A dyadic approach to the delineation of diagnostic entities in clinical genomics

doi:10.1016/j.ajhg.2020.11.013

Review

. 2021 Jan 7;108(1):8-15.

doi: 10.1016/j.ajhg.2020.11.013.

A dyadic approach to the delineation of diagnostic entities in clinical genomics

Leslie G Biesecker¹, Margaret P Adam², Fowzan S Alkuraya³, Anne R Amemiya⁴, Michael J Bamshad⁵, Anita E Beck⁶, James T Bennett⁷, Lynne M Bird⁸, John C Carey⁹, Brian Chung¹⁰, Robin D Clark¹¹, Timothy C Cox¹², Cynthia Curry¹³, Mary Beth Palko Dinulos¹⁴, William B Dobyns¹⁵, Philip F Giampietro¹⁶, Katta M Girisha¹⁷, Ian A Glass¹⁸, John M Graham Jr¹⁹, Karen W Gripp²⁰, Chad R Haldeman-Englert²¹, Bryan D Hall²², A Micheil Innes²³, Jennifer M Kalish²⁴, Kim M Keppler-Noreuil²⁵, Kenjiro Kosaki²⁶, Beth A Kozel²⁷, Ghayda M Mirzaa²⁸, John J Mulvihill²⁹, Malgorzata J M Nowaczyk³⁰, Roberta A Pagon², Kyle Retterer³¹, Alan F Rope³², Pedro A Sanchez-Lara³³, Laurie H Seaver³⁴, Joseph T Shieh³⁵, Anne M Slavotinek³⁵, Andrew K Sobering³⁶, Cathy A Stevens³⁷, David A Stevenson³⁸, Tiong Yang Tan³⁹, Wen-Hann Tan⁴⁰, Anne C Tsai⁴¹, David D Weaver⁴², Marc S Williams⁴³, Elaine Zackai⁴⁴, Yuri A Zarate⁴⁵

Affiliations

¹ Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: lesb@mail.nih.gov.
² Division of Genetic Medicine, Department of Pediatrics, University of Washington School of Medicine, Seattle, WA 98105, USA.
³ Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
⁴ Computercraft Corporation, McLean, VA 20005, USA.
⁵ Department of Pediatrics and Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA; Brotman Baty Institute for Precision Medicine, Seattle, WA 98195, USA.
⁶ Pediatric Genetic Medicine Service, University of Washington, Seattle, WA 98195, USA; Seattle Children's Hospital, Seattle, WA 98015, USA.
⁷ Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute and Division Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98101, USA.
⁸ Department of Pediatrics, University of California San Diego, San Diego 92123, USA; Rady Children's Hospital, San Diego, CA 92123, USA.
⁹ Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT 84108, USA.
¹⁰ Department of Paediatrics and Adolescent Medicine, Hong Kong Children's Hospital, Queen Mary Hospital, LKS Faculty of Medicine, University of Hong Kong, Hong Kong, China.
¹¹ Loma Linda University School of Medicine, Department of Pediatrics, Division of Medical Genetics, Loma Linda, CA 92354, USA.
¹² Department of Oral and Craniofacial Sciences, School of Dentistry and Department of Pediatrics, School of Medicine, University of Missouri-Kansas City, Kansas City, MO 64108, USA.
¹³ Genetic Medicine, Department of Pediatrics, University of California, Fresno, Fresno, CA 93701, USA.
¹⁴ The Geisel School of Medicine at Dartmouth, Department of Pediatrics, Section of Genetics and Child Development, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USA.
¹⁵ Division of Genetics, Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA.
¹⁶ Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA.
¹⁷ Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal 576104, India.
¹⁸ Department of Pediatrics and Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA.
¹⁹ Cedars-Sinai Medical Center and Harbor-UCLA Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, CA 90048, USA.
²⁰ Division of Medical Genetics, Department of Pediatrics, AI DuPont Hospital for Children/Nemours, Wilmington, DE 19803, USA.
²¹ Mission Fullerton Genetics Center, Asheville, NC 28803, USA.
²² Greenwood Genetic Center, Greenwood, SC 29646, USA.
²³ Department of Medical Genetics and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T3B 6A8, Canada.
²⁴ Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Departments of Pediatrics and Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
²⁵ Division of Genetics, Children's National Medical Center, Washington, DC 20010, USA.
²⁶ Keio University School of Medicine, Tokyo 160-8582, Japan.
²⁷ Translational Vascular Medicine Branch, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
²⁸ Brotman Baty Institute for Precision Medicine, Seattle, WA 98195, USA; Center for Integrative Brain Research, Seattle Children's Research Institute, Department of Pediatrics, University of Washington, Seattle, WA 98101, USA.
²⁹ University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; National Human Genome Research Institute, Bethesda, MD 20892, USA.
³⁰ Molecular Medicine & Pathology and Pediatrics, McMaster University, Hamilton, ON L8S 3K9, Canada.
³¹ GeneDx, Gaithersburg, MD 20877, USA.
³² Genome Medical, South San Francisco, CA 94080, USA.
³³ Department of Pediatrics, Cedars-Sinai Medical Center and David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90048, USA.
³⁴ Spectrum Health Medical Genetics and Genomics/Helen Devos Children's Hospital, Department of Pediatrics and Human Development, Michigan State University College of Human Medicine, Grand Rapids, MI 49503, USA.
³⁵ Institute for Human Genetics and Division of Medical Genetics, Department of Pediatrics Benioff Children's Hospital, University of California, San Francisco, San Francisco, CA 94143, USA.
³⁶ Department of Biochemistry, St. George's University School of Medicine, St. George's, Grenada.
³⁷ Department of Pediatrics, University of Tennessee College of Medicine, Chattanooga, TN 37403, USA.
³⁸ Division of Medical Genetics, Department of Pediatrics, Stanford University, Palo Alto, CA 94305, USA.
³⁹ Victorian Clinical Genetics Services, Murdoch Children's Research Institute and Department of Paediatrics, University of Melbourne, Melbourne, VIC 3052, Australia.
⁴⁰ Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA.
⁴¹ Section of Genetics, Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
⁴² Department of Medical and Molecular Genetics, Indiana University School of Medicine, 975 W. Walnut Street, Indianapolis, IN 46202, USA.
⁴³ Genomic Medicine Institute, Geisinger, Danville, PA 17822, USA.
⁴⁴ Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, PA 19104, USA.
⁴⁵ Section of Genetics and Metabolism, Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA.

PMID: 33417889
PMCID: PMC7820621
DOI: 10.1016/j.ajhg.2020.11.013

Review

A dyadic approach to the delineation of diagnostic entities in clinical genomics

Leslie G Biesecker et al. Am J Hum Genet. 2021.

. 2021 Jan 7;108(1):8-15.

doi: 10.1016/j.ajhg.2020.11.013.

Authors

Affiliations

¹ Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: lesb@mail.nih.gov.
² Division of Genetic Medicine, Department of Pediatrics, University of Washington School of Medicine, Seattle, WA 98105, USA.
³ Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
⁴ Computercraft Corporation, McLean, VA 20005, USA.
⁵ Department of Pediatrics and Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA; Brotman Baty Institute for Precision Medicine, Seattle, WA 98195, USA.
⁶ Pediatric Genetic Medicine Service, University of Washington, Seattle, WA 98195, USA; Seattle Children's Hospital, Seattle, WA 98015, USA.
⁷ Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute and Division Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98101, USA.
⁸ Department of Pediatrics, University of California San Diego, San Diego 92123, USA; Rady Children's Hospital, San Diego, CA 92123, USA.
⁹ Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT 84108, USA.
¹⁰ Department of Paediatrics and Adolescent Medicine, Hong Kong Children's Hospital, Queen Mary Hospital, LKS Faculty of Medicine, University of Hong Kong, Hong Kong, China.
¹¹ Loma Linda University School of Medicine, Department of Pediatrics, Division of Medical Genetics, Loma Linda, CA 92354, USA.
¹² Department of Oral and Craniofacial Sciences, School of Dentistry and Department of Pediatrics, School of Medicine, University of Missouri-Kansas City, Kansas City, MO 64108, USA.
¹³ Genetic Medicine, Department of Pediatrics, University of California, Fresno, Fresno, CA 93701, USA.
¹⁴ The Geisel School of Medicine at Dartmouth, Department of Pediatrics, Section of Genetics and Child Development, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USA.
¹⁵ Division of Genetics, Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA.
¹⁶ Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA.
¹⁷ Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal 576104, India.
¹⁸ Department of Pediatrics and Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA.
¹⁹ Cedars-Sinai Medical Center and Harbor-UCLA Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, CA 90048, USA.
²⁰ Division of Medical Genetics, Department of Pediatrics, AI DuPont Hospital for Children/Nemours, Wilmington, DE 19803, USA.
²¹ Mission Fullerton Genetics Center, Asheville, NC 28803, USA.
²² Greenwood Genetic Center, Greenwood, SC 29646, USA.
²³ Department of Medical Genetics and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T3B 6A8, Canada.
²⁴ Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Departments of Pediatrics and Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
²⁵ Division of Genetics, Children's National Medical Center, Washington, DC 20010, USA.
²⁶ Keio University School of Medicine, Tokyo 160-8582, Japan.
²⁷ Translational Vascular Medicine Branch, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
²⁸ Brotman Baty Institute for Precision Medicine, Seattle, WA 98195, USA; Center for Integrative Brain Research, Seattle Children's Research Institute, Department of Pediatrics, University of Washington, Seattle, WA 98101, USA.
²⁹ University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; National Human Genome Research Institute, Bethesda, MD 20892, USA.
³⁰ Molecular Medicine & Pathology and Pediatrics, McMaster University, Hamilton, ON L8S 3K9, Canada.
³¹ GeneDx, Gaithersburg, MD 20877, USA.
³² Genome Medical, South San Francisco, CA 94080, USA.
³³ Department of Pediatrics, Cedars-Sinai Medical Center and David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90048, USA.
³⁴ Spectrum Health Medical Genetics and Genomics/Helen Devos Children's Hospital, Department of Pediatrics and Human Development, Michigan State University College of Human Medicine, Grand Rapids, MI 49503, USA.
³⁵ Institute for Human Genetics and Division of Medical Genetics, Department of Pediatrics Benioff Children's Hospital, University of California, San Francisco, San Francisco, CA 94143, USA.
³⁶ Department of Biochemistry, St. George's University School of Medicine, St. George's, Grenada.
³⁷ Department of Pediatrics, University of Tennessee College of Medicine, Chattanooga, TN 37403, USA.
³⁸ Division of Medical Genetics, Department of Pediatrics, Stanford University, Palo Alto, CA 94305, USA.
³⁹ Victorian Clinical Genetics Services, Murdoch Children's Research Institute and Department of Paediatrics, University of Melbourne, Melbourne, VIC 3052, Australia.
⁴⁰ Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA.
⁴¹ Section of Genetics, Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
⁴² Department of Medical and Molecular Genetics, Indiana University School of Medicine, 975 W. Walnut Street, Indianapolis, IN 46202, USA.
⁴³ Genomic Medicine Institute, Geisinger, Danville, PA 17822, USA.
⁴⁴ Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, PA 19104, USA.
⁴⁵ Section of Genetics and Metabolism, Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA.

PMID: 33417889
PMCID: PMC7820621
DOI: 10.1016/j.ajhg.2020.11.013

Abstract

The delineation of disease entities is complex, yet recent advances in the molecular characterization of diseases provide opportunities to designate diseases in a biologically valid manner. Here, we have formalized an approach to the delineation of Mendelian genetic disorders that encompasses two distinct but inter-related concepts: (1) the gene that is mutated and (2) the phenotypic descriptor, preferably a recognizably distinct phenotype. We assert that only by a combinatorial or dyadic approach taking both of these attributes into account can a unitary, distinct genetic disorder be designated. We propose that all Mendelian disorders should be designated as "GENE-related phenotype descriptor" (e.g., "CFTR-related cystic fibrosis"). This approach to delineating and naming disorders reconciles the complexity of gene-to-phenotype relationships in a simple and clear manner yet communicates the complexity and nuance of these relationships.

PubMed Disclaimer

Conflict of interest statement

L.G.B. receives in-kind research support from ArQule (now a wholly owned subsidiary of Merck) and Pfizer and receives honoraria from Cold Spring Harbor Press. K.W.G. is Chief Medical Officer for FDN (Face to DNA). K.R. is an employee of GeneDx, a subsidiary of Opko Health, and a shareholder of Opko Health. The other authors declare no competing interests.

Comment in

Response to Biesecker et al.
Hamosh A, Amberger JS, Bocchini CA, Bodurtha J, Bult CJ, Chute CG, Cutting GR, Dietz HC, Firth HV, Gibbs RA, Grody WW, Haendel MA, Lupski JR, Posey JE, Robinson PN, Schriml LM, Scott AF, Sobreira NL, Valle D, Wu N, Rasmussen SA. Hamosh A, et al. Am J Hum Genet. 2021 Sep 2;108(9):1807-1808. doi: 10.1016/j.ajhg.2021.07.004. Am J Hum Genet. 2021. PMID: 34478655 Free PMC article. No abstract available.
Response to Hamosh et al.
Biesecker LG, Adam MP, Alkuraya FS, Amemiya AR, Bamshad MJ, Beck AE, Bennett JT, Bird LM, Carey JC, Chung B, Clark RD, Cox TC, Curry C, Dinulos MBP, Dobyns WB, Giampietro PF, Girisha KM, Glass IA, Graham JM Jr, Gripp KW, Haldeman-Englert CR, Hall BD, Innes AM, Kalish JM, Keppler-Noreuil KM, Kosaki K, Kozel BA, Mirzaa GM, Mulvihill JJ, Nowaczyk MJM, Pagon RA, Retterer K, Rope AF, Sanchez-Lara PA, Seaver LH, Shieh JT, Slavotinek AM, Sobering AK, Stevens CA, Stevenson DA, Tan TY, Tan WH, Tsai AC, Weaver DD, Williams MS, Zackai E, Zarate YA. Biesecker LG, et al. Am J Hum Genet. 2021 Sep 2;108(9):1809-1810. doi: 10.1016/j.ajhg.2021.07.006. Am J Hum Genet. 2021. PMID: 34478656 Free PMC article. No abstract available.

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References

1. Bamshad M.J., Nickerson D.A., Chong J.X. Mendelian Gene Discovery: Fast and Furious with No End in Sight. Am. J. Hum. Genet. 2019;105:448–455. - PMC - PubMed
1. Sakai L.Y., Keene D.R., Renard M., De Backer J. FBN1: The disease-causing gene for Marfan syndrome and other genetic disorders. Gene. 2016;591:279–291. - PMC - PubMed
1. Gross A.M., Frone M., Gripp K.W., Gelb B.D., Schoyer L., Schill L., Stronach B., Biesecker L.G., Esposito D., Hernandez E.R. Advancing RAS/RASopathy therapies: An NCI-sponsored intramural and extramural collaboration for the study of RASopathies. Am. J. Med. Genet. A. 2020;182:866–876. - PMC - PubMed
1. Amberger J.S., Bocchini C.A., Scott A.F., Hamosh A. OMIM.org: leveraging knowledge across phenotype-gene relationships. Nucleic Acids Res. 2019;47(D1):D1038–D1043. - PMC - PubMed
1. Zielenski J. Genotype and phenotype in cystic fibrosis. Respiration. 2000;67:117–133. - PubMed

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[1] Bamshad M.J., Nickerson D.A., Chong J.X. Mendelian Gene Discovery: Fast and Furious with No End in Sight. Am. J. Hum. Genet. 2019;105:448–455. - PMC - PubMed

[2] Bamshad M.J., Nickerson D.A., Chong J.X. Mendelian Gene Discovery: Fast and Furious with No End in Sight. Am. J. Hum. Genet. 2019;105:448–455. - PMC - PubMed

[3] Sakai L.Y., Keene D.R., Renard M., De Backer J. FBN1: The disease-causing gene for Marfan syndrome and other genetic disorders. Gene. 2016;591:279–291. - PMC - PubMed

[4] Sakai L.Y., Keene D.R., Renard M., De Backer J. FBN1: The disease-causing gene for Marfan syndrome and other genetic disorders. Gene. 2016;591:279–291. - PMC - PubMed

[5] Gross A.M., Frone M., Gripp K.W., Gelb B.D., Schoyer L., Schill L., Stronach B., Biesecker L.G., Esposito D., Hernandez E.R. Advancing RAS/RASopathy therapies: An NCI-sponsored intramural and extramural collaboration for the study of RASopathies. Am. J. Med. Genet. A. 2020;182:866–876. - PMC - PubMed

[6] Gross A.M., Frone M., Gripp K.W., Gelb B.D., Schoyer L., Schill L., Stronach B., Biesecker L.G., Esposito D., Hernandez E.R. Advancing RAS/RASopathy therapies: An NCI-sponsored intramural and extramural collaboration for the study of RASopathies. Am. J. Med. Genet. A. 2020;182:866–876. - PMC - PubMed

[7] Amberger J.S., Bocchini C.A., Scott A.F., Hamosh A. OMIM.org: leveraging knowledge across phenotype-gene relationships. Nucleic Acids Res. 2019;47(D1):D1038–D1043. - PMC - PubMed

[8] Amberger J.S., Bocchini C.A., Scott A.F., Hamosh A. OMIM.org: leveraging knowledge across phenotype-gene relationships. Nucleic Acids Res. 2019;47(D1):D1038–D1043. - PMC - PubMed

[9] Zielenski J. Genotype and phenotype in cystic fibrosis. Respiration. 2000;67:117–133. - PubMed

[10] Zielenski J. Genotype and phenotype in cystic fibrosis. Respiration. 2000;67:117–133. - PubMed

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A dyadic approach to the delineation of diagnostic entities in clinical genomics

Affiliations

A dyadic approach to the delineation of diagnostic entities in clinical genomics

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