Evidence of pathogenicity for the leaky splice variant c.1066‐6T>G in ATM. Issue 12 (11th September 2020)

• Record Type: Journal Article
• Authors: Schröder, Simone; Wieland, Britta; Ohlenbusch, Andreas; Yigit, Gökhan; Altmüller, Janine; Boltshauser, Eugen; Dörk, Thilo; Brockmann, Knut
• Is Part Of: American journal of medical genetics. Volume 182:Issue 12(2020)
• Page Start: 2971
• Page End: 2975
• Publication Date: 2020-09-11
• Subjects: ataxia telangiectasia -- ataxia‐telangiectasia mutated gene -- IVS10‐6T>G -- leaky splice site variant -- ocular motor apraxia -- variant A‐T; Medical genetics -- Periodicals; 616.14205
• DOI: 10.1002/ajmg.a.61870
• Languages: English
• ISSNs: 1552-4825

Abstract

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.