Non-homologous recombination between Alu and LINE-1 repeats results in a 91 kb deletion in MERTK causing severe retinitis pigmentosa
| Autor: | Jonsson, Frida, Burstedt, Marie, Kellgren, Therese G., Golovleva, Irina |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Male
Recombination Genetic Whole Genome Sequencing c-Mer Tyrosine Kinase Siblings Mutation Missense Exons Polymerase Chain Reaction Polymorphism Single Nucleotide Proto-Oncogene Mas Pedigree Long Interspersed Nucleotide Elements Alu Elements Child Preschool Humans Female Child Gene Deletion Retinitis Pigmentosa Research Article |
| Zdroj: | Molecular Vision |
| ISSN: | 1090-0535 |
| Popis: | Purpose Retinitis pigmentosa (RP) represents a large group of inherited retinal diseases characterized by clinical and genetic heterogeneity. Among patients with RP in northern Sweden, we identified two severely affected siblings and aimed to reveal a genetic cause underlying their disease. Methods Whole exome sequencing (WES) was performed on both affected individuals. Sequence variants were filtered using a custom pipeline to find a rare or novel variant predicted to affect protein function. Genome-wide genotyping was used to identify copy number variants (CNVs) and homozygous regions with potential disease causative genes. Results WES uncovered a novel heterozygous variant in the MER proto-oncogene, tyrosine kinase (MERTK) gene, c.2309A>G, p.Glu770Gly located in the tyrosine kinase domain and predicted to be likely pathogenic. The second variant, a large heterozygous deletion encompassing exons 1 to 7 of the MERTK gene, was revealed with genome-wide genotyping. The CNV analysis suggested breakpoints of the deletion, in the 5′-untranslated region and in intron 7. We identified genomic sequences at the site of the deletion as part of L1ME4b (LINE/L1) and AluSx3 that indicated a non-homologous recombination as a mechanism of the deletion evolvement. Conclusions Patients with RP in this study were carriers of two novel allelic mutations in the MERTK gene, a missense variant in exon 17 and an approximate 91 kb genomic deletion. Mapping of the deletion breakpoints allowed molecular testing of a cohort of patients with RP with allele-specific PCR. These findings provide additional information about mutations in MERTK for molecular testing of unsolved recessive RP cases and highlight the necessity for analysis of large genomic deletions. |
| Databáze: | OpenAIRE |
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