# Multiple Congenital Anomalies-Hypotonia-Seizures Syndrome 2 Caused by a Novel PIGA Variant Not Associated with a Skewed X-Inactivation Pattern

## TL;DR

A new PIGA gene variant causes a rare genetic disorder in a male infant, with his mother showing normal X-chromosome inactivation.

## Contribution

A novel PIGA variant is identified in MCAHS2, not linked to skewed X-inactivation in the carrier mother.

## Key findings

- A male infant with MCAHS2 was found to have a novel PIGA variant.
- The mother showed a non-skewed X-inactivation pattern despite carrying the variant.
- Testing GPI-anchored protein expression in neutrophils is proposed for variant evaluation.

## Abstract

Germline variants in the phosphatidylinositol glycan class A (PIGA) gene, which is involved in glycosylphosphatidylinositol (GPI) biosynthesis, cause multiple congenital anomalies-hypotonia-seizures syndrome 2 (MCAHS2) with X-linked recessive inheritance. The available literature has described a pattern of almost 100% X-chromosome inactivation in mothers carrying PIGA variants. Here, we report a male infant with MCAHS2 caused by a novel PIGA variant inherited from his mother, who has a non-skewed pattern of X inactivation. Phenotypic evidence supporting the pathogenicity of the variant was obtained by flow-cytometry tests. We propose that the assessment in neutrophils of the expression of GPI-anchored proteins (GPI-APs), especially CD16, should be considered in cases with variants of unknown significance with random X-inactivation in carrier mothers in order to clarify the pathogenic role of PIGA or other gene variants linked to the synthesis of GPI-APs.