patient showed 2 abnormal ossification centers in each vertebral body on either side of a radiolucent midline structure. No clinical information was available from the affected child in the third family. Postma et al. (2014) hypothesized that notochordal regression was delayed in these infants, which resulted in a persistent longitudinal canal that connected the midline structures of affected vertebrae with the nucleus pulposis of adjacent intervertebral discs. This canal interfered with normal ossification of the vertebral bodies, resulting in a vertebral cleft.

Inheritance

The transmission pattern of SAVA in the families reported by Postma et al. (2014) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 4 affected individuals from 3 unrelated consanguineous families with sacral agenesis with vertebral anomalies, Postma et al. (2014) identified a homozygous mutation in the T gene (H171R; 601397.0002). The mutation was found by homozygosity mapping followed by candidate gene sequencing. In vitro functional expression studies in a cell line with chondrogenic potential showed that the mutant protein had about 50% loss of DNA-binding activity compared to wildtype. Overexpression of the mutant protein in embryonic cells resulted in an increase in alkaline phosphatase, suggesting a misdirection towards the endoderm lineage in vitro. The mutation also caused an increase in cell growth and interfered with the normal expression of genes involved in ossification, notochord maintenance, and axial mesoderm development.