Evidence for pathogenicity of variant ATM Val1729Leu in a family with ataxia telangiectasia

Shalash, Ali; Rösler, Thomas W.; Salama, Mohamed; Pendziwiat, Manuela; Müller, Stefanie H.; Hopfner, Franziska; Höglinger, Günter U.; Kuhlenbäumer, Gregor

doi:10.1007/s10048-021-00639-4

Cited by 2 publications

(2 citation statements)

References 17 publications

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“…62 cases (27 studies [ 33 , 38 , 41 , 49 , 53 , 55 , 72 , 118 , 120 , 123 , 139 , 143 , 186 , 208 , 212 , 213 , 338 , 358 , 366 , 368 , 372 , 388 , 392 , 519 , 528 , 683 , 684 ]) reported an abnormal EMG. The youngest age at which an abnormal EMG was reported was 4 years 0 months.…”

Section: Resultsmentioning

confidence: 99%

The natural history of ataxia-telangiectasia (A-T): A systematic review

et al. 2022

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Background Ataxia-telangiectasia is an autosomal recessive, multi-system, and life-shortening disease caused by mutations in the ataxia-telangiectasia mutated gene. Although widely reported, there are no studies that give a comprehensive picture of this intriguing condition. Objectives Understand the natural history of ataxia-telangiectasia (A-T), as reported in scientific literature. Search methods 107 search terms were identified and divided into 17 searches. Each search was performed in PubMed, Ovid SP (MEDLINE) 1946-present, OVID EMBASE 1980 –present, Web of Science core collection, Elsevier Scopus, and Cochrane Library. Selection criteria All human studies that report any aspect of A-T. Data collection and analysis Search results were de-duplicated, data extracted (including author, publication year, country of origin, study design, population, participant characteristics, and clinical features). Quality of case-control and cohort studies was assessed by the Newcastle-Ottawa tool. Findings are reported descriptively and where possible data collated to report median (interquartile range, range) of outcomes of interest. Main results 1314 cases reported 2134 presenting symptoms. The most common presenting symptom was abnormal gait (1160 cases; 188 studies) followed by recurrent infections in classical ataxia-telangiectasia and movement disorders in variant ataxia-telangiectasia. 687 cases reported 752 causes of death among which malignancy was the most frequently reported cause. Median (IQR, range) age of death (n = 294) was 14 years 0 months (10 years 0 months to 23 years 3 months, 1 year 3 months to 76 years 0 months). Conclusions This review demonstrates the multi-system involvement in A-T, confirms that neurological symptoms are the most frequent presenting features in classical A-T but variants have diverse manifestations. We found that most individuals with A-T have life limited to teenage or early adulthood. Predominance of case reports, and case series demonstrate the lack of robust evidence to determine the natural history of A-T. We recommend population-based studies to fill this evidence gap.

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Section: Resultsmentioning

confidence: 99%

The natural history of ataxia-telangiectasia (A-T): A systematic review

et al. 2022

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“…To validate the clinical suspicion of A-T, exome sequencing was performed using the peripheral blood from the patient. The procedures of genetic analysis and the filtering condition for variants were described by Shalash et al ( 10 ). We identified compound heterozygous variants in the ATM gene, NM_000051.4 ( ATM ): c.4195dup and c.6006 + 1G>T. The intronic variant c.6006 + 1G>T (ClinVar Variation ID: 2029577) was expected to disrupt RNA splicing by affecting a donor splice site in intron 40 of the ATM gene, thereby it was classified as pathogenic in the ClinVar database.…”

Section: Case Presentationmentioning

confidence: 99%

Ataxia-telangiectasia in China: a case report of a novel ATM variant and literature review

Shao¹,

Wang

Xu³

et al. 2023

Front. Neurol.

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BackgroundAtaxia-telangiectasia (A-T) is a multisystem genetic disorder involving ataxia, oculocutaneous telangiectasia, and immunodeficiency caused by biallelic pathogenic variants in the ATM gene. To date, most ATM variants have been reported in the Caucasian population, and few studies have focused on the genotype–phenotype correlation of A-T in the Chinese population. We herein present a Chinese patient with A-T who carries compound heterozygous variants in the ATM gene and conducted a literature review for A-T in China.Case presentationA 7-year-old Chinese girl presented with growth retardation, ataxia, medium ocular telangiectasia, cerebellar atrophy, and elevated serum alpha-fetoprotein (AFP) level, which supported the suspicion of A-T. Notably, the serum levels of immunoglobulins were all normal, ruling out immunodeficiency. Exome sequencing and Sanger sequencing revealed two likely pathogenic ATM variants, namely NM_000051.4: c.4195dup (p.Thr1399Asnfs*15) and c.6006 + 1G>T (p.?), which were inherited from her father and mother, respectively. From the Chinese literature review, we found that there was a marked delay in the diagnosis of A-T, and 38.9% (7/18) of A-T patients did not suffer from immunodeficiency in China. No genotype–phenotype correlation was observed in this group of A-T patients.ConclusionThese results extend the genotype spectrum of A-T in the Chinese population and imply that the diagnosis of A-T in China should be improved.

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Evidence for pathogenicity of variant ATM Val1729Leu in a family with ataxia telangiectasia

Cited by 2 publications

References 17 publications

The natural history of ataxia-telangiectasia (A-T): A systematic review

The natural history of ataxia-telangiectasia (A-T): A systematic review

Ataxia-telangiectasia in China: a case report of a novel ATM variant and literature review

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