Compound Heterozygous ATM Variants Cause Adolescent-Onset Cerebellar and Extrapyramidal Disease Without Telangiectasia in a Consanguineous Pakistani Family.

Ataxia-telangiectasia (A-T) is a heterogeneous genetic disorder with a recessive mode of inheritance resulting from biallelic variants in the A-T mutated gene (ATM). Besides ataxia, the disorder involves compromised immunity and an increased risk of malignancies. We recruited a consanguineous Pakistani family with multiple individuals having adolescent-onset ataxia. Phenotyping and clinical testing were completed for the patients. DNA samples from multiple individuals were used for bidirectional exome sequencing at 100X coverage, and data were aligned to the hg19 genome assembly. Sanger sequencing was completed to confirm the segregation of the variants. Multiple sequence alignments of orthologous proteins from diverse species were performed using ClustalO to check the amino acid conservation. Patients in the family manifested gait and limb ataxia, postural instability, and dystonia. A known heterozygous pathogenic nonsense ATM variant, c.2413C > T, p.(Arg805Ter), in trans with a new unreported missense variant, c.8708C > T, p.(Pro2903Leu), was identified, which segregated with the disease. The missense variant affected an amino acid, which was conserved in evolution. Telangiectasia of the eyes and skin was absent in the affected individuals, which led to the initial misdiagnosis of the disease as cerebellar ataxia. There were no reports of malignancies in the family, and affected individuals were alive in their third and fourth decades of life. Thus, molecular analyses resulted in the reclassification of the disease as A-T, an example of reverse phenotyping. The study expands the phenotypic heterogeneity of A-T and extends the allelic spectrum of ATM variants.