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Evidence of pathogenicity for the leaky splice variant c. 1066‐6T >G in ATM
Author(s) -
Schröder Simone,
Wieland Britta,
Ohlenbusch Andreas,
Yigit Gökhan,
Altmüller Janine,
Boltshauser Eugen,
Dörk Thilo,
Brockmann Knut
Publication year - 2020
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.61870
Subject(s) - splice , missense mutation , genetics , ataxia telangiectasia , mutation , phenotype , rna splicing , biology , germline , microbiology and biotechnology , gene , dna , dna damage , rna
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.