| Autor: |
Anna Dvaladze, Erika Tavares, Matteo Di Scipio, Graeme Nimmo, Monika K. Grudzinska‐Pechhacker, Tara Paton, Anupreet Tumber, Shuning Li, Christabel Eileen, Birgit Ertl‐Wagner, Eva Mamak, Georg Hoffmann, Christian R. Marshall, Dorothea Haas, Ertan Mayatepek, Andreas Schulze, Elise Heon, Ajoy Vincent |
| Rok vydání: |
2022 |
| Předmět: |
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| Zdroj: |
Clinical geneticsREFERENCES. 102(6) |
| ISSN: |
1399-0004 |
| Popis: |
Non-syndromic retinitis pigmentosa (NSRP) is a clinically and genetically heterogeneous group of disorders characterized by progressive degeneration of the rod and cone photoreceptors, often leading to blindness. The evolving association of syndromic genes to cause NSRP and the increasing role of intronic variants in explaining missing heritability in genetic disorders present challenges in establishing conclusive clinical and genetic diagnoses. This study sought to identify and validate the causative genetic variant(s) in a 13-year-old male initially diagnosed with NSRP. Genome sequencing identified a pathogenic missense variant in MVK [NM_000431.3:c.803Tgt;C (p.Ile268Thr)], in trans with a novel intronic variant predicted to create a new donor splice site (c.768+71Cgt;A). Proband cDNA analysis confirmed the inclusion of the first 68 base pairs of intron 8 that resulted in a frameshift in MVK (r.768_769ins[768+1_768+68]) and significantly reduced the expression of reference transcript (17.6%). Patient re-phenotyping revealed ataxia, cerebellar atrophy, elevated urinary mevalonate and LTEsub4/sub, in keeping with mild mevalonic aciduria and associated syndromic retinitis pigmentosa. Leakage of reference transcript likely explains the milder phenotype observed in our patient. This is the first association of a deep intronic splice variant to cause MVK-related disorder. This report highlights the importance of variant validation and patient re-phenotyping in establishing accurate diagnosis in the era of genome sequencing. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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