Medically Actionable Secondary Findings from Whole-Exome Sequencing (WES) Data in a Sample of 3972 Individuals
Abstract
:1. Introduction
2. Results
2.1. Dataset
2.2. Variant Filtering and Curation
2.3. Allele Counts
2.4. Novel Variant Findings
2.5. Medically Actionable Findings and Carriers
2.5.1. Frequency of Medically Actionable Findings
2.5.2. Carrier Frequencies
3. Discussion
- Lab cohort bias. Our sample was derived from cases ascertained for the genetic diagnosis of various Mendelian disorders; therefore, a few persons in the cohort may already be affected by a disease attributable to one of the genes in the ACMG list. Despite this, when excluding L-PAT/PAT variants listed as primary diagnosis in the genetic test reports of these patients, the overall frequency did not differ significantly (only 0.6%).
- Gene list. We limited our analysis to the current set of the ACMG genes. We did not consider other clinically relevant genes, such as those curated by the ClinGen Actionability Working Group, for instance. The inclusion of additional conditions, some of specific impact in the Portuguese population, should be considered in future studies, which might increase the overall frequency of actionable findings.
- Study design. In order to minimise the impact of data used, our project protocol prevented us from including individual-level information regarding ethnic background, age, gender, reason for referral for WES, or phenotype. Additionally, the genotypes obtained were related to the whole cohort, not the patient. Consequently, we were not able to estimate compound heterozygosity or the number of findings per individual.
- Technical limitations. The methodologies used may have led to missed variants due to (i) the intrinsic WES limitation to detect deep intronic, triplet repeat expansion, and structural variants; (ii) the use of different capture kits along time within this cohort; (iii) incomplete coverage in some regions; (iv) not considering structural variants, including copy number variants (CNVs); and (v) global minor allele frequency (MAF) cut-off.
- Pseudogenes or highly homologous genomic regions. Several ACMG genes, such as BMPR1A, BRCA1, CALM1, FLNC, PKP2, PMS2, PTEN, and TTN, are associated with pseudogenes or highly homologous genomic regions, which can compromise the accurate detection of variants. The presence of pseudogenes may lead to false negatives due to challenges in aligning reads from functional genes and pseudogenes, potentially missing disease-causing variants. This aspect should be considered when interpreting our findings.
- Potential for false-positive interpretation of variants. Variants accurately classified as PAT/L-PAT, based on available evidence, may not, in fact, be disease-causing, due to incomplete penetrance or variable expressivity. This is exacerbated when genetic testing is performed in the context of population screening.
- Actionability. The term “actionable” is highly subjective and its application may fluctuate. The ClinGen Actionability Working Group is addressing this issue by curating the actionability of several gene-disease groups, including those listed by the ACMG. We took this into consideration; however, some gene-disease groups are not yet curated, and others are classified as actionable depending on individual-level information, such as age and sex, which were not considered due to our study protocol.
4. Materials and Methods
4.1. Study Design and Dataset of Exomes
4.2. Resampling from CGPP-IBMC Clinical Database
4.3. Selection of Genes for Which Reporting of Secondary Findings Is Recommended
4.4. Data Processing
4.5. Variant Annotation
4.6. Variant Filtering
4.7. Manual Variant Curation, Classification, and Actionability
4.8. Calculation of Frequency of Actionable Findings
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Green, R.C.; Berg, J.S.; Grody, W.W.; Kalia, S.S.; Korf, B.R.; Martin, C.L.; McGuire, A.L.; Nussbaum, R.L.; O’Daniel, J.M.; Ormond, K.E.; et al. ACMG Recommendations for Reporting of Incidental Findings in Clinical Exome and Genome Sequencing. Genet. Med. 2013, 15, 565–574. [Google Scholar] [CrossRef] [PubMed]
- Kalia, S.S.; Adelman, K.; Bale, S.J.; Chung, W.K.; Eng, C.; Evans, J.P.; Herman, G.E.; Hufnagel, S.B.; Klein, T.E.; Korf, B.R.; et al. Recommendations for Reporting of Secondary Findings in Clinical Exome and Genome Sequencing, 2016 Update (ACMG SF v2.0): A Policy Statement of the American College of Medical Genetics and Genomics. Genet. Med. 2017, 19, 249–255. [Google Scholar] [CrossRef]
- Biesecker, L.G. ACMG Secondary Findings 2.0. Genet. Med. 2017, 19, 604. [Google Scholar] [CrossRef]
- Miller, D.T.; Lee, K.; Gordon, A.S.; Amendola, L.M.; Adelman, K.; Bale, S.J.; Chung, W.K.; Gollob, M.H.; Harrison, S.M.; Herman, G.E.; et al. Recommendations for Reporting of Secondary Findings in Clinical Exome and Genome Sequencing, 2021 Update: A Policy Statement of the American College of Medical Genetics and Genomics (ACMG). Genet. Med. 2021, 23, 1391–1398. [Google Scholar] [CrossRef] [PubMed]
- Miller, D.T.; Lee, K.; Chung, W.K.; Gordon, A.S.; Herman, G.E.; Klein, T.E.; Stewart, D.R.; Amendola, L.M.; Adelman, K.; Bale, S.J.; et al. ACMG SF v3.0 List for Reporting of Secondary Findings in Clinical Exome and Genome Sequencing: A Policy Statement of the American College of Medical Genetics and Genomics (ACMG). Genet. Med. 2021, 23, 1381–1390. [Google Scholar] [CrossRef]
- Miller, D.T.; Lee, K.; Abul-Husn, N.S.; Amendola, L.M.; Brothers, K.; Chung, W.K.; Gollob, M.H.; Gordon, A.S.; Harrison, S.M.; Hershberger, R.E.; et al. ACMG SF v3.1 List for Reporting of Secondary Findings in Clinical Exome and Genome Sequencing: A Policy Statement of the American College of Medical Genetics and Genomics (ACMG). Genet. Med. 2022, 24, 1407–1414. [Google Scholar] [CrossRef] [PubMed]
- Miller, D.T.; Lee, K.; Abul-Husn, N.S.; Amendola, L.M.; Brothers, K.; Chung, W.K.; Gollob, M.H.; Gordon, A.S.; Harrison, S.M.; Hershberger, R.E.; et al. ACMG SF v3.2 List for Reporting of Secondary Findings in Clinical Exome and Genome Sequencing: A Policy Statement of the American College of Medical Genetics and Genomics (ACMG). Genet. Med. 2023, 25, 100866. [Google Scholar] [CrossRef]
- Van El, C.G.; Cornel, M.C.; Borry, P.; Hastings, R.J.; Fellmann, F.; Hodgson, S.V.; Howard, H.C.; Cambon-Thomsen, A.; Knoppers, B.M.; Meijers-Heijboer, H.; et al. Whole-Genome Sequencing in Health Care. Eur. J. Hum. Genet. 2013, 21, 580–584. [Google Scholar] [CrossRef]
- de Wert, G.; Dondorp, W.; Clarke, A.; Dequeker, E.M.C.; Cordier, C.; Deans, Z.; van El, C.G.; Fellmann, F.; Hastings, R.; Hentze, S.; et al. Opportunistic Genomic Screening. Recommendations of the European Society of Human Genetics. Eur. J. Hum. Genet. 2021, 29, 365–377. [Google Scholar] [CrossRef]
- Elfatih, A.; Mohammed, I.; Abdelrahman, D.; Mifsud, B. Frequency and Management of Medically Actionable Incidental Findings from Genome and Exome Sequencing Data: A Systematic Review. Physiol. Genom. 2021, 53, 373–384. [Google Scholar] [CrossRef]
- Dorschner, M.O.; Amendola, L.M.; Turner, E.H.; Robertson, P.D.; Shirts, B.H.; Gallego, C.J.; Bennett, R.L.; Jones, K.L.; Tokita, M.J.; Bennett, J.T.; et al. Actionable, Pathogenic Incidental Findings in 1,000 Participants’ Exomes. Am. J. Hum. Genet. 2013, 93, 631–640. [Google Scholar] [CrossRef] [PubMed]
- Lawrence, L.; Sincan, M.; Markello, T.; Adams, D.R.; Gill, F.; Godfrey, R.; Golas, G.; Groden, C.; Landis, D.; Nehrebecky, M.; et al. The Implications of Familial Incidental Findings from Exome Sequencing: The NIH Undiagnosed Diseases Program Experience. Genet. Med. 2014, 16, 741–750. [Google Scholar] [CrossRef] [PubMed]
- Amendola, L.M.; Dorschner, M.O.; Robertson, P.D.; Salama, J.S.; Hart, R.; Shirts, B.H.; Murray, M.L.; Tokita, M.J.; Gallego, C.J.; Kim, D.S.; et al. Actionable Exomic Incidental Findings in 6503 Participants: Challenges of Variant Classification. Genome Res. 2015, 25, 305–315. [Google Scholar] [CrossRef]
- Olfson, E.; Cottrell, C.E.; Davidson, N.O.; Gurnett, C.A.; Heusel, J.W.; Stitziel, N.O.; Chen, L.S.; Hartz, S.; Nagarajan, R.; Saccone, N.L.; et al. Identification of Medically Actionable Secondary Findings in the 1000 Genomes. PLoS ONE 2015, 10, e0135193. [Google Scholar] [CrossRef]
- Yang, Y.; Muzny, D.M.; Xia, F.; Niu, Z.; Person, R.; Ding, Y.; Ward, P.; Braxton, A.; Wang, M.; Buhay, C.; et al. Molecular Findings among Patients Referred for Clinical Whole-Exome Sequencing. J. Am. Med. Assoc. 2014, 312, 1870–1879. [Google Scholar] [CrossRef] [PubMed]
- Dewey, F.E.; Murray, M.F.; Overton, J.D.; Habegger, L.; Leader, J.B.; Fetterolf, S.N.; O’Dushlaine, C.; Van Hout, C.V.; Staples, J.; Gonzaga-Jauregui, C.; et al. Distribution and Clinical Impact of Functional Variants in 50,726 Whole-Exome Sequences from the DiscovEHR Study. Science 2016, 354, aaf6814. [Google Scholar] [CrossRef]
- Jurgens, J.; Ling, H.; Hetrick, K.; Pugh, E.; Schiettecatte, F.; Doheny, K.; Hamosh, A.; Avramopoulos, D.; Valle, D.; Sobreira, N. Assessment of Incidental Findings in 232 Whole-Exome Sequences from the Baylor-Hopkins Center for Mendelian Genomics. Genet. Med. 2015, 17, 782–788. [Google Scholar] [CrossRef]
- Strauss, K.A.; Gonzaga-Jauregui, C.; Brigatti, K.W.; Williams, K.B.; King, A.K.; Van Hout, C.; Robinson, D.L.; Young, M.; Praveen, K.; Heaps, A.D.; et al. Genomic Diagnostics within a Medically Underserved Population: Efficacy and Implications. Genet. Med. 2018, 20, 31–41. [Google Scholar] [CrossRef]
- Jain, A.; Gandhi, S.; Koshy, R.; Scaria, V. Incidental and Clinically Actionable Genetic Variants in 1005 Whole Exomes and Genomes from Qatar. Mol. Genet. Genom. 2018, 293, 919–929. [Google Scholar] [CrossRef]
- Rego, S.; Dagan-Rosenfeld, O.; Zhou, W.; Reza Sailani, M.; Limcaoco, P.; Colbert, E.; Avina, M.; Wheeler, J.; Craig, C.; Salins, D.; et al. High-Frequency Actionable Pathogenic Exome Variants in an Average-Risk Cohort. Mol. Case Stud. 2018, 4, a003178. [Google Scholar] [CrossRef]
- Tang, C.S.M.; Dattani, S.; So, M.t.; Cherny, S.S.; Tam, P.K.H.; Sham, P.C.; Garcia-Barcelo, M.M. Actionable Secondary Findings from Whole-Genome Sequencing of 954 East Asians. Hum. Genet. 2018, 137, 31–37. [Google Scholar] [CrossRef] [PubMed]
- Thompson, M.L.; Finnila, C.R.; Bowling, K.M.; Brothers, K.B.; Neu, M.B.; Amaral, M.D.; Hiatt, S.M.; East, K.M.; Gray, D.E.; Lawlor, J.M.J.; et al. Genomic Sequencing Identifies Secondary Findings in a Cohort of Parent Study Participants. Genet. Med. 2018, 20, 1635–1643. [Google Scholar] [CrossRef]
- Yehia, L.; Ni, Y.; Sesock, K.; Niazi, F.; Fletcher, B.; Chen, H.J.L.; LaFramboise, T.; Eng, C. Unexpected Cancer-Predisposition Gene Variants in Cowden Syndrome and Bannayan-Riley-Ruvalcaba Syndrome Patients without Underlying Germline PTEN Mutations. PLoS Genet. 2018, 14, e1007352. [Google Scholar] [CrossRef] [PubMed]
- Haer-Wigman, L.; van der Schoot, V.; Feenstra, I.; Vulto-van Silfhout, A.T.; Gilissen, C.; Brunner, H.G.; Vissers, L.E.L.M.; Yntema, H.G. 1 in 38 Individuals at Risk of a Dominant Medically Actionable Disease. Eur. J. Hum. Genet. 2019, 27, 325–330. [Google Scholar] [CrossRef] [PubMed]
- Ragan Hart, M.; Biesecker, B.B.; Blout, C.L.; Christensen, K.D.; Amendola, L.M.; Bergstrom, K.L.; Biswas, S.; Bowling, K.M.; Brothers, K.B.; Conlin, L.K.; et al. Secondary Findings from Clinical Genomic Sequencing: Prevalence, Patient Perspectives, Family History Assessment, and Health-Care Costs from a Multisite Study. Genet. Med. 2019, 21, 1100–1110. [Google Scholar] [CrossRef]
- Benson, K.A.; White, M.; Allen, N.M.; Byrne, S.; Carton, R.; Comerford, E.; Costello, D.; Doherty, C.; Dunleavey, B.; El-Naggar, H.; et al. A Comparison of Genomic Diagnostics in Adults and Children with Epilepsy and Comorbid Intellectual Disability. Eur. J. Hum. Genet. 2020, 28, 1066–1077. [Google Scholar] [CrossRef]
- Jalkh, N.; Mehawej, C.; Chouery, E. Actionable Exomic Secondary Findings in 280 Lebanese Participants. Front. Genet. 2020, 11, 208. [Google Scholar] [CrossRef]
- Kuo, C.W.; Hwu, W.L.; Chien, Y.H.; Hsu, C.; Hung, M.Z.; Lin, I.L.; Lai, F.; Lee, N.C. Frequency and Spectrum of Actionable Pathogenic Secondary Findings in Taiwanese Exomes. Mol. Genet. Genom. Med. 2020, 8, e1455. [Google Scholar] [CrossRef]
- Van Rooij, J.; Arp, P.; Broer, L.; Verlouw, J.; Van Rooij, F.; Kraaij, R.; Uitterlinden, A.; Verkerk, A.J. Reduced Penetrance of Pathogenic ACMG Variants in a Deeply Phenotyped Cohort Study and Evaluation of ClinVar Classification over Time. Genet. Med. 2020, 22, 1812–1820. [Google Scholar] [CrossRef]
- Kwak, S.H.; Chae, J.; Choi, S.; Kim, M.J.; Choi, M.; Chae, J.H.; Cho, E.H.; Hwang, T.J.; Jang, S.S.; Kim, J., Il; et al. Findings of a 1303 Korean Whole-Exome Sequencing Study. Exp. Mol. Med. 2017, 49, e356. [Google Scholar] [CrossRef]
- Yamaguchi-Kabata, Y.; Yasuda, J.; Tanabe, O.; Suzuki, Y.; Kawame, H.; Fuse, N.; Nagasaki, M.; Kawai, Y.; Kojima, K.; Katsuoka, F.; et al. Evaluation of Reported Pathogenic Variants and Their Frequencies in a Japanese Population Based on a Whole-Genome Reference Panel of 2049 Individuals Article. J. Hum. Genet. 2018, 63, 213–230. [Google Scholar] [CrossRef]
- Gordon, A.S.; Zouk, H.; Venner, E.; Eng, C.M.; Funke, B.H.; Amendola, L.M.; Carrell, D.S.; Chisholm, R.L.; Chung, W.K.; Denny, J.C.; et al. Frequency of Genomic Secondary Findings among 21,915 EMERGE Network Participants. Genet. Med. 2020, 22, 1470–1477. [Google Scholar] [CrossRef] [PubMed]
- Arslan Ateş, E.; Türkyilmaz, A.; Yıldırım, Ö.; Alavanda, C.; Polat, H.; Demir, Ş.; Çebi, A.H.; Geçkinli, B.B.; Güney, A.İ.; Ata, P.; et al. Secondary Findings in 622 Turkish Clinical Exome Sequencing Data. J. Hum. Genet. 2021, 66, 1113–1119. [Google Scholar] [CrossRef] [PubMed]
- Elfatih, A.; Mifsud, B.; Syed, N.; Badii, R.; Mbarek, H.; Abbaszadeh, F.; Estivill, X.; Ismail, S.; Al-Muftah, W.; Badji, R.; et al. Actionable Genomic Variants in 6045 Participants from the Qatar Genome Program. Hum. Mutat. 2021, 42, 1584–1601. [Google Scholar] [CrossRef] [PubMed]
- van der Schoot, V.; Haer-Wigman, L.; Feenstra, I.; Tammer, F.; Oerlemans, A.J.M.; van Koolwijk, M.P.A.; van Agt, F.; Arens, Y.H.J.M.; Brunner, H.G.; Vissers, L.E.L.M.; et al. Lessons Learned from Unsolicited Findings in Clinical Exome Sequencing of 16,482 Individuals. Eur. J. Hum. Genet. 2022, 30, 170–177. [Google Scholar] [CrossRef]
- Rodríguez-Salgado, L.E.; Silva-Aldana, C.T.; Medina-Méndez, E.; Bareño-Silva, J.; Arcos-Burgos, M.; Silgado-Guzmán, D.F.; Restrepo, C.M. Frequency of Actionable Exomic Secondary Findings in 160 Colombian Patients: Impact in the Healthcare System. Gene 2022, 838, 146699. [Google Scholar] [CrossRef]
- Huang, Y.; Liu, B.; Shi, J.; Zhao, S.; Xu, K.; Sun, L.; Chen, N.; Tian, W.; Zhang, J.; Wu, N. Landscape of Secondary Findings in Chinese Population: A Practice of ACMG SF v3.0 List. J. Pers. Med. 2022, 12, 1503. [Google Scholar] [CrossRef]
- Martone, S.; Buonagura, A.T.; Marra, R.; Rosato, B.E.; Del Giudice, F.; Bonfiglio, F.; Capasso, M.; Iolascon, A.; Andolfo, I.; Russo, R. Clinical Exome-Based Panel Testing for Medically Actionable Secondary Findings in a Cohort of 383 Italian Participants. Front. Genet. 2022, 13, 956723. [Google Scholar] [CrossRef]
- Kasak, L.; Lillepea, K.; Nagirnaja, L.; Aston, K.I.; Schlegel, P.N.; Gonçalves, J.; Carvalho, F.; Moreno-Mendoza, D.; Almstrup, K.; Eisenberg, M.L.; et al. Actionable Secondary Findings Following Exome Sequencing of 836 Non-Obstructive Azoospermia Cases and Their Value in Patient Management. Hum. Reprod. 2022, 37, 1652–1663. [Google Scholar] [CrossRef]
- Hershberger, R.E.; Morales, A.; Siegfried, J.D. Clinical and Genetic Issues in Dilated Cardiomyopathy: A Review for Genetics Professionals. Genet. Med. 2010, 12, 655–667. [Google Scholar] [CrossRef]
- Maron, B.; Gardin, J.; Flack, J.; Gidding, S.S.; Kurosaki, T.T.; Bild, D.E. Prevalence of Hypertrophic Cardiomyopathy in a General Population of Young Adults: Echocardiographic Analysis of 4111 Subjects in the CARDIA Study. Coronary Artery Risk Development in (Young) Adults. Circulation 1995, 92, 785–789. [Google Scholar] [CrossRef]
- Tabib, A.; Loire, R.; Chalabreysse, L.; Meyronnet, D.; Miras, A.; Malicier, D.; Thivolet, F.; Chevalier, P.; Bouvagnet, P. Circumstances of Death and Gross and Microscopic Observations in a Series of 200 Cases of Sudden Death Associated with Arrhythmogenic Right Ventricular Cardiomyopathy and/or Dysplasia. Circulation 2003, 108, 3000–3005. [Google Scholar] [CrossRef]
- Schwartz, P.J.; Stramba-Badiale, M.; Crotti, L.; Pedrazzini, M.; Besana, A.; Bosi, G.; Gabbarini, F.; Goulene, K.; Insolia, R.; Mannarino, S.; et al. Prevalence of the Congenital Long-QT Syndrome. Circulation 2009, 120, 1761–1767. [Google Scholar] [CrossRef] [PubMed]
- Akioyamen, L.E.; Genest, J.; Shan, S.D.; Reel, R.L.; Albaum, J.M.; Chu, A.; Tu, J.V. Estimating the Prevalence of Heterozygous Familial Hypercholesterolaemia: A Systematic Review and Meta-Analysis. BMJ Open 2017, 7, e016461. [Google Scholar] [CrossRef] [PubMed]
- Dietz, H. FBN1-Related Marfan Syndrome—GeneReviews®—NCBI Bookshelf. Available online: https://www.ncbi.nlm.nih.gov/books/NBK1335/ (accessed on 21 October 2024).
- Milewicz, D. Heritable Thoracic Aortic Disease Overview—GeneReviews®—NCBI Bookshelf. Available online: https://www.ncbi.nlm.nih.gov/books/NBK1120/ (accessed on 21 October 2024).
- Loeys-Dietz Syndrome—GeneReviews®—NCBI Bookshelf. Available online: https://www.ncbi.nlm.nih.gov/books/NBK1133/ (accessed on 21 October 2024).
- Byers, P. Vascular Ehlers-Danlos Syndrome—GeneReviews®—NCBI Bookshelf. Available online: https://www.ncbi.nlm.nih.gov/books/NBK1494/ (accessed on 21 October 2024).
- Ponder, B.; Pharoah, P.D.P.; Ponder, B.A.J.; Lipscombe, J.M.; Basham, V.; Gregory, J.; Gayther, S.; Dunning, A. Prevalence and Penetrance of BRCA1 and BRCA2 Mutations in a Population-Based Series of Breast Cancer Cases. Br. J. Cancer 2000, 83, 1301–1308. [Google Scholar] [CrossRef]
- Teugels, E.; De Brakeleer, S.; Goelen, G.; Lissens, W.; Sermijn, E.; De Grève, J. De Novo Alu Element Insertions Targeted to a Sequence Common to the BRCA1 and BRCA2 Genes. Hum. Mutat. 2005, 26, 284. [Google Scholar] [CrossRef]
- Win, A.K.; Jenkins, M.A.; Dowty, J.G.; Antoniou, A.C.; Lee, A.; Giles, G.G.; Buchanan, D.D.; Clendenning, M.; Rosty, C.; Ahnen, D.J.; et al. Prevalence and Penetrance of Major Genes and Polygenes for Colorectal Cancer. Cancer Epidemiol. Biomark. Prev. 2017, 26, 404–412. [Google Scholar] [CrossRef]
- Spada, M.; Pagliardini, S.; Yasuda, M.; Tukel, T.; Thiagarajan, G.; Sakuraba, H.; Ponzone, A.; Desnick, R.J. High Incidence of Later-Onset Fabry Disease Revealed by Newborn Screening. Am. J. Hum. Genet. 2006, 79, 31–40. [Google Scholar] [CrossRef]
- Sawada, T.; Kido, J.; Yoshida, S.; Sugawara, K.; Momosaki, K.; Inoue, T.; Tajima, G.; Sawada, H.; Mastumoto, S.; Endo, F.; et al. Newborn Screening for Fabry Disease in the Western Region of Japan. Mol. Genet. Metab. Rep. 2020, 22, 100562. [Google Scholar] [CrossRef]
- Burton, B.K.; Charrow, J.; Hoganson, G.E.; Waggoner, D.; Tinkle, B.; Braddock, S.R.; Schneider, M.; Grange, D.K.; Nash, C.; Shryock, H.; et al. Newborn Screening for Lysosomal Storage Disorders in Illinois: The Initial 15-Month Experience. J. Pediatr. 2017, 190, 130–135. [Google Scholar] [CrossRef]
- Hwu, W.L.; Chien, Y.H.; Lee, N.C.; Chiang, S.C.; Dobrovolny, R.; Huang, A.C.; Yeh, H.Y.; Chao, M.C.; Lin, S.J.; Kitagawa, T.; et al. Newborn Screening for Fabry Disease in Taiwan Reveals a High Incidence of the Later-Onset GLA Mutation c.936+919G>A (IVS4+919G>A). Hum. Mutat. 2009, 30, 1397–1405. [Google Scholar] [CrossRef] [PubMed]
- Gilchrist, M.; Casanova, F.; Tyrrell, J.S.; Cannon, S.; Wood, A.R.; Fife, N.; Young, K.; Oram, R.A.; Weedon, M.N. Prevalence of Fabry Disease-Causing Variants in the UK Biobank. J. Med. Genet. 2023, 60, 391–396. [Google Scholar] [CrossRef]
- Azevedo, O.; Gal, A.; Faria, R.; Gaspar, P.; Miltenberger-Miltenyi, G.; Gago, M.F.; Dias, F.; Martins, A.; Rodrigues, J.; Reimão, P.; et al. Founder Effect of Fabry Disease Due to p.F113L Mutation: Clinical Profile of a Late-Onset Phenotype. Mol. Genet. Metab. 2020, 129, 150–160. [Google Scholar] [CrossRef]
- Mehta, A.; Ricci, R.; Widmer, U.; Dehout, F.; Garcia De Lorenzo, A.; Kampmann, C.; Linhart, A.; Sunder-Plassmann, G.; Ries, M.; Beck, M. Fabry Disease Defined: Baseline Clinical Manifestations of 366 Patients in the Fabry Outcome Survey. Eur. J. Clin. Investig. 2004, 34, 236–242. [Google Scholar] [CrossRef] [PubMed]
- Andrade, C. A Peculiar Form of Peripheral Neuropathy; Familiar Atypical Generalized Amyloidosis with Special Involvement of the Peripheral Nerves. Brain 1952, 75, 408–427. [Google Scholar] [CrossRef] [PubMed]
- Sousa, A.; Coelho, T.; Barros, J.; Sequeiros, J. Genetic Epidemiology of Familial Amyloidotic Polyneuropathy (FAP)-Type I in Póvoa Do Varzim and Vila Do Conde (North of Portugal). Am. J. Med. Genet. (Neuropsychiatr. Genet.) 1995, 60, 512–521. [Google Scholar] [CrossRef]
- Inês, M.; Coelho, T.; Conceição, I.; Duarte-Ramos, F.; de Carvalho, M.; Costa, J. Epidemiology of Transthyretin Familial Amyloid Polyneuropathy in Portugal: A Nationwide Study. Neuroendocrinology 2018, 51, 177–182. [Google Scholar] [CrossRef]
- Coelho, T.; Maurer, M.S.; Suhr, O.B. THAOS—The Transthyretin Amyloidosis Outcomes Survey: Initial Report on Clinical Manifestations in Patients with Hereditary and Wild-Type Transthyretin Amyloidosis. Curr. Med. Res. Opin. 2013, 29, 63–76. [Google Scholar] [CrossRef]
- Mungunsukh, O.; Deuster, P.; Muldoon, S.; O’Connor, F.; Sambuughin, N. Estimating Prevalence of Malignant Hyperthermia Susceptibility through Population Genomics Data. Br. J. Anaesth. 2019, 123, e461–e463. [Google Scholar] [CrossRef]
- Fridriksdottir, R.; Jonsson, A.J.; Jensson, B.O.; Sverrisson, K.O.; Arnadottir, G.A.; Skarphedinsdottir, S.J.; Katrinardottir, H.; Snaebjornsdottir, S.; Jonsson, H.; Eiriksson, O.; et al. Sequence Variants in Malignant Hyperthermia Genes in Iceland: Classification and Actionable Findings in a Population Database. Eur. J. Hum. Genet. 2021, 29, 1819–1824. [Google Scholar] [CrossRef]
- Hanson, E.H.; Imperatore, G.; Burke, W. HFE Gene and Hereditary Hemochromatosis: A HuGE Review. Human Genome Epidemiology. Am. J. Epidemiol. 2001, 154, 193–206. [Google Scholar] [CrossRef] [PubMed]
- Phatak, P.D.; Sham, R.L.; Raubertas, R.F.; Dunnigan, K.; O’leary, T.; Braggins, C.; Cappuccio, J.D. Prevalence of Hereditary Hemochromatosis in 16031 Primary Care Patients. Ann. Intern. Med. 1998, 129, 954–961. [Google Scholar] [CrossRef] [PubMed]
- Adams, P.C.; Reboussin, D.M.; Barton, J.C.; Mclaren, C.E.; Eckfeldt, J.H.; Mclaren, G.D.; Dawkins, F.W.; Acton, R.T.; Harris, E.L.; Gordeuk, V.R.; et al. Hemochromatosis and Iron-Overload Screening in a Racially Diverse Population. N. Engl. J. Med. 2005, 352, 1769–1778. [Google Scholar] [CrossRef] [PubMed]
- Park, R.; McCabe, P.; Fell, G.; Russell, R. Wilson’s Disease in Scotland. Gut 1991, 32, 1541–1545. [Google Scholar] [CrossRef]
- Coffey, A.J.; Durkie, M.; Hague, S.; McLay, K.; Emmerson, J.; Lo, C.; Klaffke, S.; Joyce, C.J.; Dhawan, A.; Hadzic, N.; et al. A Genetic Study of Wilson’s Disease in the United Kingdom. Brain 2013, 136, 1476–1487. [Google Scholar] [CrossRef]
- Pinto, R.; Caseiro, C.; Lemos, M.; Lopes, L.; Fontes, A.; Ribeiro, H.; Pinto, E.; Silva, E.; Rocha, S.; Marcão, A.; et al. Prevalence of Lysosomal Storage Diseases in Portugal. Eur. J. Hum. Genet. 2004, 12, 87–92. [Google Scholar] [CrossRef]
- Wolf, B. Worldwide Survey of Neonatal Screening for Biotinidase Deficiency. J. Inherit. Metab. Dis. 1991, 14, 923–927. [Google Scholar] [CrossRef]
- Romero, S.; Biggio, J.R.; Saller, D.N.; Giardine, R. Carrier Screening in the Age of Genomic Medicine. No.690. Am. Coll. Obstet. Gynecol. 2017, 129, e35–e40. [Google Scholar]
- Poplin, R.; Ruano-Rubio, V.; DePristo, M.A.; Fennell, T.J.; Carneiro, M.O.; Van der Auwera, G.A.; Kling, D.E.; Gauthier, L.D.; Levy-Moonshine, A.; Roazen, D.; et al. Scaling accurate genetic variant discovery to tens of thousands of samples. bioRxiv 2017, 201178. [Google Scholar] [CrossRef]
- Valente, S.; Ribeiro, M.; Schnur, J.; Alves, F.; Moniz, N.; Seelow, D.; Freixo, J.P.; Silva, P.F.; Oliveira, J. Analysis of Regions of Homozygosity: Revisited Through New Bioinformatic Approaches. BioMedInformatics 2024, 4, 2374–2399. [Google Scholar] [CrossRef]
- População Residente Por Município Segundo Os Censos|Pordata. Available online: Https://Www.Pordata.Pt/Municipios/Populacao+residente+segundo+os+censos+total+e+por+sexo-17 (accessed on 13 June 2023).
- Richards, S.; Aziz, N.; Bale, S.; Bick, D.; Das, S.; Gastier-Foster, J.; Grody, W.W.; Hegde, M.; Lyon, E.; Spector, E.; 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, 405–424. [Google Scholar] [CrossRef] [PubMed]
- Best Practice Guidelines—The Association for Clinical Genomic Science. Available online: https://www.acgs.uk.com/quality/best-practice-guidelines/ (accessed on 21 October 2024).
- Criteria Specification Registry. Available online: https://cspec.genome.network/cspec/ui/svi/ (accessed on 21 October 2024).
- CanVIG-UK Consensus Specifications|CanGene-CanVar. Available online: https://www.cangene-canvaruk.org/canvig-uk-guidance (accessed on 21 October 2024).
- Hayesmoore, J.B.; Bhuiyan, Z.A.; Coviello, D.A.; du Sart, D.; Edwards, M.; Iascone, M.; Morris-Rosendahl, D.J.; Sheils, K.; van Slegtenhorst, M.; Thomson, K.L. EMQN: Recommendations for Genetic Testing in Inherited Cardiomyopathies and Arrhythmias. Eur. J. Hum. Genet. 2023, 31, 1003–1009. [Google Scholar] [CrossRef] [PubMed]
Disease | Gene | Disease Inheritance | No. of Variants Per Gene | Allele Count | Allelic Frequency (%) | ||
---|---|---|---|---|---|---|---|
Total | Hom. | Het. | |||||
Cancer phenotype group | |||||||
Familial adenomatous polyposis | APC | AD | 1 | 1 | 0 | 1 | 0.013 |
Familial medullary thyroid cancer | RET | AD | 3 | 6 | 0 | 6 | 0.076 |
Hereditary breast and/or ovarian cancer | BRCA1 | AD | 3 | 3 | 0 | 3 | 0.038 |
BRCA2 | AD | 16 | 18 | 0 | 18 | 0.227 | |
PALB2 | AD | 2 | 4 | 0 | 4 | 0.050 | |
Hereditary paraganglioma-pheochromocytoma syndrome | SDHD | AD | 0 | 0 | 0 | 0 | 0.000 |
SDHAF2 | AD | 0 | 0 | 0 | 0 | 0.000 | |
SDHC | AD | 0 | 0 | 0 | 0 | 0.000 | |
SDHB | AD | 0 | 0 | 0 | 0 | 0.000 | |
MAX | AD | 0 | 0 | 0 | 0 | 0.000 | |
TMEM127 | AD | 0 | 0 | 0 | 0 | 0.000 | |
Juvenile polyposis syndrome | BMPR1A | AD | 2 | 2 | 0 | 2 | 0.025 |
Juvenile polyposis syndrome/hereditary haemorrhagic telangiectasia syndrome | SMAD4 | AD | 1 | 1 | 0 | 1 | 0.013 |
Li–Fraumeni syndrome | TP53 | AD | 1 | 1 | 0 | 1 | 0.013 |
Lynch syndrome/hereditarynonpolyposis colorectal cancer | MLH1 | AD | 0 | 0 | 0 | 0 | 0.000 |
MSH2 | AD | 3 | 4 | 0 | 4 | 0.050 | |
MSH6 | AD | 8 | 9 | 0 | 9 | 0.113 | |
PMS2 | AD | 6 | 11 | 0 | 11 | 0.138 | |
Multiple endocrine neoplasia type 1 | MEN1 | AD | 1 | 1 | 0 | 1 | 0.013 |
MUTYH-associated polyposis | MUTYH | AR | 17 | 95 | 4 | 91 | 1.196 |
Neurofibromatosis type 2 | NF2 | AD | 1 | 1 | 0 | 1 | 0.013 |
Peutz–Jeghers syndrome | STK11 | AD | 1 | 1 | 0 | 1 | 0.013 |
PTEN hamartoma tumour syndrome | PTEN | AD | 4 | 4 | 0 | 4 | 0.050 |
Retinoblastoma | RB1 | AD | 2 | 2 | 0 | 2 | 0.025 |
Tuberous sclerosis complex | TSC1 | AD | 0 | 0 | 0 | 0 | 0.000 |
TSC2 | AD | 6 | 6 | 0 | 6 | 0.076 | |
von Hippel–Lindau syndrome | VHL | AD | 1 | 3 | 0 | 3 | 0.038 |
WT1-related Wilms tumour | WT1 | AD | 0 | 0 | 0 | 0 | 0.000 |
Cardiovascular phenotype group | |||||||
Aortopathies | FBN1 | AD | 8 | 8 | 0 | 8 | 0.101 |
TGFBR1 | AD | 0 | 0 | 0 | 0 | 0.000 | |
TGFBR2 | AD | 2 | 3 | 0 | 3 | 0.038 | |
SMAD3 | AD | 0 | 0 | 0 | 0 | 0.000 | |
ACTA2 | AD | 0 | 0 | 0 | 0 | 0.000 | |
MYH11 | AD | 3 | 5 | 0 | 5 | 0.063 | |
Arrhythmogenic right ventricular cardiomyopathy (a subcategory of arrhythmogenic cardiomyopathy) | PKP2 | AD | 3 | 3 | 0 | 3 | 0.038 |
DSP | AD | 3 | 3 | 0 | 3 | 0.038 | |
DSC2 | AD | 3 | 3 | 0 | 3 | 0.038 | |
TMEM43 | AD | 0 | 0 | 0 | 0 | 0.000 | |
DSG2 | AD | 0 | 0 | 0 | 0 | 0.000 | |
Catecholaminergic polymorphic ventricular tachycardia | RYR2 | AD | 0 | 0 | 0 | 0 | 0.000 |
CASQ2 | AR | 0 | 0 | 0 | 0 | 0.000 | |
TRDN | AR | 6 | 12 | 0 | 12 | 0.151 | |
Dilated cardiomyopathy | TNNT2 | AD | 3 | 4 | 0 | 4 | 0.050 |
LMNA | AD | 2 | 2 | 0 | 2 | 0.025 | |
FLNC | AD | 3 | 3 | 0 | 3 | 0.038 | |
TTN | AD | 18 | 18 | 0 | 18 | 0.227 | |
BAG3 | AD | 0 | 0 | 0 | 0 | 0.000 | |
DES | AD | 2 | 2 | 0 | 2 | 0.025 | |
RBM20 | AD | 0 | 0 | 0 | 0 | 0.000 | |
TNNC1 | AD | 1 | 1 | 0 | 1 | 0.013 | |
Ehlers–Danlos syndrome. vascular type | COL3A1 | AD | 2 | 2 | 0 | 2 | 0.025 |
Familial hypercholesterolemia | LDLR | AD | 15 | 19 | 0 | 19 | 0.239 |
APOB | AD | 4 | 4 | 0 | 4 | 0.050 | |
PCSK9 | AD | 0 | 0 | 0 | 0 | 0.000 | |
Hypertrophic cardiomyopathy | MYH7 | AD | 8 | 12 | 0 | 12 | 0.151 |
MYBPC3 | AD | 10 | 10 | 0 | 10 | 0.126 | |
TNNI3 | AD | 0 | 0 | 0 | 0 | 0.000 | |
TPM1 | AD | 0 | 0 | 0 | 0 | 0.000 | |
MYL3 | AD | 0 | 0 | 0 | 0 | 0.000 | |
ACTC1 | AD | 0 | 0 | 0 | 0 | 0.000 | |
PRKAG2 | AD | 0 | 0 | 0 | 0 | 0.000 | |
MYL2 | AD | 0 | 0 | 0 | 0 | 0.000 | |
Cardiovascular phenotype group | |||||||
Long QT syndrome types 1 and 2 | KCNQ1 | AD | 6 | 12 | 2 | 10 | 0.151 |
KCNH2 | AD | 2 | 2 | 0 | 2 | 0.025 | |
Long QT syndrome 3. Brugada syndrome | SCN5A | AD | 4 | 5 | 0 | 5 | 0.063 |
Long QT syndrome types 14–16 | CALM1 | AD | 0 | 0 | 0 | 0 | 0.000 |
CALM2 | AD | 0 | 0 | 0 | 0 | 0.000 | |
CALM3 | AD | 0 | 0 | 0 | 0 | 0.000 | |
Inborn errors of metabolism phenotype group | |||||||
Biotinidase deficiency | BTD | AR | 10 | 15 | 0 | 15 | 0.189 |
Fabry disease | GLA | XL | 3 | 4 | 1 | 3 | 0.063 |
Pompe disease | GAA | AR | 9 | 20 | 0 | 20 | 0.252 |
Ornithine transcarbamylase deficiency | OTC | XL | 0 | 0 | 0 | 0 | 0.000 |
Miscellaneous phenotype group | |||||||
Hereditary haemochromatosis | HFE | AR | 1 | 211 | 4 | 207 | 2.656 |
Hereditary haemorrhagic telangiectasia | ACVRL1 | AD | 2 | 2 | 0 | 2 | 0.025 |
ENG | AD | 0 | 0 | 0 | 0 | 0.000 | |
Malignant hyperthermia | RYR1 | AD | 7 | 13 | 0 | 13 | 0.164 |
CACNA1S | AD | 0 | 0 | 0 | 0 | 0.000 | |
Maturity-onset of diabetes of the young | HNF1A | AD | 3 | 7 | 0 | 7 | 0.088 |
RPE65-related retinopathy | RPE65 | AR | 11 | 21 | 0 | 21 | 0.264 |
Wilson disease | ATP7B | AR | 24 | 75 | 2 | 73 | 0.944 |
Hereditary TTR-related amyloidosis | TTR | AD | 2 | 17 | 0 | 17 | 0.214 |
Gene | cDNA (HGVS) | Predicted Splicing Impact | Protein Change (HGVS) | Freq. (gnomAD4.1) (%) | ClinVar ID (2 January 2025) |
---|---|---|---|---|---|
BMPR1A | NM_004329.3:c.231-2A>T | Y | - | - | 2866138 |
NM_004329.3:c.231-1G>T | Y | - | - | 567998 | |
BRCA1 | NM_007294.4:c.109A>G | N | NP_009225.1:p.Thr37Ala | - | 868146 |
BRCA2 | NM_000059.4:c.2974A>T | N | NP_000050.3:p.Lys992* | - | - |
NM_000059.4:c.4933A>T | N | NP_000050.3:p.Lys1645* | - | 51744 | |
NM_000059.4:c.7258delG | N | NP_000050.3:p.Glu2420Asnfs*47 | - | - | |
MEN1 | NM_130799.3:c.467G>C | N | NP_570711.2:p.Gly156Ala | - | - |
MSH2 | NM_000251.3:c.2084T>G | N | NP_000242.1:p.Val695Gly | - | - |
MSH6 | NM_000179.3:c.195_199delACCGC | N | NP_000170.1:p.Pro66Glnfs*22 | 0.0001 | - |
NM_000179.3:c.198_199insTT | N | NP_000170.1:p.Pro67Phefs*15 | - | - | |
NM_000179.3:c.841G>T | N | NP_000170.1:p.Gly281* | - | 2673649 | |
NM_000179.3:c.2437A>T | N | NP_000170.1:p.Lys813* | 0.0001 | 1791241 | |
NM_000179.3:c.3682_3698del | N | NP_000170.1:p.Ala1228Argfs*4 | - | - | |
MUTYH | NM_001128425.2:c.788+2_788+4delTAG | Y | - | - | - |
NM_001128425.2:c.785_786insG | N | NP_001121897.1:p.Trp263Leufs*66 | - | - | |
NM_001128425.2:c.781delC | N | NP_001121897.1:p.Gln261Serfs*5 | - | - | |
PTEN | NM_000314.8:c.802-1_805delGGACA | N | NP_000305.3:p.? | - | - |
NM_000314.8:c.804_805insTTTTT | N | NP_000305.3:p.Lys269Phefs*9 | - | - | |
RB1 | NM_000321.3:c.1422-2A>T | Y | - | 0.0004 | - |
SMAD4 | NM_005359.6:c.904+1_904+2ins(45) | Y | - | 0.0053 | - |
TSC2 | NM_000548.5:c.264_265delGT | N | NP_000539.2:p.Leu89Alafs*36 | 0.0160 | 45485999 |
NM_000548.5:c.340G>T | N | NP_000539.2:p.Glu114* | - | 65033 | |
NM_000548.5:c.775-2A>C | Y | - | - | - | |
NM_000548.5:c.2340_2341ins(37) | N | NP_000539.2:p.Asp781Phefs*12 | - | - | |
APOB | NM_000384.3:c.9743_9744insG | N | NP_000375.3:p.Ile3248Metfs*12 | - | - |
NM_000384.3:c.9735delC | N | NP_000375.3:p.Gln3247Lysfs*19 | - | - | |
NM_000384.3:c.2297_2298delAA | N | NP_000375.3:p.Lys766Ilefs*25 | - | 1553385715 | |
COL3A1 | NM_000090.4:c.1429G>A | N | NP_000081.2:p.Gly477Arg | - | - |
NM_000090.4:c.2229+1G>A | Y | - | - | 640856 | |
DES | NM_001927.4:c.75_76insAG | N | NP_001918.3:p.Leu26Serfs*6 | - | - |
DSC2 | NM_024422.6:c.1044_1047dupAAAT | N | NP_077740.1:p.Asp350Lysfs*2 | - | - |
NM_024422.6:c.631-1G>A | Y | - | 0.0001 | 2775190 | |
DSP | NM_004415.4:c.107delG | N | NP_004406.2:p.Gly36Alafs*12 | - | - |
NM_004415.4:c.1258G>T | N | NP_004406.2:p.Glu420* | - | - | |
NM_004415.4:c.2572delG | N | NP_004406.2:p.Glu858Lysfs*6 | - | - | |
FBN1 | NM_000138.5:c.4282C>T | N | NP_000129.3:p.Arg1428Cys | 0.0007 | - |
NM_000138.5:c.4015_4016insTG | N | NP_000129.3:p.Cys1339Leufs*75 | - | - | |
FLNC | NM_001458.5:c.502delT | N | NP_001449.3:p.Trp168Glyfs*84 | - | - |
NM_001458.5:c.2550+1G>A | Y | - | - | - | |
KCNH2 | NM_000238.4:c.1621C>T | N | NP_000229.1:p.Arg541Cys | 0.0004 | 937094 |
LDLR | NM_000527.5:c.1315A>T | N | NP_000518.1:p.Asn439Tyr | - | 375813 |
MYBPC3 | NM_000256.3:c.2995-2A>G | Y | - | 0.0001 | - |
MYH7 | NM_000257.4:c.1756G>A | N | NP_000248.2:p.Val586Met | 0.0004 | 1172186 |
PKP2 | NM_004572.4:c.1489C>T | N | NP_004563.2:p.Arg497* | 0.0003 | 78974 |
NM_004572.4:c.328delA | N | NP_004563.2:p.Met110Cysfs*2 | - | - | |
SCN5A | NM_198056.3:c.5306C>T | N | NP_932173.1:p.Ala1769Val | 0.0001 | - |
TGFBR2 | NM_003242.6:c.760C>T | N | NP_001020018.1:p.Arg279Cys | 0.0001 | 213942 |
TNNT2 | NM_001276345.2:c.87_88delGG | N | NP_001263274.1:p.Asp30Argfs*13 | - | - |
NM_001276345.2:c.80G>A | N | NP_001263274.1:p.Trp27* | - | - | |
TRDN | NM_006073.4:c.1831+1G>A | Y | - | - | - |
NM_006073.4:c.1155delA | N | NP_006064.2:p.Lys385Asnfs*5 | 0.0013 | - | |
NM_001256021.2:c.601_610delCTGGCGAAAG | N | NP_001242950.1:p.Leu201Asnfs*19 | 0.0029 | - | |
NM_001256021.2:c.439_440delAA | N | NP_001242950.1:p.Lys147Aspfs*2 | 0.0001 | 2114339116 | |
TTN | NM_001267550.2:c.107409_107410insCC | N | NP_001254479.2:p.Leu35804Profs*2 | - | - |
NM_001267550.2:c.97573_97574insTC | N | NP_001254479.2:p.Asp32525Valfs*8 | - | - | |
NM_001267550.2:c.95576_95577delAA | N | NP_001254479.2:p.Lys31859Argfs*6 | - | - | |
NM_001267550.2:c.93623_93626dupAGCC | N | NP_001254479.2:p.Gln31210Alafs*8 | - | - | |
NM_001267550.2:c.84525G>A | N | NP_001254479.2:p.Trp28175* | - | - | |
NM_001267550.2:c.79811dupT | N | NP_001254479.2:p.Arg26605Lysfs*19 | - | - | |
NM_001267550.2:c.70971_70972insT | N | NP_001254479.2:p.Leu23658Serfs*18 | - | - | |
NM_001267550.2:c.64266delA | N | NP_001254479.2:p.Asp21423Ilefs*2 | 0.0001 | - | |
NM_001267550.2:c.58709C>G | N | NP_001254479.2:p.Ser19570* | - | - | |
NM_001267550.2:c.52975_52976delCA | N | NP_001254479.2:p.Gln17659Thrfs*6 | 0.0001 | - | |
NM_001267550.2:c.41845dupA | N | NP_001254479.2:p.Ile13949Asnfs*2 | - | - | |
NM_001267550.2:c.13184delT | N | NP_001254479.2:p.Leu4395Argfs*25 | - | - | |
ACVRL1 | NM_000020.3:c.830C>T | N | NP_000011.2:p.Thr277Met | 0.0004 | 2731545 |
ATP7B | NM_000053.4:c.3959G>C | N | NP_000044.2:p.Arg1320Thr | 0.0010 | 1479012 |
RPE65 | NM_000329.3:c.1544G>A | N | NP_000320.1:p.Arg515Gln | 0.0015 | 1052287 |
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Melo, M.; Ribeiro, M.; Silva, P.F.; Valente, S.; Alves, F.; Venâncio, M.; Sequeiros, J.; Freixo, J.P.; Antunes, D.; Oliveira, J. Medically Actionable Secondary Findings from Whole-Exome Sequencing (WES) Data in a Sample of 3972 Individuals. Int. J. Mol. Sci. 2025, 26, 3509. https://doi.org/10.3390/ijms26083509
Melo M, Ribeiro M, Silva PF, Valente S, Alves F, Venâncio M, Sequeiros J, Freixo JP, Antunes D, Oliveira J. Medically Actionable Secondary Findings from Whole-Exome Sequencing (WES) Data in a Sample of 3972 Individuals. International Journal of Molecular Sciences. 2025; 26(8):3509. https://doi.org/10.3390/ijms26083509
Chicago/Turabian StyleMelo, Mafalda, Mariana Ribeiro, Paulo Filipe Silva, Susana Valente, Filipe Alves, Margarida Venâncio, Jorge Sequeiros, João Parente Freixo, Diana Antunes, and Jorge Oliveira. 2025. "Medically Actionable Secondary Findings from Whole-Exome Sequencing (WES) Data in a Sample of 3972 Individuals" International Journal of Molecular Sciences 26, no. 8: 3509. https://doi.org/10.3390/ijms26083509
APA StyleMelo, M., Ribeiro, M., Silva, P. F., Valente, S., Alves, F., Venâncio, M., Sequeiros, J., Freixo, J. P., Antunes, D., & Oliveira, J. (2025). Medically Actionable Secondary Findings from Whole-Exome Sequencing (WES) Data in a Sample of 3972 Individuals. International Journal of Molecular Sciences, 26(8), 3509. https://doi.org/10.3390/ijms26083509