Expanding the clinical and molecular characteristics of PIGT-CDG, a disorder of glycosylphosphatidylinositol anchors

Abstract

PIGT-CDG, an autosomal recessive syndromic intellectual disability disorder of glycosylphosphatidylinositol (GPI) anchors, was recently described in two independent kindreds [Multiple Congenital Anomalies-Hypotonia-Seizures Syndrome 3 (OMIM, #615398)]. PIGT encodes phosphatidylinositol-glycan biosynthesis class T, a subunit of the heteropentameric transamidase complex that facilitates the transfer of GPI to proteins. GPI facilitates attachment (anchoring) of proteins to cell membranes. We describe, at ages 7 and 6 years, two children of non-consanguineous parents; they had hypotonia, severe global developmental delay, and intractable seizures along with endocrine, ophthalmologic, skeletal, hearing, and cardiac anomalies. Exome sequencing revealed that both siblings had compound heterozygous variants in PIGT (NM_015937.5), i.e., c.918dupC, a novel duplication leading to a frameshift, and c.1342C> T encoding a previously described missense variant. Flow cytometry studies showed decreased surface expression of GPI-anchored proteins on granulocytes, consistent with findings in previous cases. These siblings further delineate the clinical spectrum of PIGT-CDG, reemphasize the neuro-ophthalmologic presentation, clarify the endocrine features, and add hypermobility, low CSF albumin quotient, and hearing loss to the phenotypic spectrum. Our results emphasize that GPI anchor-related congenital disorders of glycosylation (CDGs) should be considered in subjects with early onset severe seizure disorders and dysmorphic facial features, even in the presence of a normal carbohydrate-deficient transferrin pattern and N-glycan profiling. Currently available screening for CDGs will not reliably detect this family of disorders, and our case reaffirms that the use of flow cytometry and genetic testing is essential for diagnosis in this group of disorders.

Novel PIGT Variant in Two Brothers: Expansion of the Multiple Congenital Anomalies-Hypotonia Seizures Syndrome 3 Phenotype

“…Thus, reduced GPI-anchoring of ALPL was proposed to cause the skeletal defects and epilepsy in the patients with MCAHS3 [11]. However, a normal level of serum alkaline phosphatase was measured in the two brothers in the current report, and in the siblings reported by Lam [16], who presented with both epilepsy and skeletal defects. These findings indicate that a low serum level of the alkaline phosphatase isoenzymes, including ALPL, cannot entirely explain the presence of these clinical features in the patients with MCAHS3.…”

“…Including the present report, nine patients from four families were hitherto reported with MCAHS3, caused by PIGT mutations (Table 1) [11,16,17]. Hypotonia, global developmental delay/ID, epileptic seizures, cortical visual impairment, and craniofacial dysmorphisms were present in all patients.…”

“…It is located in the GPI-TA domain (spanning amino acids 22 to 578) [28], which transfers mature GPI-anchors to target proteins. Biallelic mutations in PIGT are known to cause MCAHS3 [11,16,17], which was compatible with the clinical phenotype in the two brothers.…”

“…In another patient, the atrophy also affected the basal ganglia [11]. Repeated MRI examinations revealed that the atrophic process, especially of the cerebellum, was most pronounced at a young age [11,16]. …”

“…Biallelic variants in PIGT were previously described in seven patients from three families with Multiple Congenital Anomalies-Hypotonia Seizures Syndrome 3 (MCAHS3, Online Mendelian Inheritance in Man (OMIM) 615398) [11,16,17], characterized by infantile onset of epilepsy, hypotonia, global developmental delay/intellectual disability (ID), craniofacial dysmorphic features, ophthalmological defects, cerebral and cerebellar atrophy, and congenital anomalies involving skeletal, cardiac, and genitourinary systems. We report a novel homozygous PIGT missense variant c.1079G>T (p.Gly360Val) in two brothers presenting with infantile onset epilepsy, hypotonia, severe ID, dysmorphic features, ophthalmological defects, and brain dysfunction typical of MCAHS3.…”