A novel ATM variant in a Colombian family with chorea-ataxia syndrome: implications for an early diagnosis

Technical Summary: A Novel ATM Variant in a Colombian Family with Chorea-Ataxia Syndrome

Problem Statement
Ataxia-telangiectasia (ATX-ATM) is a rare, multisystem autosomal recessive disorder caused by pathogenic variants in the ATM gene. While the classic phenotype presents with childhood-onset progressive cerebellar ataxia, telangiectasias, immunodeficiency, and malignancy, "variant" ATX-ATM exhibits a milder, more heterogeneous phenotype. In variant cases, cerebellar ataxia may be absent, and immune/respiratory functions are often preserved, though the risk of malignancy remains elevated. This phenotypic variability, particularly the presence of movement disorders like chorea and dystonia without classic immunodeficiency, creates significant diagnostic challenges. The paper highlights that diagnostic delays for variant ATX-ATM are common, often exceeding 10 to 20 years, which hinders appropriate oncologic surveillance and genetic counseling.

Methodology
The study presents a clinical and genetic investigation of a Colombian family with a history of chorea-ataxia syndrome and multiple malignancies.

• Clinical Evaluation: The authors conducted a detailed phenotypic assessment of the index case (a 39-year-old male) and his two affected siblings. This included neurological examinations, observation of specific signs (e.g., conjunctival telangiectasias, oculomotor apraxia, choreodystonia), and laboratory testing, specifically measuring alpha-fetoprotein (AFP) levels.
• Genetic Analysis: Whole-exome sequencing (WES) was performed on the two affected siblings and their parents to identify causative variants.
• Segregation Analysis: The inheritance pattern of identified variants was confirmed within the family pedigree to establish compound heterozygosity.
• Variant Classification: The identified missense variant was reclassified from "uncertain significance" to "likely pathogenic" based on the 2015 ACMG criteria, utilizing evidence from segregation, in silico predictions, evolutionary conservation, and absence in population databases.

Key Results

• Clinical Phenotype: The index patient and his siblings presented with progressive ataxia, chorea, dysarthria, and conjunctival telangiectasias. Notably, they lacked immunodeficiency or chronic pulmonary disease, features typical of classic ATX-ATM. However, AFP levels were markedly elevated (140 ng/mL and 198 ng/mL in the brothers).
• Malignancy History: The family exhibited a high burden of cancer. The index patient's brother developed diffuse gastric adenocarcinoma and cutaneous melanoma. The older sister died from ovarian and colon cancer. Other relatives had histories of colon, lung, and breast cancer.
• Genetic Findings: WES identified compound heterozygous variants in the ATM gene in the affected siblings:
  1. A known pathogenic splice-site variant: c.2921+1G>A.
  2. A novel missense variant of uncertain significance: c.8083G>A; p.(Gly2695Ser).
• Variant Reclassification: The c.8083G>A variant was reclassified as "likely pathogenic." This conclusion was supported by:
  • PM3: Detected in trans with a pathogenic variant in multiple affected individuals.
  • PP1: Segregation with the disease in the family.
  • PP3: Bioinformatic predictions of a deleterious effect.
  • PM2: Absence from population databases (gnomAD).
  • Functional Context: The variant affects a highly conserved glycine residue (position 2695), and similar variants at this codon have been linked to breast cancer and ATX-ATM in previous literature.

Significance and Claims
The paper claims that the identification of this novel ATM variant and its association with a specific clinical presentation contributes to the understanding of genotype-phenotype correlations in ataxia-telangiectasia. The authors emphasize several key points:

1. Diagnostic Utility: The case underscores the importance of measuring alpha-fetoprotein as a screening biomarker for ataxia, even in the absence of immunodeficiency or classic telangiectasias, particularly when a family history of malignancy is present.
2. Variant Form Recognition: The family represents a "variant" form of ATX-ATM, characterized by a progressive chorea-ataxia syndrome and elevated malignancy risk but preserved immune function. Distinguishing this from the classic form is critical for predicting disease course and life expectancy.
3. Clinical Implications: Early recognition of variant ATX-ATM is essential for implementing appropriate oncologic surveillance and providing accurate genetic counseling, given the increased risk of breast, gastric, and colorectal cancers in heterozygous carriers and the high malignancy risk in affected homozygotes/compound heterozygotes.
4. Contribution to Knowledge: Reporting novel ATM variants helps refine the spectrum of disease variability and supports the reclassification of variants of uncertain significance, ultimately aiding in the diagnosis of similar cases globally.