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In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila
Published on: August 20, 2019
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PIGF deficiency causes a phenotype overlapping with DOORS syndrome
Smrithi Salian1, Hind Benkerroum1, Thi Tuyet Mai Nguyen1
1Department of Pediatrics, CHU Sainte-Justine Research Center, University of Montreal, 3175, Côte-Sainte-Catherine, Montreal, QC, H3T 1C5, Canada.
Human Genetics
|January 2, 2021
Summary
DOORS syndrome can occur without deafness. A novel PIGF gene variant impairs glycosylphosphatidylinositol (GPI) biosynthesis, linking PIGF to DOORS syndrome and GPI deficiency disorders.
Area of Science:
- Genetics and Molecular Biology
- Rare Diseases
- Biochemistry
Background:
- DOORS syndrome is a rare genetic disorder typically presenting with deafness, onychodystrophy, osteodystrophy, intellectual disability, and seizures.
- Mutations in several genes have been linked to DOORS syndrome, but the genetic landscape remains incompletely understood.
- Inherited disorders of glycosylphosphatidylinositol (GPI) biosynthesis are a group of rare conditions with significant clinical heterogeneity.
Purpose of the Study:
- To investigate the genetic cause of DOORS syndrome in two unrelated individuals presenting without the typical deafness phenotype.
- To identify novel genes associated with DOORS syndrome and explore potential overlaps with GPI deficiency disorders.
- To elucidate the functional consequences of identified genetic variants on GPI biosynthesis.
Main Methods:
- Whole exome sequencing was performed to identify genetic variants in the affected individuals.
- Flow cytometry analysis was utilized to assess glycosylphosphatidylinositol (GPI) biosynthesis.
- Clinical data from the affected individuals were reviewed and compared to known DOORS syndrome and GPI deficiency phenotypes.
Main Results:
- Two unrelated individuals with DOORS syndrome lacking deafness were found to harbor a homozygous missense variant (c.515C>G, p.Pro172Arg) in the PIGF gene.
- Functional analysis confirmed impaired glycosylphosphatidylinositol (GPI) biosynthesis in the affected individuals.
- This study identifies PIGF as a novel disease-causing gene for DOORS syndrome.
Conclusions:
- The PIGF gene plays a causal role in DOORS syndrome, particularly in cases presenting without deafness.
- This finding highlights a significant overlap between DOORS syndrome and inherited GPI deficiency disorders.
- Clinical variability is a key feature, necessitating a high index of suspicion for DOORS syndrome and GPI deficiencies even with atypical presentations.
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