Rare Noncoding Mutations Extend the Mutational Spectrum in the PGAP3 Subtype of Hyperphosphatasia with Mental Retardation Syndrome

Abstract

HPMRS or Mabry syndrome is a heterogeneous glycosylphosphatidylinositol (GPI) anchor deficiency that is caused by an impairment of synthesis or maturation of the GPI‐anchor. The expressivity of the clinical features in HPMRS varies from severe syndromic forms with multiple organ malformations to mild nonsyndromic intellectual disability. In about half of the patients with the clinical diagnosis of HPMRS, pathogenic mutations can be identified in the coding region in one of the six genes, one among them is PGAP3. In this work, we describe a screening approach with sequence specific baits for transcripts of genes of the GPI pathway that allows the detection of functionally relevant mutations also including introns and the 5′ and 3′ UTR. By this means, we also identified pathogenic noncoding mutations, which increases the diagnostic yield for HPMRS on the basis of intellectual disability and elevated serum alkaline phosphatase. In eight affected individuals from different ethnicities, we found seven novel pathogenic mutations in PGAP3. Besides five missense mutations, we identified an intronic mutation, c.558‐10G>A, that causes an aberrant splice product and a mutation in the 3′UTR, c.*559C>T, that is associated with substantially lower mRNA levels. We show that our novel screening approach is a useful rapid detection tool for alterations in genes coding for key components of the GPI pathway.

PGAP3‐related hyperphosphatasia with mental retardation syndrome: Report of 10 new patients and a homozygous founder mutation

“…Pathogenic variants in PIGV gene are considered the most common cause of HPMRS and have been described in 16 unrelated families worldwide followed by PGAP3 mutations which were found in 9 different families . In the current study, we report on the clinical and molecular findings of 10 new patients from 8 unrelated Egyptian families with HPRMRS which is considered the largest cohort of patients from the same ethnic group.…”

“…The PGAP3 is the most recent identified gene incriminated in HPMRS. Authors distinguished PGAP3 ‐ related HPMRS from other types by the lack of brachytelephalangy in any of the affected individuals and designated it as HPMRS type 4 . In the current study, we describe 10 unreported patients with HPMRS harboring homozygous loss of function mutations in PGAP3 gene including a founder mutation.…”

“…To date, mutations in genes involved in the GPI‐anchor synthesis, PIGV ( MIM #610274), PIGW (MIM # 610275), PIGY (MIM # 610662), PIGO (MIM # 614730), and those of the anchor maturation, PGAP2 (MIM #614207) and PGAP3 (MIM #615716) have been described in patients with HPMRS …”

Genome-wide association study identifies novel recessive genetic variants for high TGs in an Arab population

“…Inbreeding helps with the aggregation of risk alleles in families; three of the reported gene loci in this study were also associated with phenotypes characterizing familial aggregation. PGAP3 is linked to congenital disorder of glycosylation (mabry syndrome) (92,93), SMOC1 is associated with microphthalmia with limb anomalies (94); and RPS6KA1 is associated with by guest, on April 8, 2019…”

A likely pathogenic variant putatively affecting splicing of PIGA identified in a multiple congenital anomalies hypotonia‐seizures syndrome 2 (MCAHS2) family pedigree via whole‐exome sequencing

“…Also, at least three splicing defective variants of PGAP1 (MIM 611655) have been reported in autosomal recessive mental retardation‐42 (MRT42, MIM 615802) and related syndromes with psychomotor retardation and brain atrophy as well as other features (Granzow et al., ; Kettwig et al., ; Novarino et al., ). More IGD cases with splicing defective variants include one variant of PGAP3 (MIM 611801) in hyperphosphatasia with mental retardation syndrome 4 (HPMRS4, MIM 615716) (Knaus et al., ), two variants of PIGL (MIM 605947) in Chime syndrome (MIM 280000) and related neurodevelopmental disorder (Ng et al., ; Pagnamenta et al., ), one variant of PIGO (MIM 614730) in HPMRS2 (MIM 614749) (Krawitz et al., ), and one variant of PIGG (MIM 616918) in autosomal recessive mental retardation‐53 (MRT53, MIM 616917) (Makrythanasis et al., ), etc . Therefore, it is not quite surprising that a putative splicing defective variant was uncovered in PIGA gene under a disease condition.…”