Excluding Digenic Inheritance of and Variants in Mabry Syndrome (OMIM 239300) Patient: Phenotypic Spectrum Associated with Gene Variants in Hyperphosphatasia with Mental Retardation Syndrome-3 (HPMRS3).

UNLABELLED

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, and , that underlie HPMRS 3 and 4.

BACKGROUND

In addition to HPMRS 3 and 4, disruption of four phosphatidylinositol glycan (PIG) biosynthesis genes, , , and , result in HPMRS 1, 2, 5 and 6, respectively.

METHODS

Targeted exome panel sequencing identified homozygous variants of unknown significance (VUS) in c:284A>G and c:259G>A. To assay the pathogenicity of these variants, we conducted a rescue assay in and deficient CHO cell lines.

RESULTS

Using a strong (pME) promoter, the 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 . By contrast, activity of the 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 c:284A>G, p.Tyr95Cys. We discuss strategies for establishing evidence for putative digenic inheritance in GPI deficiency disorders.