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Non-homologous recombination between Alu and LINE-1 repeats results in a 91 kb deletion in MERTK causing severe retinitis pigmentosa
Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Oftalmiatrik.
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik. (Computational Life Science Cluster (CLiC))
Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
2018 (Engelska)Ingår i: Molecular Vision, ISSN 1090-0535, Vol. 24, s. 667-678Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

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.

Ort, förlag, år, upplaga, sidor
2018. Vol. 24, s. 667-678
Nationell ämneskategori
Medicinsk genetik
Identifikatorer
URN: urn:nbn:se:umu:diva-153121ISI: 000447627900001Scopus ID: 2-s2.0-85055736745OAI: oai:DiVA.org:umu-153121DiVA, id: diva2:1262724
Tillgänglig från: 2018-11-12 Skapad: 2018-11-12 Senast uppdaterad: 2023-02-03Bibliografiskt granskad

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Scopushttp://www.molvis.org/molvis/v24/667

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Jonsson, FridaBurstedt, MarieKellgren, ThereseGolovleva, Irina

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Jonsson, FridaBurstedt, MarieKellgren, ThereseGolovleva, Irina
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Medicinsk och klinisk genetikOftalmiatrikInstitutionen för matematik och matematisk statistik
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