A novel ATM frameshift mutation (c.3613dup) leading to ataxia-telangiectasia with early-onset severe immunodeficiency: A case report and literature review

Abstract

Background: Ataxia-telangiectasia (A-T) is a rare, autosomal recessive, multisystem disorder caused by mutations in the ATM gene. Atypical presentations that lack classic ocular telangiectasias or present predominantly with early-onset movement disorders pose significant diagnostic challenges and frequently lead to misdiagnosis during early childhood. Case Presentation: We reported a 6-year-old Chinese boy who was presented with delayed motor milestones and dysarthria since 1 year of age. Brain magnetic resonance imaging (MRI) revealed distinct cerebellar atrophy. Notably, classic oculocutaneous telangiectasias were absent; instead, atypical hypopigmented macules were observed on the skin. Whole-exome sequencing identified compound heterozygous mutations in the ATM gene: A known pathogenic missense variant (c.8110T>G) and a novel, maternally inherited frameshift mutation (c.3613dup, p.Arg1205Profs*24) were found in exon 25. In silico analysis predicted that this novel variant triggers nonsense-mediated mRNA decay (NMD), potentially leading to loss of the ATM protein kinase catalytic domain, which aligns with his mild- to-moderate neurological and severe immunological phenotypes. Conclusion: This case highlights that progressive cerebellar involvement and profound immunological compromise can manifest in A-T patients even in the absence of classic telangiectasias. The identification of the novel c.3613dup mutation broadens the genotypic spectrum of the ATM gene. Furthermore, it underscores the critical importance of integrating early genetic screening for atypical childhood- onset movement disorders to prevent diagnostic delays and facilitate timely multidisciplinary management.

Keywords

ataxia-telangiectasia / ATM gene / frameshift mutation / nonsense-mediated mRNA decay / movement disorders / case report

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