Sedaghatian type spondylometaphyseal dysplasia (SSMD) is a rare skeletal dysplasia with only 24 reported cases to date. Despite the limited literature available, evidence suggests this is a multi-system disorder, with neurological and cardiovascular abnormalities reported in addition to the skeletal features. We report a new family with two affected siblings and detailed phenotypic description of the affected proband. Diagnosis in the neonatal period led to retrospective genetic diagnosis of a previous affected pregnancy that was terminated due to severe ventriculomegaly. We suggest that a diagnosis of SSMD should be considered when shortened long bones are found in combination with significant brain abnormalities.

BACKGROUND: Sedaghatian-type spondylometaphyseal dysplasia (SSMD) is a neonatal lethal form of spondylometaphyseal dysplasia characterised by severe metaphyseal chondrodysplasia with mild limb shortening, platyspondyly, cardiac conduction defects, and central nervous system abnormalities. As part of the FORGE Canada Consortium we studied two unrelated families to identify the genetic aetiology of this rare disease.
RESULTS: Whole exome sequencing of a child affected with SSMD and her unaffected parents identified two rare variants in GPX4. The first (c.587+5G>A) was inherited from the mother, and the second (c.588-8_588-4del) was de novo (NM_001039848.1); both were predicted to impact splicing of GPX4. In vitro studies confirmed the mutations spliced out part of exon 4 and skipped exon 5, respectively, with both resulting in a frameshift and premature truncation of GPX4. Subsequently, a second child with SSMD was identified; although DNA from the child was not available, the two unaffected parents were found by Sanger sequencing to each carry the same heterozygous stop mutation in exon 3 of GPX4, c.381C>A, p.Tyr127* (NM_001039848.1).
CONCLUSIONS: Our identification of truncating mutations in GPX4 in two families affected with SSMD supports the pathogenic role of mutated GPX4 in this very rare disease. GPX4 is a member of the glutathione peroxidase family of antioxidant defence enzymes and protects cells against membrane lipid peroxidation. GPX4 is essential for early embryo development, regulating anti-oxidative and anti-apoptotic activities. Our findings highlight the importance of this enzyme in development of the cardiac, nervous, and skeletal systems.