IMPG1 – Adult-onset Foveomacular Vitelliform Dystrophy

Adult-onset foveomacular vitelliform dystrophy (AVMD) is an autosomal-dominant macular dystrophy characterized by dome-shaped, yellowish subretinal deposits at the fovea and typically presents in mid-adult life. AVMD falls within the spectrum of vitelliform macular dystrophies (Disease Name). While BEST1 and PRPH2 explain many cases, a subset of patients lacks variants in these genes.

In a large multiplex family with autosomal-dominant AVMD, linkage analysis and exome sequencing identified an IMPG1 c.713T>G (p.Leu238Arg) variant that co-segregated with disease in multiple affected members (PMID:23993198). The same variant recurred in two additional unrelated AVMD pedigrees, bringing the total to ≥3 independent families with definitive segregation (≥8 affected relatives) and a consistent adult-onset phenotype.

Screening of 144 probands with various macular dystrophies uncovered two individuals homozygous for a splice-site variant, c.807+1G>T, and two patients compound heterozygous for c.461T>C (p.Leu154Pro) and c.1519C>T (p.Arg507Ter), establishing autosomal-recessive IMPG1-associated VMD in separate kindreds (PMID:23993198). These findings demonstrate both dominant and recessive inheritance modes.

A functional study in BEST1/PRPH2-negative VMD patients confirmed two novel IMPG1 variants: a heterozygous p.Leu238Pro missense change and a homozygous c.807+5G>A splice variant. The latter induced partial exon skipping in an in vitro assay, supporting a loss-of-function mechanism through impaired interphotoreceptor matrix assembly (PMID:28644393).

Collectively, >5 unrelated probands, multi-family segregation in autosomal-dominant cases, identified autosomal-recessive pedigrees, and concordant functional data establish a strong clinical validity for IMPG1 in AVMD. These insights enable targeted genetic testing and inform prognosis and counseling for affected individuals.

Key Take-home: IMPG1 testing should be included in the diagnostic evaluation of adult-onset foveomacular vitelliform dystrophy due to its strong genetic and functional evidence base.

References

• American Journal of Human Genetics • 2013 • Mutations in IMPG1 cause vitelliform macular dystrophies. PMID:23993198
• Genes • 2017 • Mutations in the Genes for Interphotoreceptor Matrix Proteoglycans, IMPG1 and IMPG2, in Patients with Vitelliform Macular Lesions. PMID:28644393

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