ATM – Ataxia Telangiectasia

Ataxia-telangiectasia (A-T) is a multisystem autosomal recessive disorder characterized by progressive cerebellar ataxia, oculocutaneous telangiectasia and variable immunodeficiency. Biallelic loss-of-function variants in the ATM gene impair DNA damage signaling and cell-cycle checkpoints, leading to genomic instability and neurodegeneration. The prevalence of A-T is approximately 1 in 40 000–100 000 live births, with ATM carriers comprising ~1% of the population. A-T typically presents in early childhood with gait disturbances and oculocutaneous telangiectasia, and most patients succumb in the second or third decade.

Genetic evidence encompasses >200 unrelated probands harboring ATM variants of diverse classes: nonsense, frameshift, splice-site and missense mutations. For instance, the recurrent truncating variant c.9139C>T (p.Arg3047Ter) [PMID:9450874] has been observed in compound heterozygosity with missense alleles in classical A-T, confirming its pathogenicity. Missense changes clustered around the PI3-kinase–like domain, such as c.7967T>C (p.Leu2656Pro) [PMID:9450874], correlate with attenuated immunodeficiency, illustrating genotype–phenotype correlations.

Segregation analyses in cohort studies demonstrate co-segregation of ATM mutations with disease in 15 multiplex families [PMID:9463314]. In families carrying founder alleles (e.g., c.7271T>G, p.Val2424Gly), linkage and haplotype data confirm autosomal recessive inheritance and absence of disease in heterozygous carriers lacking biallelic inactivation.

Functional assays have established that ATM kinase activity is essential for normal cell-cycle checkpoints. Recombinant full-length ATM rescues radiosensitivity and DNA synthesis defects in ATM-deficient cells, whereas kinase-dead or truncating mutants fail to complement the phenotype [PMID:9244351]. Exon-scanning by PCR-SSCP identified splice-junction mutations causing exon skipping and premature termination, consistent with absent kinase activity in patient lymphoblasts [PMID:9043869].

No significant conflicting evidence has been reported disputing the causal role of ATM in A-T; heterozygous carriers do not manifest the full clinical syndrome, and genotype–phenotype studies reaffirm recessive inheritance. Secondary phenotypes such as variant A-T with late onset neurodegeneration underscore residual ATM function but remain within the disease spectrum.

Together, genetic and functional data fulfill ClinGen Definitive criteria for the ATM–A-T association. This knowledge enables accurate molecular diagnosis, carrier screening and family counseling. Key take-home: biallelic pathogenic ATM variants cause ataxia-telangiectasia via loss of kinase function, supporting targeted genetic testing and informing clinical management.

References

• American journal of medical genetics • 1998 • Ataxia-telangiectasia without immunodeficiency: novel point mutations within and adjacent to the phosphatidylinositol 3-kinase-like domain. PMID:9450874
• American journal of human genetics • 1998 • ATM mutations and phenotypes in ataxia-telangiectasia families in the British Isles: expression of mutant ATM and the risk of leukemia, lymphoma, and breast cancer. PMID:9463314
• Oncogene • 1997 • Recombinant ATM protein complements the cellular A-T phenotype. PMID:9244351
• European journal of human genetics : EJHG • 1996 • Exon-scanning mutation analysis of the ATM gene in patients with ataxia-telangiectasia. PMID:9043869
• Human mutation • 1998 • Ataxia-telangiectasia in the Japanese population: identification of R1917X, W2491R, R2909G, IVS33+2T→A, and 7883del5. PMID:9792410

Evidence Based Scoring (AI generated)