Increasing pathogenic germline variant diagnosis rates in precision medicine: current best practices and future opportunities

Yang Y, Lyu J, Wang R, Wen Q, Zhao L, Chen W, et al. A digital mask to safeguard patient privacy. Nat Med. 2022;28(9):1883–92.

CAS  PubMed  PubMed Central  Google Scholar 

Ginsburg GS, Phillips KA. Precision medicine: from science to value. Health Aff (Millwood). 2018;37(5):694–701.

PubMed  Google Scholar 

Petersen B-S, Fredrich B, Hoeppner MP, Ellinghaus D, Franke A. Opportunities and challenges of whole-genome and -exome sequencing. BMC Genet. 2017;18(1):14.

PubMed  PubMed Central  Google Scholar 

Magger O, Waldman YY, Ruppin E, Sharan R. Enhancing the prioritization of disease-causing genes through tissue specific protein interaction networks. PLoS Comput Biol. 2012;8(9):e1002690.

CAS  PubMed  PubMed Central  Google Scholar 

Field MA, Cho V, Andrews TD, Goodnow CC. Reliably detecting clinically important variants requires both combined variant calls and optimized filtering strategies. PLoS ONE. 2015;10(11):e0143199.

PubMed  PubMed Central  Google Scholar 

Berger SM, Appelbaum PS, Siegel K, Wynn J, Saami AM, Brokamp E, et al. Challenges of variant reinterpretation: opinions of stakeholders and need for guidelines. Genet Med. 2022;24(9):1878–87.

CAS  PubMed  PubMed Central  Google Scholar 

Field MA, Burgio G, Chuah A, Al Shekaili J, Hassan B, Al Sukaiti N, et al. Recurrent miscalling of missense variation from short-read genome sequence data. BMC Genomics. 2019;20(Suppl 8):546.

PubMed  PubMed Central  Google Scholar 

Chen J, Li X, Zhong H, Meng Y, Du H. Systematic comparison of germline variant calling pipelines cross multiple next-generation sequencers. Sci Rep. 2019;9(1):9345.

PubMed  PubMed Central  Google Scholar 

Murphy DA, Elyashiv E, Amster G, Sella G. Broad-scale variation in human genetic diversity levels is predicted by purifying selection on coding and non-coding elements. Elife. 2023;12.

Virolainen SJ, VonHandorf A, Viel K, Weirauch MT, Kottyan LC. Gene-environment interactions and their impact on human health. Genes Immun. 2023;24(1):1–11.

PubMed  Google Scholar 

Jeffreys AJ, Wilson V, Thein SL, Weatherall DJ, Ponder BA. DNA fingerprints and segregation analysis of multiple markers in human pedigrees. Am J Hum Genet. 1986;39(1):11–24.

CAS  PubMed  PubMed Central  Google Scholar 

Field MA, Cho V, Cook MC, Enders A, Vinuesa C, Whittle B et al. Reducing the search space for causal genetic variants with VASP: variant analysis of sequenced pedigrees. Bioinformatics. 2015.

Aureliano W. Difficult decisions and possible choices: rare diseases, genetic inheritance and reproduction of the family. Soc Sci Med. 2024;363:117380.

PubMed  Google Scholar 

Strianese O, Rizzo F, Ciccarelli M, Galasso G, D’Agostino Y, Salvati A et al. Precision and Personalized Medicine: How Genomic Approach Improves the Management of Cardiovascular and Neurodegenerative Disease. Genes (Basel). 2020;11(7).

Rehm HL, Fowler DM. Keeping up with the genomes: scaling genomic variant interpretation. Genome Med. 2019;12(1):5.

PubMed  PubMed Central  Google Scholar 

Pei XM, Yeung MHY, Wong ANN, Tsang HF, Yu ACS, Yim AKY et al. Targeted sequencing approach and its clinical applications for the molecular diagnosis of human diseases. Cells. 2023;12(3).

Merker JD, Wenger AM, Sneddon T, Grove M, Zappala Z, Fresard L, et al. Long-read genome sequencing identifies causal structural variation in a Mendelian disease. Genet Med. 2018;20(1):159–63.

CAS  PubMed  Google Scholar 

Young C, Singh M, Jackson KJL, Field MA, Peters TJ, Angioletti-Uberti S et al. A triad of somatic mutagenesis converges in self-reactive B cells to cause a virus-induced autoimmune disease. Immunity. 2025.

Singh M, Louie RHY, Samir J, Field MA, Milthorpe C, Adikari T, et al. Expanded T cell clones with lymphoma driver somatic mutations accumulate in refractory Celiac disease. Sci Transl Med. 2025;17(798):eadp6812.

CAS  PubMed  Google Scholar 

McCabe MJ, Gauthier M-EA, Chan C-L, Thompson TJ, De Sousa SMC, Puttick C, et al. Development and validation of a targeted gene sequencing panel for application to disparate cancers. Sci Rep. 2019;9(1):17052.

PubMed  PubMed Central  Google Scholar 

Rehm HL. Disease-targeted sequencing: a cornerstone in the clinic. Nat Rev Genet. 2013;14(4):295–300.

CAS  PubMed  PubMed Central  Google Scholar 

Andrews TD, Jeelall Y, Talaulikar D, Goodnow CC, Field MA. DeepSNVMiner: a sequence analysis tool to detect emergent, rare mutations in subsets of cell populations. PeerJ. 2016;4:e2074.

PubMed  PubMed Central  Google Scholar 

Yu H, Yu H, Zhang R, Peng D, Yan D, Gu Y et al. Targeted gene panel provides advantages over whole-exome sequencing for diagnosing obesity and diabetes mellitus. J Mol Cell Biol. 2023.

Johar AS, Mastronardi C, Rojas-Villarraga A, Patel HR, Chuah A, Peng K, et al. Novel and rare functional genomic variants in multiple autoimmune syndrome and sjogren’s syndrome. J Transl Med. 2015;13:173.

PubMed  PubMed Central  Google Scholar 

Dunkerton S, Field M, Cho V, Bertram E, Whittle B, Groves A et al. A de Novo mutation in KMT2A (MLL) in monozygotic twins with Wiedemann-Steiner syndrome. Am J Med Genet A. 2015.

Bamshad MJ, Ng SB, Bigham AW, Tabor HK, Emond MJ, Nickerson DA, et al. Exome sequencing as a tool for Mendelian disease gene discovery. Nat Rev Genet. 2011;12(11):745–55.

CAS  PubMed  Google Scholar 

Botstein D, Risch N. Discovering genotypes underlying human phenotypes: past successes for Mendelian disease, future approaches for complex disease. Nat Genet. 2003;33(Suppl):228–37.

CAS  PubMed  Google Scholar 

Majewski J, Schwartzentruber J, Lalonde E, Montpetit A, Jabado N. What can exome sequencing do for you? J Med Genet. 2011;48(9):580–9.

CAS  PubMed  Google Scholar 

Ng SB, Buckingham KJ, Lee C, Bigham AW, Tabor HK, Dent KM, et al. Exome sequencing identifies the cause of a Mendelian disorder. Nat Genet. 2010;42(1):30–5.

CAS  PubMed  Google Scholar 

Rabbani B, Tekin M, Mahdieh N. The promise of whole-exome sequencing in medical genetics. J Hum Genet. 2014;59(1):5–15.

CAS  PubMed  Google Scholar 

Nakagawa H, Wardell CP, Furuta M, Taniguchi H, Fujimoto A. Cancer whole-genome sequencing: present and future. Oncogene. 2015;34(49):5943–50.

CAS  PubMed  Google Scholar 

Scocchia A, Wigby KM, Masser-Frye D, Del Campo M, Galarreta CI, Thorpe E, et al. Clinical whole genome sequencing as a first-tier test at a resource-limited dysmorphology clinic in Mexico. NPJ Genom Med. 2019;4:5.

PubMed  PubMed Central  Google Scholar 

Belkadi A, Bolze A, Itan Y, Cobat A, Vincent QB, Antipenko A, et al. Whole-genome sequencing is more powerful than whole-exome sequencing for detecting exome variants. Proc Natl Acad Sci USA. 2015;112(17):5473–8.

CAS  PubMed  PubMed Central  Google Scholar 

Lelieveld SH, Spielmann M, Mundlos S, Veltman JA, Gilissen C. Comparison of exome and genome sequencing technologies for the complete capture of Protein-Coding regions. Hum Mutat. 2015;36(8):815–22.

CAS  PubMed  Google Scholar 

Lionel AC, Costain G, Monfared N, Walker S, Reuter MS, Hosseini SM, et al. Improved diagnostic yield compared with targeted gene sequencing panels suggests a role for whole-genome sequencing as a first-tier genetic test. Genet Med. 2018;20(4):435–43.

CAS  PubMed  Google Scholar 

Bertoli-Avella AM, Beetz C, Ameziane N, Rocha ME, Guatibonza P, Pereira C, et al. Successful application of genome sequencing in a diagnostic setting: 1007 index cases from a clinically heterogeneous cohort. Eur J Hum Genet. 2021;29(1):141–53.

CAS  PubMed  Google Scholar 

Stavropoulos DJ, Merico D, Jobling R, Bowdin S, Monfared N, Thiruvahindrapuram B, et al. Whole genome sequencing expands diagnostic utility and improves clinical management in pediatric medicine. NPJ Genom Med. 2016;1:15012.

CAS  PubMed  PubMed Central  Google Scholar 

Willig LK, Petrikin JE, Smith LD, Saunders CJ, Thiffault I, Miller NA, et al. Whole-genome sequencing for identification of Mendelian disorders in critically ill infants: a retrospective analysis of diagnostic and clinical findings. Lancet Respir Med. 2015;3(5):377–87.

CAS  PubMed  PubMed Central  Google Scholar 

Ostrander BEP, Butterfield RJ, Pedersen BS, Farrell AJ, Layer RM, Ward A, et al. Whole-genome analysis for effective clinical diagnosis and gene discovery in early infantile epileptic encephalopathy. Npj Genomic Med. 2018;3(1):22.

Google Scholar 

Rajagopalan R, Gilbert MA, McEldrew DA, Nassur JA, Loomes KM, Piccoli DA, et al. Genome sequencing increases diagnostic yield in clinically diagnosed Alagille syndrome patients with previously negative test results. Genet Sci. 2021;23(2):323–30.

CAS  Google Scholar 

Austin-Tse CA, Jobanputra V, Perry DL, Bick D, Taft RJ, Venner E, et al. Best practices for the interpretation and reporting of clinical whole genome sequencing. Npj Genomic Med. 2022;7(1):27.

Google Scholar 

Hamzeh AR, Andrews TD, Field MA. Detecting causal variants in Mendelian disorders using Whole-Genome sequencing. Methods Mol Biol. 2021;2243:1–25.

CAS  PubMed  Google Scholar 

Hegenbarth J-C, Lezzoche G, De Windt LJ, Stoll M. Perspectives on Bulk-Tissue RNA sequencing and Single-Cell RNA sequencing for cardiac transcriptomics. Front Mol Med. 2022;2.

Cummings BB, Marshall JL, Tukiainen T, Lek M, Donkervoort S, Foley AR et al. Improving genetic diagnosis in Mendelian disease with transcriptome sequencing. Sci Transl Med. 2017;9(386).

Deng Q, Ramsköld D, Reinius B, Sandberg R. Single-cell RNA-seq reveals dynamic, random monoallelic gene expression in mammalian cells. Science. 2014;343(6167):193–6.

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