Ten new <i><scp>ATM</scp></i> alterations in Polish patients with ataxia‐telangiectasia

Podralska, Marta; Stembalska, Agnieszka; Ślężak, Ryszard; Lewandowicz-Uszyńska, Aleksandra; Pietrucha, Barbara; Kołtan, Sylwia; Wigowska-Sowińska, J; Pilch, Jacek; Mosor, Maria; Ziółkowska-Suchanek, Iwona; Dzikiewicz‐Krawczyk, Agnieszka; Słomski, Ryszard

doi:10.1002/mgg3.98

Cited by 20 publications

(7 citation statements)

References 27 publications

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“…A few recurring mutations in the ATM gene have been detected in Polish ataxia-telangiectasia patients. Three of the mutations, c.6095G > A, c.7630-2A > C and c.5932G > T, were the most frequent [ 27 , 28 ]. A mutation at position 5932 creates a stop codon and changes a GAA codon, specifying glutamine, into a UAA.…”

Section: Discussionmentioning

confidence: 99%

Genetic variants in ATM, H2AFX and MRE11 genes and susceptibility to breast cancer in the polish population

et al. 2018

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BackgroundDNA damage repair is a complex process, which can trigger the development of cancer if disturbed. In this study, we hypothesize a role of variants in the ATM, H2AFX and MRE11 genes in determining breast cancer (BC) susceptibility.MethodsWe examined the whole sequence of the ATM kinase domain and estimated the frequency of founder mutations in the ATM gene (c.5932G > T, c.6095G > A, and c.7630-2A > C) and single nucleotide polymorphisms (SNPs) in H2AFX (rs643788, rs8551, rs7759, and rs2509049) and MRE11 (rs1061956 and rs2155209) among 315 breast cancer patients and 515 controls. The analysis was performed using high-resolution melting for new variants and the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method for recurrent ATM mutations. H2AFX and MRE11 polymorphisms were analyzed using TaqMan assays. The cumulative genetic risk scores (CGRS) were calculated using unweighted and weighted approaches.ResultsWe identified four mutations (c.6067G > A, c.8314G > A, c.8187A > T, and c.6095G > A) in the ATM gene in three BC cases and two control subjects. We observed a statistically significant association of H2AFX variants with BC. Risk alleles (the G of rs7759 and the T of rs8551 and rs2509049) were observed more frequently in BC cases compared to the control group, with P values, odds ratios (OR) and 95% confidence intervals (CIs) of 0.0018, 1.47 (1.19 to 1.82); 0.018, 1.33 (1.09 to 1.64); and 0.024, 1.3 (1.06 to 1.59), respectively. Haplotype-based tests identified a significant association of the H2AFX CACT haplotype with BC (P < 0.0001, OR = 27.29, 95% CI 3.56 to 209.5). The risk of BC increased with the growing number of risk alleles. The OR (95% CI) for carriers of ≥ four risk alleles was 1.71 (1.11 to 2.62) for the CGRS.ConclusionsThis study confirms that H2AFX variants are associated with an increased risk of BC. The above-reported sequence variants of MRE11 genes may not constitute a risk factor of breast cancer in the Polish population. The contribution of mutations detected in the ATM gene to the development of breast cancer needs further detailed study.

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Section: Discussionmentioning

confidence: 99%

Genetic variants in ATM, H2AFX and MRE11 genes and susceptibility to breast cancer in the polish population

et al. 2018

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“…A deletion of the last 2 exons of ATM (62–63) was detected in patient 32. Deletions of exon 63 or exons 62–63 of the ATM gene have previously been reported in patients with ataxia telangiectasia and are considered to be functionally relevant [ 39 , 40 ]. In two further patients (60, 40), we detected previously described ATM nonsense variants; the variant ATM:p.(Glu1978*) has been reported in BC cases before [ 41 ], whereas the variant ATM:p.(Cys2931*) has been described as a class 5 variant in a patient with ataxia telangiectasia [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

Breast cancer patients suggestive of Li-Fraumeni syndrome: mutational spectrum, candidate genes, and unexplained heredity

et al. 2018

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BackgroundBreast cancer is the most prevalent tumor entity in Li-Fraumeni syndrome. Up to 80% of individuals with a Li-Fraumeni-like phenotype do not harbor detectable causative germline TP53 variants. Yet, no systematic panel analyses for a wide range of cancer predisposition genes have been conducted on cohorts of women with breast cancer fulfilling Li-Fraumeni(-like) clinical diagnostic criteria.MethodsTo specifically help explain the diagnostic gap of TP53 wild-type Li-Fraumeni(-like) breast cancer cases, we performed array-based CGH (comparative genomic hybridization) and panel-based sequencing of 94 cancer predisposition genes on 83 breast cancer patients suggestive of Li-Fraumeni syndrome who had previously had negative test results for causative BRCA1, BRCA2, and TP53 germline variants.ResultsWe identified 13 pathogenic or likely pathogenic germline variants in ten patients and in nine genes, including four copy number aberrations and nine single-nucleotide variants or small indels. Three patients presented as double-mutation carriers involving two different genes each. In five patients (5 of 83; 6% of cohort), we detected causative pathogenic variants in established hereditary breast cancer susceptibility genes (i.e., PALB2, CHEK2, ATM). Five further patients (5 of 83; 6% of cohort) were found to harbor pathogenic variants in genes lacking a firm association with breast cancer susceptibility to date (i.e., Fanconi pathway genes, RECQ family genes, CDKN2A/p14ARF, and RUNX1).ConclusionsOur study details the mutational spectrum in breast cancer patients suggestive of Li-Fraumeni syndrome and indicates the need for intensified research on monoallelic variants in Fanconi pathway and RECQ family genes. Notably, this study further reveals a large portion of still unexplained Li-Fraumeni(-like) cases, warranting comprehensive investigation of recently described candidate genes as well as noncoding regions of the TP53 gene in patients with Li-Fraumeni(-like) syndrome lacking TP53 variants in coding regions.Electronic supplementary materialThe online version of this article (10.1186/s13058-018-1011-1) contains supplementary material, which is available to authorized users.

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“…Huang et al reported the heterozygous state in an A-T patient with a CNV in exon 63 and a nonsense variant (c.3174G > A) in exon 22 whose ataxia-age at onset was 48 months and serum levels of IgG, IgA, IgM, and Ig E were normal [ 18 ]. Podralska et al identified a CNV of exons 62 and 63, combined with a nonsense variant c.5932G > T in exon 42 [ 40 ]. A general summary of the characteristics of the atypical A-T with compound heterozygous SNV and CNV in ATM are shown in Table 2 .…”

Section: Discussionmentioning

confidence: 99%

“…Atypical A-T is frequently associated either with missense or leaky splice site variants that allow for some ATM protein with residual ATM kinase activity to be formed [ 32 ]. Podralska et al reported a compound heterozygous with 2 CNVs in ATM that was related mixed phenotype involving onset of ataxia at 2 years old, decreased level of immunoglobulins and normal level of AFP [ 40 ]. Previous reports described mixed phenotypes encompassing typical and atypical clinical features in the atypical A-T patients with compound heterozygous SNV and CNV in ATM [ 18 , 37 , 39 – 42 ].…”

Section: Discussionmentioning

confidence: 99%

Compound heterozygous variants including a novel copy number variation in a child with atypical ataxia-telangiectasia: a case report

et al. 2021

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Background Ataxia-telangiectasia is a rare autosomal recessive, neurodegenerative disorder caused by alterations in the ATM gene. The majority of ATM pathogenic variants are frameshift or nonsense variants which are predicted to truncate the whole ATM protein. Herein, we report on an ataxia telangiectasia child with atypical phenotype who was identified as compound heterozygous for two ATM variants involving a previously described pathogenic single nucleotide variation (SNV) and a novel copy number variation (CNV). Case presentation A 6-year-old boy presented with delayed development and oculomotor apraxia. Brain magnetic resonance imaging showed interval development of mild atrophy in the cerebellum. Serum alpha fetoprotein level was in normal range. Next-generation sequencing and single-nucleotide polymorphism array tests were performed. Next-generation sequencing revealed a heterozygous nonsense pathogenic variant in ATM, c.742C > T (p.Arg248Ter) inherited from the father. Single-nucleotide polymorphism array revealed a compound heterozygous CNV, arr[GRCh37] 11q22.3(10851766–108183226) × 1, 31460 bp (exons 24–40 deletion of ATM) inherited from the mother, which was validated by reverse transcription-polymerase chain reaction analysis (RT-PCR). We demonstrated that this variant (NM_000051.4:c.3403_6006del) generated a product of in-frame deletion of exon 24–40 of ATM (p.Ser1135_Gln2002del). Conclusions The compound heterozygosity for ATM variants involving a previously described pathogenic SNV and a novel CNV may be associated with the atypical clinical manifestations. This clinical report extends the genetic and phenotypic spectrum of ATM pathogenic variants in atypical ataxia-telangiectasia, thus making implementation of advanced analysis beyond the routine next-generation sequencing an important consideration in diagnosis and rehabilitation services for children with ataxia-telangiectasia.

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Ten new ATM alterations in Polish patients with ataxia‐telangiectasia

Cited by 20 publications

References 27 publications

Genetic variants in ATM, H2AFX and MRE11 genes and susceptibility to breast cancer in the polish population

Genetic variants in ATM, H2AFX and MRE11 genes and susceptibility to breast cancer in the polish population

Breast cancer patients suggestive of Li-Fraumeni syndrome: mutational spectrum, candidate genes, and unexplained heredity

Compound heterozygous variants including a novel copy number variation in a child with atypical ataxia-telangiectasia: a case report

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