Intellectual disability and hemizygous GPD2 mutation.

Area of Science:

• Genetics
• Developmental Biology
• Biochemistry

Background:

• Intellectual disability (ID) and pervasive developmental disorders (PDDs) often have complex genetic etiologies.
• Array comparative genomic hybridization (aCGH) is a key tool for identifying copy number variations (CNVs) in patients with unexplained developmental disorders.
• Identifying causative genetic variants requires robust evidence, often including functional studies.

Observation:

• A 25-year-old female with ID, dysmorphic features, and PDD presented with a de novo 298 kb deletion at chromosome 2q24.1.
• This deletion encompassed the NR4A2 and GPD2 genes.
• Additional molecular analysis revealed a potentially pathogenic GPD2 variant (c.614C > T, p.Pro205Leu) in the patient, her mother, and sister.

Findings:

• Functional studies demonstrated absent GPD2 enzyme activity in the patient and 50% activity in her mother and sister, indicating a dose-dependent effect.
• While the GPD2 variant was present in healthy individuals, the combination of the deletion and the variant provided circumstantial evidence for its role in the patient's phenotype.
• Full confirmation of pathogenicity was limited without further studies or animal models.

Implications:

• This case highlights the challenges in definitively proving pathogenicity for genetic variants, especially when they occur in seemingly healthy relatives.
• The high cost of genetic workups and functional studies necessitates efficient diagnostic strategies.
• Advocates for the creation and utilization of accessible international genotype-phenotype databases to aid variant interpretation and reduce healthcare costs.