Syndromic Intellectual Disability via the PIGY Gene

Intellectual Disability (ID) is a heterogeneous group of neurodevelopmental disorders, characterized by congenital limitation in intellectual functioning (intelligence quotient, IQ ≤70), and adaptive behavior. It is diagnosed in ~1–3% of the population before 18 years of age (American Association of Intellectual and Developmental Disabilities, AAIDD).

Hyperphosphatasia with mental retardation syndrome 6 (HPMRS6) is a form of syndromic ID caused by a defect in glycosylphosphatidylinositol (GPI) biosynthesis. The clinical features are variable, and in severe forms death may occur (Ilkovski et al. 2015. PubMed ID: 26293662). Individuals with HPMRS6 may present with global developmental delay, developmental regression, dysmorphic features, hypotonia, seizures, congenital cataracts, and anomalies of the abdominal, skeletal, genitourinary, dental, cardiac and muscular systems. Biochemical abnormalities include increased serum alkaline phosphatase, increased serum creatine kinase and decreased expression of GPI-anchored proteins (CD55 and CD59) on fibroblasts (Ilkovski et al. 2015. PubMed ID: 26293662).

Hyperphosphatasia with mental retardation syndrome 6 (HPMRS6) is an autosomal recessive disorder caused by pathogenic variants in human ‘Phosphatidylinositol Glycan Anchor Biosynthesis Class Y Protein’ gene (PIGY). PIGY maps to chromosome 4q22.1 and consists of one coding exon that translates into the 71 amino acid polypeptide PIGY. PIGY is a part of the GPI-N-acetylglucosaminyltransferase (GIP-GnT) complex, required for the biosynthesis of glycosylphosphatidylinositol (GPI). GPI is synthesized within the endoplasmic reticulum and serves as an anchor for many surface proteins, implicated in cell-cell interactions. To date, only two pathogenic variants (one missense and one in the regulatory region) have been reported in human PIGY, and there is no report of any gross deletion/duplication that includes PIGY.

This test is predicted to detect pathogenic variants in <0.1% of individuals with intellectual disability (ID). In this context, it is important to note that although pathological variants over 800 genes have been identified in individuals with ID, a genetic diagnosis is still lacking in most cases due to extreme clinical and genetic heterogeneity of the condition (Vissers et al. 2016. PubMed ID: 26503795). Analytical sensitivity should be high because all pathogenic variants reported within this gene to date are detectable by sequencing.

This test provides full coverage of all coding exons of the PIGY gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).