We present a case report of a child with features of hyperphosphatasia with neurologic deficit (HPMRS) or Mabry syndrome (MIM 239300) with variants of unknown significance in two post-GPI attachments to proteins genes,
PGAP2 and
PGAP3, that underlie HPMRS 3 and 4.
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We present a case report of a child with features of hyperphosphatasia with neurologic deficit (HPMRS) or Mabry syndrome (MIM 239300) with variants of unknown significance in two post-GPI attachments to proteins genes,
PGAP2 and
PGAP3, that underlie HPMRS 3 and 4. Background: In addition to HPMRS 3 and 4, disruption of four phosphatidylinositol glycan (PIG) biosynthesis genes,
PIGV,
PIGO,
PIGW and
PIGY, result in HPMRS 1, 2, 5 and 6, respectively. Methods: Targeted exome panel sequencing identified homozygous variants of unknown significance (VUS) in
PGAP2 c:284A>G and
PGAP3 c:259G>A. To assay the pathogenicity of these variants, we conducted a rescue assay in
PGAP2 and
PGAP3 deficient CHO cell lines. Results: Using a strong (pME) promoter, the
PGAP2 variant did not rescue activity in CHO cells and the protein was not detected. Flow cytometric analysis showed that CD59 and CD55 expression on the PGAP2 deficient cell line was not restored by variant
PGAP2. By contrast, activity of the
PGAP3 variant was similar to wild-type. Conclusions: For this patient with Mabry syndrome, the phenotype is likely to be predominantly HPMRS3: resulting from autosomal recessive inheritance of NM_001256240.2
PGAP2 c:284A>G, p.Tyr95Cys. We discuss strategies for establishing evidence for putative digenic inheritance in GPI deficiency disorders.
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