Abstract
Purpose :
Our purpose is to describe the clinical and molecular genetic findings of a family with multiple variants in genes causing inherited retinal dystrophies (IRDs).
Methods :
5-year-old dizygous twin brother and sister, born in 31st gestational week, were examined due to nyctalopia and reduced visual acuity. Clinical evaluation included visual acuity (BCVA), fundoscopy, OCT, autofluorescence imaging (FAF), ISCEV full-field electroretinography (ERG). Exome sequencing (WES) was carried out, a panel of 351 genes was analyzed. The identified variants were confirmed, segregation analysis of the asymptomatic parents was performed.
Results :
No signs of ROP were noticed in the children. BCVA was 0.8 in the boy (Patient A) and 1.0 in the girl (Patient B). Even though both had nyctalopic complaints, electroretinography showed reduced scotopic responses only in the girl. Photopic ERGs were normal in both cases. OCT and FAF images were also unremarkable.
Genetic testing has identified homozygous deletion in the GRK1 gene, heterozygous missense variants in GUCY2D and TYR genes in Patient B. In Patient A, the same deletion in GRK1 gene was found in heterozygous form, beside missense variant in the RHO gene. Segregation analysis showed the GRK1 and TYR variants in the father, the GRK1, RHO and GUCY2D variants in the mother, all in heterozygous form.
Conclusions :
Mutations in the GRK1 gene are associated with autosomal recessive Oguchi disease. The deletion found in the family (c.1610_1613del, p.Asp537Valfs*7), is a previously reported pathogenic variant. This finding explains the signs and symptoms of the homozygous Patient B.
Mutations in RHO gene cause autosomal dominant retinitis pigmentosa. Based on ACMG classification and in silico tools, the c.62G>A, p.Arg21His, found in Patient A is a variant of unknown significance. His normal ERG and the heterozygous father being asymptomatic imply this variant has no pathogenic role.
GUCY2D and TYR are associated with autosomal recessive IRDs and OCA. Although the variants found in this family are classified pathogenic, the heterozygosity suggest they play no pathogenic role. The subjective symptoms of Patient A are thus not confirmed by nor genetic, nor clinical findings.
Although IRDs are rare diseases, asymptomatic carriership is common in the IRD genes. However, having possible disease-causing variants in 4 genes within a family is rather unusual.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.