Early-onset breast cancer in a woman with a germline mobile element insertion resulting in BRCA2 disruption: a case report

Deuitch, Natalie; Li, Shao-Tzu; Courtney, Eliza; Shaw, T. Claye; Dent, Rebecca; Tan, Veronique Kiak‐Mien; Yackowski, Lauren; Torene, Rebecca; Berkofsky-Fessler, Windy; Ngeow, Joanne

doi:10.1038/s41439-020-00111-z

Cited by 3 publications

(2 citation statements)

References 18 publications

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“…These include an SVA F in the PNPLA2 gene associated with neutral lipid storage disease with subclinical myopathy, an SVA E in the BRCA2 gene associated with breast cancer and an SVA F1 in the MSH2 gene associated with the cancer predisposition disease Lynch syndrome. 39,53,56 An SVA F insertion in exon 13 of the BBS1 gene was identified as the second most common pathogenic variant associated with the rare recessive disease Bardet-Beidl syndrome, which occurred in a common ancestor at an estimated 74 generations ago. 36,37 In addition, a recent report of SVA F1 insertion with accompanying 5 ′ and 3 ′ transductions of Alu sequences was associated with X-linked dominant chondrodysplasia punctata (CDPX2).…”

Section: Exonic Sva Insertions and Loss-offunction Mutationsmentioning

confidence: 99%

Mechanisms of disease-associated SINE-VNTR-Alus

Pfaff

Singleton

Kõks

2022

Exp Biol Med (Maywood)

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SINE-VNTR-Alus (SVAs) are the youngest retrotransposon family in the human genome. Their ongoing mobilization has generated genetic variation within the human population. At least 24 insertions to date, detailed in this review, have been associated with disease. The predominant mechanisms through which this occurs are alterations to normal splicing patterns, exonic insertions causing loss-of-function mutations, and large genomic deletions. Dissecting the functional impact of these SVAs and the mechanism through which they cause disease provides insight into the consequences of their presence in the genome and how these elements could influence phenotypes. Many of these disease-associated SVAs have been difficult to characterize and would not have been identified through routine analyses. However, the number identified has increased in recent years as DNA and RNA sequencing data became more widely available. Therefore, as the search for complex structural variation in disease continues, it is likely to yield further disease-causing SVA insertions.

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Section: Exonic Sva Insertions and Loss-offunction Mutationsmentioning

confidence: 99%

Mechanisms of disease-associated SINE-VNTR-Alus

Pfaff

Singleton

Kõks

2022

Exp Biol Med (Maywood)

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“…Pathogenic MEIs have been detected in multiple cancerassociated genes, including HBOC susceptibility genes [17,18]. In a large cohort study [19], enriched for HBOC patients, 45.9% of all pathogenic MEIs found were located in BRCA2.…”

Section: Introductionmentioning

confidence: 99%

A Novel Alu Element Insertion in ATM Induces Exon Skipping in Suspected HBOC Patients

et al. 2023

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The vast majority of patients at risk of hereditary breast and/or ovarian cancer (HBOC) syndrome remain without a molecular diagnosis after routine genetic testing. One type of genomic alteration that is commonly missed by diagnostic pipelines is mobile element insertions (MEIs). Here, we reanalyzed multigene panel data from suspected HBOC patients using the MEI detection tool Mobster. A novel Alu element insertion in ATM intron 54 (ATM:c.8010+30_8010+31insAluYa5) was identified as a potential contributing factor in seven patients. Transcript analysis of patient-derived RNA from three heterozygous carriers revealed exon 54 skipping in 38% of total ATM transcripts. To manifest the direct association between the Alu element insertion and the aberrant splice pattern, HEK293T and MCF7 cells were transfected with wild-type or Alu element-carrying minigene constructs. On average, 77% of plasmid-derived transcripts lacked exon 54 in the presence of the Alu element insertion compared to only 4.7% of transcripts expressed by the wild-type minigene. These results strongly suggest ATM:c.8010+30_8010+31insAluYa5 as the main driver of ATM exon 54 skipping. Since this exon loss is predicted to cause a frameshift and a premature stop codon, mutant transcripts are unlikely to translate into functional proteins. Based on its estimated frequency of up to 0.05% in control populations, we propose to consider ATM:c.8010+30_8010+31insAluYa5 in suspected HBOC patients and to clarify its role in carcinogenesis through future epidemiological and functional analyses. Generally, the implementation of MEI detection tools in diagnostic sequencing pipelines could increase the diagnostic yield, as MEIs are likely underestimated contributors to genetic diseases.

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Retrotransposon insertion as a novel mutational cause of spinal muscular atrophy

et al. 2022

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Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder resulting from biallelic alterations of the SMN1 gene: deletion, gene conversion or, in rare cases, intragenic variants. The disease severity is mainly in uenced by the copy number of SMN2, a nearly identical gene, which produces only low amounts of full-length (FL) mRNA. Here we describe the rst example of retrotransposon insertion as a pathogenic SMN1 mutational event. The 50-year-old patient is clinically affected by SMA type III with a diagnostic odyssey spanning nearly 30 years. Despite a mild disease course, he carries a single SMN2 copy. Using Exome Sequencing and Sanger sequencing, we characterized a SVA-F retrotransposon inserted in SMN1 intron 7. Using RT-PCR and RNASeq experiments on lymphoblastoid cell lines, we documented the dramatic decrease of FL transcript production in the patient compared to subjects with the same SMN1 and SMN2 copy number, thus validating the pathogenicity of this SVA insertion. We characterized the mutant FL-SMN1-SVA transcript and showed that it is subject to degradation by nonsense-mediated mRNA decay. The stability of the SMN-SVA protein may explain the mild course of the disease. This observation exempli es the role of retrotransposons in human genetic disorders.

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Early-onset breast cancer in a woman with a germline mobile element insertion resulting in BRCA2 disruption: a case report

Cited by 3 publications

References 18 publications

Mechanisms of disease-associated SINE-VNTR-Alus

Mechanisms of disease-associated SINE-VNTR-Alus

A Novel Alu Element Insertion in ATM Induces Exon Skipping in Suspected HBOC Patients

Retrotransposon insertion as a novel mutational cause of spinal muscular atrophy

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