Rhizomelic Chondrodysplasia Punctata Type 3 via the AGPS Gene

Rhizomelic Chondrodysplasia Punctata (RCDP) is neonatal onset and characterized by proximal shortening of the long bones (rhizomelia), multiple epiphyseal calcifications and joint contractures, cataracts, dysmorphic facies, and profound intellectual disability and growth deficiency. Most patients with RCDP die in the first or second year, and a few survive beyond the first decade of life (Braverman et al. 2012). RCDP has three subtypes which are indistinguishable based on clinical presentation. Type 1 accounts for ~ 90% of clincially diagnosed RCDP and is a peroxisome biogenesis disorder caused by PEX7 mutations. RCDP types 2 and 3 are due to defects in GNPAT and AGPS, respectively, which encode two peroxisomal single enzymes required for plasmalogen synthesis. Less than 10 patients with AGPS mutations have been reported so far. The characteristic biochemical findings are the same in both RCDP types 2 and 3 patients, including deficient plasmalogen synthesis and normal levels of plasma phytanic acid and VLCFAs (C24:0 and C26:0) (Thai et al. 2001; Itzkovitz et al. 2011). Diagnosis is confirmed by measuring enzyme activity in cultured skin fibroblasts and/or identifying disease causing mutations in the AGPS gene.

RCDP type 3 is an autosomal recessive disorder caused by AGPS defects. AGPS encodes the enzyme alkyl-dihydroxyacetone phosphate synthase which mediates the second step of plasmalogen synthesis in the peroxisomes. The reported AGPS mutations include missense mutations and a gross deletion of exon 11 (Thai et al. 2001; Itzkovitz et al. 2011).

PEX7 mutations account for over 90% of all individuals with RCDP. The remaining 10% are caused by defects in GNPAT and AGPS (Braverman et al. 2012). To date, only about 20 patients with RCDP type 2 and less than 10 patients with RCDP type 3 have been reported (Thai et al. 2001; Itzkovitz et al. 2011).

Only one gross deletion affecting AGPS exon 11 has been reported so far (Itzkovitz et al. 2011).

This test provides full coverage of all coding exons of the AGPS gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.