Phenotype-genotype correlations of PIGO deficiency with variable phenotypes from infantile lethality to mild learning difficulties

Abstract

Inherited GPI (glycosylphosphatidylinositol) deficiencies (IGDs), a recently defined group of diseases, show a broad spectrum of symptoms. Hyperphosphatasia mental retardation syndrome, also known as Mabry syndrome, is a type of IGDs. There are at least 26 genes involved in the biosynthesis and transport of GPI-anchored proteins; however, IGDs constitute a rare group of diseases, and correlations between the spectrum of symptoms and affected genes or the type of mutations have not been shown. Here, we report four newly identified and five previously described Japanese families with PIGO (phosphatidylinositol glycan anchor biosynthesis class O) deficiency. We show how the clinical severity of IGDs correlates with flow cytometric analysis of blood, functional analysis using a PIGO-deficient cell line, and the degree of hyperphosphatasia. The flow cytometric analysis and hyperphosphatasia are useful for IGD diagnosis, but the expression level of GPI-anchored proteins and the degree of hyperphosphatasia do not correlate, although functional studies do, with clinical severity. Compared with PIGA (phosphatidylinositol glycan anchor biosynthesis class A) deficiency, PIGO deficiency shows characteristic features, such as Hirschsprung disease, brachytelephalangy, and hyperphosphatasia. This report shows the precise spectrum of symptoms according to the severity of mutations and compares symptoms between different types of IGD.

Characterization of glycosylphosphatidylinositol biosynthesis defects by clinical features, flow cytometry, and automated image analysis

“…Psychomotor delay, ID, and variable AP elevation are the only consistent features of all individuals with pathogenic mutations in PIGV [ 9 , 28 – 34 ], PIGO [ 7 , 16 , 17 , 31 , 35 – 37 ], PGAP2 [ 4 , 8 , 18 , 38 ], PGAP3 [ 5 , 19 , 39 – 41 ], and PIGY [ 6 ]. Speech development, especially expressive language, is more severely affected than motor skills in the majority of the affected individuals (Table 1 ).…”

Characterization of Glycosylphosphatidylinositol Biosynthesis Defects by Clinical Features, Flow Cytometry, and Automated Image Analysis

“…Psychomotor delay, ID and variable AP elevation are the only consistent features of all individuals with pathogenic mutations in PIGV [9, 27-33], PIGO [7, 16, 17, 30, 34-36], PGAP2 [4, 8, 18, 37], PGAP3 [5, 19, 38-40], PIGW [3, 41], and PIGY [6]. Speech development, especially expressive language, is more severely affected than motor skills in the majority of the affected individuals (Table S1).…”

A homozygous variant disrupting the PIGH start-codon is associated with developmental delay, epilepsy, and microcephaly

“…One method commonly used to functionally assess variants in genes associated with the GPI‐anchor biogenesis is to perform FACS analysis on patient granulocytes. CD16 is often used as it is thought to be the most sensitive marker (Kato et al., ; Tanigawa et al., ). However, CD16 levels are also affected by how blood samples are handled and so patient samples are often compared to a small number of unrelated controls processed in the same batch.…”