Reclassification of variants of uncertain significance in neonatal genetic diseases: implications from a clinician’s perspective

Yang L, Liu X, Li Z, Zhang P, Wu B, Wang H, et al. Genetic aetiology of early infant deaths in a neonatal intensive care unit. J Med Genet. 2020;57:169–77.

Article  PubMed  CAS  Google Scholar 

Meng L, Pammi M, Saronwala A, Magoulas P, Ghazi AR, Vetrini F, et al. Use of exome sequencing for infants in intensive care units: ascertainment of severe single-gene disorders and effect on medical management. JAMA Pediatr. 2017;171:e173438.

Article  PubMed  PubMed Central  Google Scholar 

Tan TY, Dillon OJ, Stark Z, Schofield D, Alam K, Shrestha R, et al. Diagnostic impact and cost-effectiveness of whole-exome sequencing for ambulant children with suspected monogenic conditions. JAMA Pediatr. 2017;171:855–62.

Article  PubMed  PubMed Central  Google Scholar 

Wright CF, FitzPatrick DR, Firth HV. Paediatric genomics: diagnosing rare disease in children. Nat Rev Genet. 2018;19:253–68.

Article  PubMed  CAS  Google Scholar 

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24.

Article  PubMed  PubMed Central  Google Scholar 

Clift K, Macklin S, Halverson C, McCormick JB, Abu Dabrh AM, Hines S. Patients’ views on variants of uncertain significance across indications. J Community Genet. 2020;11:139–45.

Article  PubMed  Google Scholar 

Tsai GJ, Rañola JMO, Smith C, Garrett LT, Bergquist T, Casadei S, et al. Outcomes of 92 patient-driven family studies for reclassification of variants of uncertain significance. Genet Med. 2019;21:1435–42.

Article  PubMed  CAS  Google Scholar 

SoRelle JA, Thodeson DM, Arnold S, Gotway G, Park JY. Clinical utility of reinterpreting previously reported genomic epilepsy test results for pediatric patients. JAMA Pediatr. 2019;173:e182302.

Article  PubMed  Google Scholar 

So M-K, Jeong T-D, Lim W, Moon B-I, Paik NS, Kim SC, et al. Reinterpretation of BRCA1 and BRCA2 variants of uncertain significance in patients with hereditary breast/ovarian cancer using the ACMG/AMP 2015 guidelines. Breast Cancer. 2019;26:510–9.

Article  PubMed  Google Scholar 

Bennett JS, Bernhardt M, McBride KL, Reshmi SC, Zmuda E, Kertesz NJ, et al. Reclassification of variants of uncertain significance in children with inherited arrhythmia syndromes is predicted by clinical factors. Pediatr Cardiol. 2019;40:1679–87.

Article  PubMed  Google Scholar 

Wright M, Menon V, Taylor L, Shashidharan M, Westercamp T, Ternent CA. Factors predicting reclassification of variants of unknown significance. Am J Surg. 2018;216:1148–54.

Article  PubMed  Google Scholar 

Chen E, Facio FM, Aradhya KW, Rojahn S, Hatchell KE, Aguilar S, et al. Rates and classification of variants of uncertain significance in hereditary disease genetic testing. JAMA Netw Open. 2023;6:e2339571.

Article  PubMed  PubMed Central  Google Scholar 

Chourasia N, Vaidya R, Sengupta S, Mefford HC, Wheless J. A Retrospective review of reclassification of variants of uncertain significance in a pediatric epilepsy cohort undergoing genetic panel testing. Pediatr Neurol. 2024;161:101–7.

Article  PubMed  Google Scholar 

Zhang L, Shen M, Shu X, Zhou J, Ding J, Lin H, et al. The recommendation of re-classification of variants of uncertain significance (VUS) in adult genetic disorders patients. J Hum Genet. 2024;69:425–31.

Article  PubMed  CAS  Google Scholar 

Fowler DM, Rehm HL. Will variants of uncertain significance still exist in 2030? Am J Hum Genet. 2024;111:5–10.

Tavtigian SV, Harrison SM, Boucher KM, Biesecker LG. Fitting a naturally scaled point system to the ACMG/AMP variant classification guidelines. Hum Mutat. 2020;41:1734–7.

Article  PubMed  Google Scholar 

Ellard S, Baple EL, Callaway A, Berry I, Forrester N, Turnbull C, et al. ACGS best practice guidelines for variant classification in rare disease 2020. http://www.acgs.uk.com/quality/best-practice-guidelines/.

Sequence Variant Interpretation, ClinGen. https://clinicalgenome.org/working-groups/sequence-variant-interpretation/.

Zhang J, Yao Y, He H, Shen J. Clinical interpretation of sequence variants. Curr Protoc Hum Genet. 2020;106:e98.

Article  PubMed  PubMed Central  Google Scholar 

Rehm HL, Bale SJ, Bayrak-Toydemir P, Berg JS, Brown KK, Deignan JL, et al. ACMG clinical laboratory standards for next-generation sequencing. Genet Med. 2013;15:733–47.

Article  PubMed  PubMed Central  Google Scholar 

Zhu Y, Cao Y, Ma L, Fan L, Pu W, Xia Y. Trichohepatoenteric syndrome and cytomegalovirus infection: case report and literature summary. SAGE Open Med Case Rep. 2024;12:2050313X241248393.

Article  PubMed  PubMed Central  Google Scholar 

Ackerman MJ. Genetic purgatory and the cardiac channelopathies: exposing the variants of uncertain/unknown significance issue. Heart Rhythm. 2015;12:2325–31.

Article  PubMed  Google Scholar 

Mercati O, Abi Warde M-T, Lina-Granade G, Rio M, Heide S, de Lonlay P, et al. PRPS1 loss-of-function variants, from isolated hearing loss to severe congenital encephalopathy: new cases and literature review. Eur J Med Genet. 2020;63:104033.

Article  PubMed  Google Scholar 

Ioannidis NM, Rothstein JH, Pejaver V, Middha S, McDonnell SK, Baheti S, et al. REVEL: an ensemble method for predicting the pathogenicity of rare missense variants. Am J Hum Genet. 2016;99:877–85.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Pejaver V, Byrne AB, Feng B-J, Pagel KA, Mooney SD, Karchin R, et al. Calibration of computational tools for missense variant pathogenicity classification and ClinGen recommendations for PP3/BP4 criteria. Am J Hum Genet. 2022;109:2163–77.

Article  PubMed  PubMed Central  CAS  Google Scholar 

He W-B, Xiao W-J, Dai C-L, Wang Y-R, Li X-R, Gong F, et al. RNA splicing analysis contributes to reclassifying variants of uncertain significance and improves the diagnosis of monogenic disorders. J Med Genet. 2022;59:1010–6.

Article  PubMed  CAS  Google Scholar 

Wenger AM, Guturu H, Bernstein JA, Bejerano G. Systematic reanalysis of clinical exome data yields additional diagnoses: implications for providers. Genet Med. 2017;19:209–14.

Article  PubMed  Google Scholar 

Macklin SK, Jackson JL, Atwal PS, Hines SL. Physician interpretation of variants of uncertain significance. Fam Cancer. 2019;18:121–6.

Article  PubMed  Google Scholar 

Cherny S, Olson R, Chiodo K, Balmert LC, Webster G. Changes in genetic variant results over time in pediatric cardiomyopathy and electrophysiology. J Genet Couns. 2021;30:229–36.

Article  PubMed  CAS  Google Scholar 

David KL, Best RG, Brenman LM, Bush L, Deignan JL, Flannery D, et al. Patient re-contact after revision of genomic test results: points to consider—a statement of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2019;21:769–71.

Article  PubMed  Google Scholar 

Comments (0)

No login
gif