Dataset Information

Mild Neurological Phenotype Associated with Hypomorphic Variants in the Ataxia-Telangiectasia Mutated Gene.

ABSTRACT:

Background

Ataxia-telangiectasia (A-T) is a progressive multisystemic neurodegenerative disease. The phenotypic spectrum includes conditions (variant A-T) with mild, late-onset, and atypical clinical presentations characterized by the prevalence of dyskinetic rather than ataxic features.

Cases

We describe the clinical presentations of 3 siblings with early-onset truncal ataxia without obvious neurological deterioration or biological markers of classic A-T phenotype. We performed functional and genetic evaluation of 3 siblings with very mild neurological phenotype. Genetic evaluation with a next-generation sequencing panel for genes causative of cerebellar ataxia detected 2 known ATM gene variants, missense c.9023G>A p.(Arg3008His), and leaky splicing c.1066-6T>G variants. Functional studies showed mildly reduced ATM expression and residual kinase activity in the probands compared with healthy controls.

Conclusions

These results suggest the importance of investigating ATM variants even in the presence of clinical and biological atypical cases to ensure specific therapeutic regimens and oncological surveillance in these patients.

SUBMITTER: Caputi C

PROVIDER: S-EPMC9847291 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Publications

Mild Neurological Phenotype Associated with Hypomorphic Variants in the Ataxia-Telangiectasia Mutated Gene.

Caputi Caterina C Federici Giulia G Soddu Silvia S Travaglini Lorena L Piane Maria M Bertini Enrico E Zanni Ginevra G Leuzzi Vincenzo V

Movement disorders clinical practice 20221210 1

<h4>Background</h4>Ataxia-telangiectasia (A-T) is a progressive multisystemic neurodegenerative disease. The phenotypic spectrum includes conditions (variant A-T) with mild, late-onset, and atypical clinical presentations characterized by the prevalence of dyskinetic rather than ataxic features.<h4>Cases</h4>We describe the clinical presentations of 3 siblings with early-onset truncal ataxia without obvious neurological deterioration or biological markers of classic A-T phenotype. We performed f ...[more]

PMID: 36704080

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Project description:Pathogenic variants (PVs) in ATM are relatively common, but the scope and magnitude of risk remains uncertain. This study aimed to estimate ATM PV cancer risks independent of family cancer history. This analysis included patients referred for hereditary cancer testing with a multi-gene panel (N = 627,742). Cancer risks for ATM PV carriers (N = 4,607) were adjusted for family history using multivariable logistic regression and reported as ORs with 95% confidence intervals (CIs). Subanalyses of the c.7271T>G missense PV were conducted. Moderate-to-high risks for pancreatic (OR, 4.21; 95% CI, 3.24-5.47), prostate (OR, 2.58; 95% CI, 1.93-3.44), gastric (OR, 2.97; 95% CI, 1.66-5.31), and invasive ductal breast (OR, 2.03; 95% CI, 1.89-2.19) cancers were estimated for ATM PV carriers. Notably, c.7271T>G was associated with higher invasive ductal breast cancer risk (OR, 3.76; 95% CI, 2.76-5.12) than other missense and truncating ATM PVs. Low-to-moderate risks were seen for ductal carcinoma in situ (OR, 1.80; 95% CI, 1.61-2.02), male breast cancer (OR, 1.72; 95% CI, 1.08-2.75), ovarian cancer (OR, 1.57; 95% CI, 1.35-1.83), colorectal cancer (OR, 1.49; 95% CI, 1.24-1.79), and melanoma (OR, 1.46; 95% CI, 1.18-1.81). ATM PVs are associated with multiple cancer risks and, while professional society guidelines support that carriers are eligible for increased breast and pancreatic cancer screening, increased screening for prostate and gastric cancer may also be warranted. c.7271T>G is associated with high risk for breast cancer, with a 3- to 4-fold risk increase that supports consideration of strategies for prevention and/or early detection. PREVENTION RELEVANCE: This study estimated risks for multiple cancers associated with ATM pathogenic variants independent of family history. These results indicate that some common variants may be associated with higher breast cancer risks than previously appreciated and increased screening for prostate and gastric cancer may be warranted for carriers of ATM pathogenic variants.

Dataset Information

Mild Neurological Phenotype Associated with Hypomorphic Variants in the Ataxia-Telangiectasia Mutated Gene.

Background

Cases

Conclusions

Publications

Mild Neurological Phenotype Associated with Hypomorphic Variants in the Ataxia-Telangiectasia Mutated Gene.

Similar Datasets

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