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Background <p>Present study aimed to identify the underlying genetic defect for autosomal recessive retinitis pigmentosa (arRP) with moderate myopia (-3.0D to -5.0D) in a North Indian family.</p> Methods <p>Family history and clinical data were collected from all the available affected and unaffected members of an arRP family and a pedigree was drawn. Whole genome homozygosity mapping using SNP markers was performed, and variants were prioritized. Further, the potential pathogenic variant detected in the proband was tested for familial segregation by Sanger sequencing.</p> Results <p>A 15&#xa0;bp non-canonical splice-site (NCSS) deletion (c.6729 + 5_6729 + 19del) in intron 48 of <i>ABCA4</i> was observed that co-segregated with the phenotype in all the affected members of the family. The clinically tested unaffected family members were either heterozygous or wild-type homozygous for the observed 15&#xa0;bp NCSS deletion. The identified change was not detected in 100 ethnically matched controls, hence excluding it as a polymorphism. Bioinformatics analysis indicated that due to this 15&#xa0;bp non-canonical splice-site deletion there occurred a loss of predicted RNA-binding motifs for heterogeneous nuclear ribonucleoproteins (hnRNPs H1, H2, H3, F) and Y box binding protein 1 (YB-1), which are essential for normal RNA splicing, hence suggesting aberrant splicing in the patients.</p> Conclusions <p>The present study identified a 15&#xa0;bp NCSS deletion (c.6729 + 5_6729 + 19del) in intron 48 of <i>ABCA4</i> linked with arRP and moderate myopia. This pathogenic <i>ABCA4</i> variant is predicted to cause the loss of binding sites for hnRNPs and YB-1 proteins which play crucial role in normal splicing, hence might result in alternative splicing. The identified 15&#xa0;bp NCSS deletion has previously been reported in isolated cases of cone-rod dystrophy, early-onset severe retinal dystrophy and Stargardt’s disease. The patients in the present study showed typical features of RP and myopia, indicating phenotypic variability as compared to the previous reports.</p>

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A 15 bp non-canonical splice-site deletion in ABCA4 linked with retinitis pigmentosa and myopia: insights into splicing defects and phenotypic variability

  • 期刊论文

  • 发表日期：

    2025年9月26日

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  • Vanita Vanita,
  • Shiwali Goyal,
  • Indu R. Singh

摘要

Background

Present study aimed to identify the underlying genetic defect for autosomal recessive retinitis pigmentosa (arRP) with moderate myopia (-3.0D to -5.0D) in a North Indian family.

Methods

Family history and clinical data were collected from all the available affected and unaffected members of an arRP family and a pedigree was drawn. Whole genome homozygosity mapping using SNP markers was performed, and variants were prioritized. Further, the potential pathogenic variant detected in the proband was tested for familial segregation by Sanger sequencing.

Results

A 15 bp non-canonical splice-site (NCSS) deletion (c.6729 + 5_6729 + 19del) in intron 48 of ABCA4 was observed that co-segregated with the phenotype in all the affected members of the family. The clinically tested unaffected family members were either heterozygous or wild-type homozygous for the observed 15 bp NCSS deletion. The identified change was not detected in 100 ethnically matched controls, hence excluding it as a polymorphism. Bioinformatics analysis indicated that due to this 15 bp non-canonical splice-site deletion there occurred a loss of predicted RNA-binding motifs for heterogeneous nuclear ribonucleoproteins (hnRNPs H1, H2, H3, F) and Y box binding protein 1 (YB-1), which are essential for normal RNA splicing, hence suggesting aberrant splicing in the patients.

Conclusions

The present study identified a 15 bp NCSS deletion (c.6729 + 5_6729 + 19del) in intron 48 of ABCA4 linked with arRP and moderate myopia. This pathogenic ABCA4 variant is predicted to cause the loss of binding sites for hnRNPs and YB-1 proteins which play crucial role in normal splicing, hence might result in alternative splicing. The identified 15 bp NCSS deletion has previously been reported in isolated cases of cone-rod dystrophy, early-onset severe retinal dystrophy and Stargardt’s disease. The patients in the present study showed typical features of RP and myopia, indicating phenotypic variability as compared to the previous reports.