Evidence of pathogenicity for the leaky splice variant c.1066-6T>G in ATM
Simone Schröder1, Britta Wieland2, Andreas Ohlenbusch1
1Interdisciplinary Pediatric Center for Children with Developmental Disabilities and Severe Chronic Disorders, University Medical Center Göttingen, Göttingen, Germany.
Abstract:
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.
Insights
Mild ataxia-telangiectasia (variant A-T) is linked to ATM variants with residual kinase function. This study confirms the pathogenicity of the leaky ATM splice site variant c.1066-6T>G in variant A-T patients.
Area of Science:
- Genetics and Molecular Biology
- Neuroscience
Background:
- Mild clinical phenotypes of ataxia-telangiectasia (variant A-T) are associated with biallelic ATM variants.
- These variants result in residual function of the ATM kinase, with identified mutations including missense or leaky splice site alterations.
Observation:
- Whole-exome sequencing identified compound heterozygous ATM variants (c.1066-6T>G and c.2250G>A) in a patient diagnosed with congenital ocular motor apraxia type Cogan.
- Reappraisal of the patient's phenotype aligned with variant A-T.
- Functional analyses revealed reduced ATM protein expression and residual ATM kinase activity.
Findings:
- The study provides evidence for the pathogenicity of the leaky ATM splice site variant c.1066-6T>G.
- This variant, in conjunction with c.2250G>A, results in a mild clinical phenotype consistent with variant A-T.
Implications:
- Confirms the role of the c.1066-6T>G splice site variant in the etiology of variant ataxia-telangiectasia.
- Highlights the importance of functional analyses in determining the pathogenicity of splice site variants.
- Contributes to a better understanding of genotype-phenotype correlations in ATM-related disorders.
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