PGAP3 – Hyperphosphatasia-Intellectual Disability Syndrome type 4

PGAP3 encodes a glycosylphosphatidylinositol (GPI)‐anchor remodeling enzyme. Biallelic loss‐of‐function or hypomorphic variants in PGAP3 cause autosomal recessive hyperphosphatasia-intellectual disability syndrome type 4 (Hyperphosphatasia-intellectual disability syndrome). Affected individuals present with global developmental delay, severe intellectual disability, hypotonia, facial dysmorphism and elevated serum alkaline phosphatase.

Multiple case reports and series describe over 32 probands from more than 14 unrelated families supporting a strong gene–disease relationship. Initial reports identified a novel missense variant c.851A>G (p.His284Arg) in two siblings (PMID:28794914) and a homozygous nonsense variant c.507C>A (p.Tyr169Ter) in two siblings (PMID:30217754). Monozygotic twins harboring c.203delC (p.Cys68LeufsTer88) were also described (PMID:31684969), as was a singleton case carrying c.320C>T (p.Ser107Leu) with atypical glaucoma features (PMID:38558875).

A cohort of 10 Egyptian patients revealed a recurrent founder frameshift c.402dupC (p.Met135HisfsTer28) and a novel c.817_820delGACT (p.Asp273SerfsTer37) in consanguineous families (PMID:28390064). Three unrelated South African patients share a homozygous missense c.557G>C (p.Arg186Thr) suggesting possible drift (PMID:32845056). Overall, segregation analysis confirms co-segregation in at least 9 affected relatives.

The variant spectrum includes missense (p.His284Arg), nonsense (p.Tyr169Ter), frameshift (p.Met135HisfsTer28, p.Asp273SerfsTer37), and founder alleles across diverse populations. No deep-intronic or structural variants have been reported, and carrier frequencies remain to be defined.

Functional studies demonstrate that PGAP3 mutations impair GPI-anchor maturation. CHO cell assays show loss of CD55/CD59 surface expression for p.Leu147ProfsTer16 and p.Gly92Asp alleles, implicating haploinsufficiency (PMID:24439110). Zebrafish morphants carrying p.Gln89Ter exhibit brain morphogenesis defects, hypotonia, and seizure-like behavior, phenocopying human patients (PMID:32726939).

Collectively, the evidence meets ClinGen criteria for a Strong gene–disease association in autosomal recessive HPMRS4. Both genetic and experimental data are concordant. PGAP3 molecular testing is recommended for patients with syndromic intellectual disability and elevated alkaline phosphatase. Key Take-home: PGAP3 loss-of-function causes autosomal recessive hyperphosphatasia-intellectual disability syndrome type 4 with consistent cellular and animal model support.

References

• Journal of pediatric genetics • 2017 • Hyperphosphatasia with Mental Retardation Syndrome Due to a Novel Mutation in PGAP3. PMID:28794914
• European journal of medical genetics • 2019 • Hyperphosphatasia with mental retardation syndrome type 4 In two siblings-expanding the phenotypic and mutational spectrum. PMID:30217754
• Diagnostic pathology • 2019 • Clinical, genetic, and molecular characterization of hyperphosphatasia with mental retardation: a case report and literature review. PMID:31684969
• Case reports in genetics • 2024 • Bilateral Glaucoma as Possible Additional Feature for PGAP3-Associated Hyperphosphatasia. PMID:38558875
• Clinical genetics • 2018 • PGAP3-related hyperphosphatasia with mental retardation syndrome: Report of 10 new patients and a homozygous founder mutation. PMID:28390064
• American journal of medical genetics. Part A • 2020 • Hyperphosphatasia with mental retardation syndrome type 4 in three unrelated South African patients. PMID:32845056
• American journal of human genetics • 2014 • Mutations in PGAP3 impair GPI-anchor maturation, causing a subtype of hyperphosphatasia with mental retardation. PMID:24439110
• Cells • 2020 • PGAP3 Associated with Hyperphosphatasia with Mental Retardation Plays a Novel Role in Brain Morphogenesis and Neuronal Wiring at Early Development. PMID:32726939

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