Late-Onset Ataxia-Telangiectasia Presenting With Dystonia and Tremor: The Use of Nanopore Long-Read Sequencing Solving the Variant Phase

Abstract

Objectives: This study investigates atypical late-onset ataxia-telangiectasia (AT) cases in a Korean family, diagnosed via Nanopore long-read sequencing, diverging from the typical early childhood onset caused by biallelic pathogenic ATM variants.

Methods: A 52-year-old Korean woman exhibiting dystonia and tremor, with a family history of similar symptoms in her older sister, underwent comprehensive tests including routine laboratory tests, neuropsychological assessments, and neuroimaging. Genetic analysis was conducted through targeted sequencing of 29 dystonia-associated genes and Nanopore long-read sequencing to assess the configuration of 2 ATM gene variants.

Results: Routine blood tests and brain imaging studies returned normal results, except for elevated α-fetoprotein levels. Neurologic examination revealed dystonia in the face, hand, and trunk, along with cervical dystonia in the proband. Her sister exhibited similar symptoms without evident telangiectasia. Genetic testing revealed 2 heterozygous pathogenic ATM gene variants (p.Glu2014Ter and p.Glu2052Lys). Nanopore long-read sequencing confirmed these variants were in trans configuration, establishing a definite molecular diagnosis in the proband.

Discussion: This report expands the known clinical spectrum of AT, highlighting a familial case of atypical AT. Moreover, it underscores the clinical utility of Nanopore long-read sequencing in phasing variant haplotypes, essential for diagnosing autosomal recessive disorders, especially beneficial for cases without parental samples.

Figure. Clinical and Genomic Findings of the Patient

(A) Family pedigree. The patient's father succumbed to lung cancer, and the elder sister exhibited breast cancer and neurologic symptoms similar to the patients, while the younger brother exhibited no relevant presentations. Subsequent Sanger sequencing confirmed that the elder sister had the identical 2 pathogenic variants (p.Glu2014Ter and p.Glu2052Lys) in the ATM gene, while the younger brother harbored 1 (p.Glu2052Lys). (B) Ocular telangiectasia (indicated by a black arrow) observed in our patient. (C) Integrative Genomic Viewer (IGV) findings of the amplicon sequenced with Nanopore long-read sequencing. Nanopore long-read sequencing resolved haplotype configurations of 2 pathogenic ATM variants (p.Glu2014Ter and p.Glu2052Lys) located in exon 41 (red) and 42 (green), respectively, thus confirming the trans configuration.