PGAP1-Related Encephalopathy in an Infant With Neurodevelopmental Delay: Novel Variant and Review of Literature

Abstract

Spastic paraplegia-67, caused by a defect in glycosylphosphatidylinositol (GPI) biosynthesis, is an autosomal recessive neurodevelopmental disorder. It is characterized by dysmorphic features, spasticity, brain abnormalities, hypotonia, impaired intellectual development and speech difficulties. A 9-month-old girl was admitted to our clinic with a neurodevelopmental disorder, hepatomegaly, occasional vomiting, spasticity and hypotonicity. Whole exome sequencing (WES) was planned in the patient who had microcephaly, dysmorphic facial appearance, short and blunt fingers, a wide mouth, lacking physical sensation, dyskinetic movements, agenesis of the corpus callosum and cerebellar hypoplasia on MRI. In our study, we used whole-exome sequencing, family segregation and bioinformatics to identify a homozygous 3 bp duplication in the GPI remodelling gene PGAP1 (c.1226_1229dup p.(Val411Argfs*3) [NM_024989.4]) in a female patient with a neurodevelopmental disorder, encephalopathy and nonspecific autosomal recessive forms of intellectual disability (ARID). At least 26 genes are involved in the biosynthesis and remodelling of GPI junctions. Hypomorphic coding variants in seven of these genes have been reported to cause reduced expression of GPI-associated proteins (GPI-APs) on the cell surface and ARID. PGAP1 gene variants are important in understanding GPI biosynthesis defects, which can lead to severe neurodevelopmental disorders like spastic paraplegia-67. The identified homozygous variant (c.1226_1229dup) further expands the genetic spectrum of GPI-related disorders and underscores the role of WES in diagnosing rare encephalopathies with dysmorphic features.