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IMPG2 – Inherited Retinal Dystrophy

Biallelic truncating variants in IMPG2 cause autosomal recessive inherited retinal dystrophy (IRD) with a pseudodominant presentation in a consanguineous family. In Family 4 of a cohort study, the index patient and both parents were homozygous for c.2274G>A (p.Arg964Ter), segregating with retinitis pigmentosa across two generations ([PMID:33634125]).

Functional studies support a loss‐of‐function mechanism. A complex allele including c.3023-15T>A and c.3023G>A (p.Gly1008Asp) induces aberrant splicing and decreased full-length IMPG2 transcripts in HEK293T midigene assays and patient-derived photoreceptor precursor cells ([PMID:35608844]). In Impg2 mouse models, homozygous frameshift and nonsense mutations recapitulate early gliosis, photoreceptor outer segment loss, subretinal deposits, and outer retinal disruption ([PMID:37975905]).

Key Take-home: Loss-of-function IMPG2 variants underlie autosomal recessive IRD; genetic testing for truncating alleles informs diagnosis and family counseling.

References

  • Frontiers in cell and developmental biology • 2021 • Different Phenotypes in Pseudodominant Inherited Retinal Dystrophies. PMID:33634125
  • Investigative ophthalmology & visual science • 2022 • Identification of a Complex Allele in IMPG2 as a Cause of Adult-Onset Vitelliform Macular Dystrophy. PMID:35608844
  • Human molecular genetics • 2024 • Heterogeneity in the progression of retinal pathologies in mice harboring patient mimicking Impg2 mutations. PMID:37975905

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

One consanguineous family with pseudodominant AR inheritance; single proband with biallelic truncating variants

Genetic Evidence

Limited

Biallelic truncating variants in one family with pseudodominant inheritance ([PMID:33634125])

Functional Evidence

Moderate

In vitro splice assays demonstrate reduced full-length IMPG2 transcripts ([PMID:35608844]); mouse models with patient-mimicking LOF variants recapitulate retinal degeneration ([PMID:37975905])