Intellectual Disability via the PIGG 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).

Glycosylphosphatidylinositol (GPI) is a glycolipid that anchors various proteins to the cell surface. Defects in GPI biosynthesis cause congenital disorders of glycosylation, with clinical features including intellectual disability. PIGG-related GPI deficiency leads to a form of syndromic ID (Mental retardation, autosomal recessive 53, MRT53). The clinical features of MRT53 are variable and may include (but may not be limited to) delayed psychomotor development, intellectual disability, poor/absent speech, early-onset seizures, autistic features, cerebellar hypoplasia, ataxia, cerebral atrophy, hyporeflexia, joint laxity, muscular hypotonia, feeding difficulties, hearing impairment, growth retardation, dysmorphic features including hypertelorism, broad nose, depressed nasal bridge, thin upper lip and abnormalities of the head, neck, skeletal, genitourinary and cardiac systems (Makrythanasis et al. 2016. PubMed ID: 26996948; Zhao et al. 2017. PubMed ID: 28581210). Of note, some patients have been reported with increased serum alkaline phosphatase.

Pathogenic variants in human gene “Phosphatidylinositol glycan anchor biosynthesis class G protein” (PIGG) cause an autosomal recessive form of intellectual disability. PIGG maps to chromosome 4p16.3 and consists of 13 coding exons that translate into a 983 amino acid polypeptide. PIGG (alternatively known as GPI7) is an ER (endoplasmic reticulum)-associated phosphatidyl glycan that forms a complex with PIGF and attaches ethanolamine phosphate (EtNP) to the second mannose of GPI-AP (GPI-anchored protein) backbone, thus impacting the regulation of glycosylphostidylinositol (GPI) biosynthesis (Shishioh et al. 2005. PubMed ID: 15632136; Zhao et al. 2017. PubMed ID: 28581210). To date, missense, nonsense and splice site variants have been reported in human PIGG gene (Human Gene Mutation Database).

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 the majority of pathogenic variants reported within this gene to date are detectable by sequencing. To date, one gross deletion involving PIGG has been reported (Human Gene Mutation Database).

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