Evidence of Pathogenicity for the Leaky Splice Variant c.1066-6T>G in ATM in a Patient with Variant Ataxia Telangiectasia

Background: 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.

Methods: Clinical observation, whole-exome sequencing, immunoblots of ATM protein, testing of radiation-induced phosphorylation of ATM targets.

Results: A 27-year-old woman had been diagnosed with congenital ocular motor apraxia type Cogan (COMA) in her childhood. Her motor development was delayed, and she walked without support at the age of 24 months, and showed early-onset ataxia, learning disability, short stature, kyphoscoliosis, and fatigue. Ataxia telangiectasia was not considered clinically as a differential diagnosis. Ocular apraxia and ataxia persisted, but without any evidence for deterioration. There was no telangiectasia, choreoathetosis, or signs of immunodeficiency.

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 this patient. 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.

Conclusion: Our results provide evidence for pathogenicity of the leaky ATM splice site variant c.1066-6T>G. COMA may be the presenting clinical feature in variant A-T.

No conflict of interest has been declared by the author(s).

Publication History

Article published online:
28 October 2021