Evidence of pathogenicity for the leaky splice variant c.1066-6T>G inATM

Mild clinical phenotypes of ataxia-telangiectasia (variant A-T) are associated with biallelicATMvariants 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 splicingATMvariant c.1066-6T>G have provided conflicting results. Using whole-exome sequencing, we identified two splice siteATMvariants, 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 leakyATMsplice site variant c.1066-6T>G.