Genotype–phenotype correlations in ataxia telangiectasia patients with ATM c.3576G>A and c.8147T>C mutations (original) (raw)
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Evidence for pathogenicity of variant ATM Val1729Leu in a family with ataxia telangiectasia
Neurogenetics, 2021
Ataxia telangiectasia is a rare autosomal recessive multisystem disorder caused by mutations in the gene of ATM serine/threonine kinase. It is characterized by neurodegeneration, leading to severe ataxia, immunodeficiency, increased cancer susceptibility, and telangiectasia. Here, we discovered a co-segregation of two ATM gene variants with ataxia telangiectasia in an Egyptian family. While one of these variants (NM_000051.4(ATM_i001):p.(Val128*)) has previously been reported as pathogenic, the other one (NM_000051.4(ATM_i001):p.(Val1729Leu)) is regarded as a variant of uncertain significance. Our findings in this family provide additional evidence for causality of the second variant and argue that its status should be changed to pathogenic.
Movement Disorders Clinical Practice, 2022
Background Background: Ataxia-telangiectasia (A-T) is a progressive multisystemic neurodegenerative disease. The phenotypic spectrum includes conditions (variant AT) with mild, late-onset, and atypical clinical presentations characterized by the prevalence of dyskinetic rather than ataxic features. Cases Cases: We describe the clinical presentations of 3 siblings with early-onset truncal ataxia without obvious neurological deterioration or biological markers of classic AT 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 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. Ataxia-telangiectasia (A-T) is a rare autosomal recessive neurodegenerative disorder. Classic AT forms are characterized by early-onset progressive cerebellar ataxia resulting in the loss of autonomous walking by the age of 10, oculomotor apraxia, oculocutaneous telangiectasia, cancer susceptibility, and immunodeficiency. Exitus occurs by the second or third decade of life due to chronic lung disease or malignancies. Increased alpha-fetoprotein (AFP), immunodeficiency, and radiosensitivity are typical biomarkers. In the past 20 years, expanded AT phenotypes (variant AT) have been identified, which are characterized by late-onset, mild, or absent cerebellar involvement, prevalent dyskinetic movement disorders, and mild/absent systemic features. 1 AT is caused by biallelic variants in the AT mutated (ATM) gene, encoding for a Phosphatidyl Inositol 3-kinase-related serine/ threonine protein kinase involved in DNA damage response (DDR). In classic AT , ATM nonsense or frameshift truncating variants lead to undetectable ATM expression and consequent loss of kinase activity. In variant AT , splice site or missense ATM variants are commonly associated with residual ATM expression and kinase activity. 2 Here, we report 3 brothers with early-onset nonprogressive truncal ataxia without any other key diagnostic features of AT. Their ATM genotype included compound heterozygosity for missense c.9023G>A p.(Arg3008His) and splicing c.1066-6T>G variants.
ATM Gene Mutations Detection in Iranian Ataxia-Telangiectasia Patients
2004
Ataxia-Telangiectasia (AT) is an autosomal recessive disorder involving cerebellar degeneration, immunodeficiency, radiation sensitivity and cancer predisposition. The ATM gene on human chromosome 11q22.3 has recently been identified as the gene responsible for ataxia-telangiectasia (AT). The gene mutated in AT, which has been designated as the ATM gene, encodes a large protein kinase with a PI-3 kinase-related domain. More than 100 mutations are broadly distributed throughout the ATM gene. The large size of the ATM gene (66 exons spanning ~150kb of genomic DNA) together with the diversity and broad distribution of mutations in AT patients, greatly limits the utility of direct mutation screening as a diagnostic tool.
ARTICLE Predominance of null mutations in ataxia-telangiectasia
1995
GenBank accession no. U33841 Ataxia-telangiectasia (A-T) is an autosomal recessive disorder involving cerebellar degeneration, immunodeficiency, chromosomal instability, radiosensitivity and cancer predisposition. The responsible gene, ATM, was recently identified by positional cloning and found to encode a putative 350 kDa protein with a PI 3-kinase-like domain, presumably involved in mediating cell cycle arrest in response to radiation-induced DNA damage. The nature and location of A-T mutations should provide insight into the function of the ATM protein and the molecular basis of this pleiotropic disease. Of 44 A-T mutations identified by us to date, 39 (89%) are expected to inactivate
Predominance of null mutations in ataxia-telangiectasia
Human Molecular Genetics, 1996
is an autosomal recessive disorder involving cerebellar degeneration, immunodeficiency, chromosomal instability, radiosensitivity and cancer predisposition. The responsible gene, ATM, was recently identified by positional cloning and found to encode a putative 350 kDa protein with a PI 3-kinase-like domain, presumably involved in mediating cell cycle arrest in response to radiation-induced DNA damage. The nature and location of A-T mutations should provide insight into the function of the ATM protein and the molecular basis of this pleiotropic disease. Of 44 A-T mutations identified by us to date, 39 (89%) are expected to inactivate the ATM protein by truncating it, by abolishing correct initiation or termination of translation, or by deleting large segments. Additional mutations are four smaller in-frame deletions and insertions, and one substitution of a highly conserved amino acid at the PI 3-kinase domain. The emerging profile of mutations causing A-T is thus dominated by those expected to completely inactivate the ATM protein. ATM mutations with milder effects may result in phenotypes related, but not identical, to A-T.
American Journal of Medical Genetics Part A, 2007
Ataxia-telangiectasia (A-T) is an autosomal recessive disorder characterized by progressive neurodegeneration, immunodeficiency, susceptibility to cancer, genomic instability, and sensitivity to ionizing radiation. A-T is caused by mutations that eliminate or inactivate the nuclear protein kinase ATM, the chief activator of the cellular response to double strand breaks (DSBs) in the DNA. Mild A-T is usually caused by ATM mutations that leave residual amounts of active ATM. We studied two siblings with mild A-T, as defined by clinical examination and a quantitative A-T neurological index. Surprisingly, no ATM was detected in the patients' cells, and sequence analysis revealed that they were homozygous for a truncating ATM mutation (5653delA) that is expected to lead to the classical, severe neurological presentation. Moreover, the cellular phenotype of these patients was indistinguishable from that of classical A-T: all the tested parameters of the DSB response were severely defective as in typical A-T. This analysis shows that the severity of the neurological component of A-T is determined not only by ATM mutations but also by other influences yet to be found. ß 2007 Wiley-Liss, Inc.
Six Novel ATM Gene Variants in Sri Lankan Patients with Ataxia Telangiectasia
Case Reports in Genetics
Introduction. Ataxia telangiectasia is a rare genetic condition with an estimated prevalence of 1 in 40,000–100,000 live births. This condition predominantly affects the nervous and immune systems. It is characterized by progressive ataxia beginning from early childhood. The neurological deficit associated with this condition affects one’s balance, coordination, walking, and speech and can be accompanied by chorea, myoclonus, and neuropathy. They may also have ocular telangiectasias and high levels of blood alpha-fetoprotein (AFP). The ataxia telangiectasia mutated gene (ATM) is associated with this condition and codes for the ATM protein which is a phosphatidylinositol 3-kinase. This gene occupies 150 kb on chromosome 11q22–23 and contains 66 exons encoding a 13 kb transcript. ATM is a relatively large protein with a molecular weight of 350 kDa and 3,056 amino acids. Methods. Four patients of Sri Lankan origin presenting with features suggestive of ataxia telangiectasia were referr...