Evidence of pathogenicity for the leaky splice variant c. 1066‐6T >G in ATM
| Autor: | Simone Schröder, Britta Wieland, Janine Altmüller, Thilo Dörk, Eugen Boltshauser, Knut Brockmann, Gökhan Yigit, Andreas Ohlenbusch |
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| Rok vydání: | 2020 |
| Předmět: |
Genetics
0303 health sciences Splice site mutation Alternative splicing Biology Compound heterozygosity medicine.disease Phenotype 3. Good health 03 medical and health sciences 0302 clinical medicine RNA splicing Ataxia-telangiectasia medicine Missense mutation Kinase activity 030217 neurology & neurosurgery Genetics (clinical) 030304 developmental biology |
| Zdroj: | American Journal of Medical Genetics Part A. 182:2971-2975 |
| ISSN: | 1552-4833 1552-4825 |
| Popis: | Mild clinical phenotypes of ataxia-telangiectasia (variant A-T) are associated with biallelic ATM variants resulting in residual function of the ATM kinase. At least one regulatory, missense, or leaky splice site mutation resulting in expression of ATM with low level kinase activity was identified in subjects with variant A-T. Studies on the pathogenicity of the germline splicing ATM variant c.1066-6T>G have provided conflicting results. Using whole-exome sequencing, we identified two splice site ATM variants, c.1066-6T>G; [p.?], and c.2250G>A, [p.Ile709_Lys750del], in a compound heterozygous state in a 27-year-old woman who had been diagnosed as having congenital ocular motor apraxia type Cogan in her childhood. Reappraisal of her clinical phenotype revealed consistency with variant A-T. Functional analyses showed reduced expression of ATM protein and residual activity of the ATM kinase at a level consistent with variant A-T. Our results provide evidence for pathogenicity of the leaky ATM splice site variant c.1066-6T>G. |
| Databáze: | OpenAIRE |
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