Patterns of mosaicism for sequence and copy-number variants discovered through clinical deep sequencing of disease-related genes in one million individuals

Truty, Rebecca; Rojahn, Susan; Ouyang, Karen; Kautzer, Curtis; Kennemer, Michael; Pineda-Álvarez, Daniel E.; Johnson, Britt; Stafford, Amanda; Basel‐Salmon, Lina; Saitta, Sulagna C.; Slavotinek, Anne; Chandrasekharappa, Settara C.; Suarez, Carlos J.; Burnett, Leslie; Nussbaum, Robert L.; Aradhya, Swaroop

doi:10.1016/j.ajhg.2023.02.013

Cited by 10 publications

(2 citation statements)

References 41 publications

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“…For the 15% of clinical indications not transferable to GS (responsible for 29% of individuals referred), we noted trends, such that most of these required somatic structural variant detection, currently assayed via karyotyping, FISH and/or arrays, or variants were located in complex regions of the genome, currently assessed by amplicon-based long-read sequencing strategies [ 49 ]. These technical challenges can — in part — be overcome by sequencing at higher depth (e.g., ~ 100 × or even ~ 350 ×) to allow better somatic SNV/indel detection [ 50 ]. Yet, it could also be considered to maintain workflows for dedicated diagnostic referrals.…”

Section: Discussionmentioning

confidence: 99%

Genome sequencing as a generic diagnostic strategy for rare disease

Schobers,

Derks,

den Ouden

et al. 2024

Genome Med

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Background To diagnose the full spectrum of hereditary and congenital diseases, genetic laboratories use many different workflows, ranging from karyotyping to exome sequencing. A single generic high-throughput workflow would greatly increase efficiency. We assessed whether genome sequencing (GS) can replace these existing workflows aimed at germline genetic diagnosis for rare disease. Methods We performed short-read GS (NovaSeq™6000; 150 bp paired-end reads, 37 × mean coverage) on 1000 cases with 1271 known clinically relevant variants, identified across different workflows, representative of our tertiary diagnostic centers. Variants were categorized into small variants (single nucleotide variants and indels < 50 bp), large variants (copy number variants and short tandem repeats) and other variants (structural variants and aneuploidies). Variant calling format files were queried per variant, from which workflow-specific true positive rates (TPRs) for detection were determined. A TPR of ≥ 98% was considered the threshold for transition to GS. A GS-first scenario was generated for our laboratory, using diagnostic efficacy and predicted false negative as primary outcome measures. As input, we modeled the diagnostic path for all 24,570 individuals referred in 2022, combining the clinical referral, the transition of the underlying workflow(s) to GS, and the variant type(s) to be detected. Results Overall, 95% (1206/1271) of variants were detected. Detection rates differed per variant category: small variants in 96% (826/860), large variants in 93% (341/366), and other variants in 87% (39/45). TPRs varied between workflows (79–100%), with 7/10 being replaceable by GS. Models for our laboratory indicate that a GS-first strategy would be feasible for 84.9% of clinical referrals (750/883), translating to 71% of all individuals (17,444/24,570) receiving GS as their primary test. An estimated false negative rate of 0.3% could be expected. Conclusions GS can capture clinically relevant germline variants in a ‘GS-first strategy’ for the majority of clinical indications in a genetics diagnostic lab.

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Section: Discussionmentioning

confidence: 99%

Genome sequencing as a generic diagnostic strategy for rare disease

Schobers,

Derks,

den Ouden

et al. 2024

Genome Med

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“…At present, opinions are divided in the field regarding screening donors for CHIP [47,48] . To understand the impact of donor or recipient CHIP on transplant outcomes, and subsequently make clinical recommendations for donor selection and genetic counseling, larger population studies and clinical trials will be necessary [49,50] . From a patient care and genetic counseling perspective, CHIP highlights unique considerations of caring for transplant patients and their donors.…”

Section: Discussionmentioning

confidence: 99%

Pathogenic and likely pathogenic germline variation in patients with myeloid malignancies and their unrelated HLA-matched hematopoietic stem cell donors

Clay-Gilmour,

Cooper,

Wang

et al. 2024

J Transl Genet Genom

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Aims: The revised 2022 World Health Organization classification recognizes myeloid neoplasms with associated germline predisposition as a defined subcategory, underscoring the clinical significance of likely pathogenic (LPV) and pathogenic (PV) germline variation in these diseases. To better understand the role of LPV/PV in blood or marrow transplants (BMT), a curative therapy for myeloid neoplasms, we measure their frequency and association with mortality in two cohorts of donor-recipient pairs. Methods: LPV/PV frequencies in 665 cancer-related genes were measured using exomechip genotyping data in 1990 acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) patients and their unrelated donors, registered with the Center for International Blood and Marrow Transplant Research. Cox proportional hazard models were used to test variant association with recipient mortality one-year post-transplant. Results: Thirteen autosomal dominant (AD) LPV/PV in eight genes were found in 2.8% of patients and 2.2% of donors; those linked to autosomal recessive conditions appeared in 11.1% of patients and 11% of donors. The most common AD LPV/PV mutations in recipients were found in DDX41 (n = 18). For donors, the most frequent AD PVs occurred in CHEK2 (n = 21) and Fanconi Anemia (FA) genes (n = 7). DDX41 and CHEK2 variation did not correlate with patient survival, but patients with donors with an LPV/PVs in an FA gene had lower survival (HR = 2.38, 95%CI: 1.06-5.31, P = 0.035) than patients whose donors did not have an FA LPV/PV. Conclusion: We identified LPVs/PVs in cancer genes in donors and recipients and are the first to show an association of donor FA PVs with mortality after BMT.

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Genomic mosaicism in colorectal cancer and polyposis syndromes: a systematic review and meta-analysis

de Moraes,

Moretti,

Sano

et al. 2024

Int J Colorectal Dis

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Background Colorectal cancer (CRC) and polypoid syndromes are significant public health concerns, with somatic mosaicism playing a crucial role in their genetic diversity. This study aimed to investigate the prevalence and impact of somatic mosaicism in these conditions. Methods A search was conducted using PubMed, Scopus, and Web of Sciences to identify studies evaluating mosaicism in patients with CRC or polyposis syndromes. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to determine prevalence rates. Statistical analyses were performed using R software 4.3. Results A total of 27 studies, encompassing 2272 patients, were included in the analysis. Of these, 108 patients exhibited somatic mosaicism, resulting in an overall prevalence of 8.79% (95% CI 5.1 to 14.70%, I2 = 85; p < 0.01). Subgroup analyses revealed a significantly higher prevalence of mosaicism in patients with APC mutations (OR 13.43%, 95% CI 6.36 to 26.18%, I2 = 87; p < 0.01). Additionally, mosaicism in MLH1 and MSH2 genes was observed at rates of 2.75% (95% CI 1.20 to 6.18%) and 9.69% (95% CI 2.98 to 27.24%), respectively. Conclusions Our findings support the growing recognition of mosaicism as a critical factor in CRC susceptibility and underscore the importance of incorporating mosaicism screening into routine genetic testing for at-risk patients.

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Patterns of mosaicism for sequence and copy-number variants discovered through clinical deep sequencing of disease-related genes in one million individuals

Cited by 10 publications

References 41 publications

Genome sequencing as a generic diagnostic strategy for rare disease

Genome sequencing as a generic diagnostic strategy for rare disease

Pathogenic and likely pathogenic germline variation in patients with myeloid malignancies and their unrelated HLA-matched hematopoietic stem cell donors

Genomic mosaicism in colorectal cancer and polyposis syndromes: a systematic review and meta-analysis

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