Multiple Congenital Anomalies-Hypotonia-Seizures Syndrome 2 via the PIGA Gene

Multiple congenital anomalies-hypotonia-seizures syndrome 2 is a rare neurodevelopmental disorder with onset in utero or early infancy. It may be lethal in infancy. The major features include dysmorphic features, neonatal hypotonia, myoclonic seizures, and variable congenital anomalies involving the central nervous, cardiac, and urinary systems (Johnston et al. 2012. PubMed ID: 22305531; Kato et al. 2014. PubMed ID: 24706016; Tarailo-Graovac et al. 2015. PubMed ID: 25885527).

Females with a heterozygous pathogenic variant in PIGA are normally unaffected. Somatic pathogenic variants in PIGA are considered to be causative for paroxysmal nocturnal hemoglobinuria (Johnston et al. 2012. PubMed ID: 22305531; Belet et al. 2014. PubMed ID: 24357517).

Multiple congenital anomalies-hypotonia-seizures syndrome 2 is inherited in an X-linked recessive manner and caused by pathogenic variants in the PIGA gene which encodes the phosphatidylinositol glycan anchor biosynthesis class A protein. This protein is one of the enzymes involved in the first step of biosynthesis of the glycosylphosphatidylinositol (GPI) anchor, a glycolipid structure embedded in the plasma membrane. PIGA pathogenic variants are one genetic cause of early onset epileptic encephalopathy. Pathogenic variants in PIGA gene include missense, nonsense, splicing, and small deletion/duplications (both frameshift and in-frame). No large deletions and duplications have been reported (Johnston et al. 2012. PubMed ID: 22305531; Kato et al. 2014. PubMed ID: 24706016; Tarailo-Graovac et al. 2015. PubMed ID: 25885527; Human Gene Mutation Database).

Clinical sensitivity of PIGA in a large cohort of patients with Multiple congenital anomalies-hypotonia-seizures syndrome 2 relevant phenotypes is unavailable in the literature, because most of the studies are case reports. Analytical sensitivity is expected to be high because the pathogenic variants reported should be detectable by sequencing. PIGA pathogenic variants appear to be a rare cause of disease.

No large deletions and duplications have been reported involving the PIGA gene (Johnston et al. 2012. PubMed ID: 22305531; Kato et al. 2014. PubMed ID: 24706016; Tarailo-Graovac et al. 2015. PubMed ID: 25885527; Human Gene Mutation Database).

This test involves bidirectional Sanger sequencing of all coding exons and splice sites of the PIGA gene. The full coding sequence of each exon plus ~10 bp of flanking DNA on either side are sequenced. We will also sequence any single exon (Test #100) or pair of exons (Test #200) in family members of patients with known mutations or to confirm research results.