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Reporting a Novel Disease Causing Variant in PGAP3 Associated With Hyperphosphatasia and Intellectual Disability: A
Arash Salmaninejad1,2,3, Mohammad Reza Seyedtaghia4, Ali Hosseini Bereshneh5
1Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, USA.
Background:
A rare autosomal recessive disorder known as hyperphosphatasia with impaired intellectual development syndrome (HPMRS), also referred to as Mabry syndrome, is caused by a deficiency in glycosylphosphatidylinositol (GPI). Elevated blood alkaline phosphatase (ALP) levels, cognitive impairment, and epileptic seizures are among its key features. These pathways are involved in the synthesis of GPI and the transfer of GPI anchor to the proteins, fatty acid remodeling, and transport of GPI-anchored proteins (GPI-APs).
Methods:
Using exome sequencing (ES), the cause of hyperphosphatasia and ID of an 11-year-old girl from non-consanguineous parents was solved, and the results confirmed by direct Sanger sequencing method.
Results:
ES identified a novel homozygous pathogenic variant, PGAP3 (NM_033419.5: c.202dupT, p.Cys68fs*2) that segregated within the family members. To the best of our knowledge at the time of writing this manuscript, this variant has not been reported in HPMRS in the literature.
Conclusion:
Our findings indicate that the p.Cys68fs*2 variant may disrupt normal protein function and likely disrupt its interaction with its associated partner proteins, potentially leading to disruption of GPI biosynthesis. We present a novel pathogenic variant thus expanding the phenotypic and mutational spectrum of this extremely rare disorder. Elevated ALP assays and ES are valuable diagnostic tools for HPMRS. Additionally, a comprehensive literature review was conducted to expand the phenotypic and genotypic spectrum within the PGAP3 gene responsible for HPMRS.
Insights
A novel pathogenic variant in the PGAP3 gene was identified in a patient with hyperphosphatasia with impaired intellectual development syndrome (HPMRS). This discovery expands the known genetic causes of this rare disorder.
Area of Science:
- Genetics
- Biochemistry
- Rare Diseases
Background:
- Hyperphosphatasia with impaired intellectual development syndrome (HPMRS), or Mabry syndrome, is a rare autosomal recessive disorder.
- It is characterized by elevated alkaline phosphatase (ALP) levels, cognitive impairment, and seizures, stemming from deficiencies in glycosylphosphatidylinositol (GPI) synthesis or anchoring.
- Key affected pathways include GPI biosynthesis, GPI anchor transfer, fatty acid remodeling, and GPI-anchored protein transport.
Purpose of the Study:
- To identify the genetic cause of HPMRS in an 11-year-old girl with hyperphosphatasia and intellectual disability.
- To expand the understanding of the genetic and phenotypic spectrum of HPMRS.
- To evaluate the utility of exome sequencing (ES) and ALP assays in diagnosing HPMRS.
Main Methods:
- Exome sequencing (ES) was employed to diagnose the proband.
- Sanger sequencing was used to confirm the identified variant.
- A comprehensive literature review was performed to analyze the PGAP3 gene's role in HPMRS.
Main Results:
- A novel homozygous pathogenic variant (c.202dupT, p.Cys68fs*2) in the PGAP3 gene was identified in the patient.
- This variant segregated within the family and has not been previously reported in association with HPMRS.
- The identified variant is predicted to disrupt PGAP3 protein function and potentially impair GPI biosynthesis.
Conclusions:
- The p.Cys68fs*2 variant in PGAP3 is likely pathogenic and contributes to HPMRS.
- This finding broadens the mutational spectrum of HPMRS.
- Elevated ALP assays and ES are crucial diagnostic tools for identifying HPMRS and understanding its genetic basis.
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