Standard clinical interpretation of DNA copy number variants (CNVs) identified by cytogenomic microarray involves examining protein-coding genes within the region and comparison to other CNVs. Emerging basic research suggests that CNVs can also exert a pathogenic effect through disruption of DNA structural elements such as topologically associated domains (TADs). To begin to integrate these discoveries with current practice, we developed ClinTAD, a free browser-based tool to assist with interpretation of CNVs in the context of TADs (www.clintad.com). We used ClinTAD to examine 209 randomly selected single-nucleotide polymorphism microarray cases with a total of 236 CNVs. We compared 118 CNVs classified as variants of uncertain clinical significance (VUS), where additional insight into pathogenicity of these CNVs would be of greatest utility, to 118 CNVs classified as benign. We found that a higher proportion of VUS had at least two genes in a nearby TAD related to a phenotype seen in the patient based on Human Phenotype Ontology (HPO) annotation. We present example cases demonstrating scenarios where ClinTAD may either increase or decrease clinical suspicion of pathogenicity for VUS, depending on disruption of TAD boundaries and HPO phenotype match. ClinTAD is an easy-to-use tool, based on emerging research in chromatin architecture, that can help inform CNV interpretation.
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Kearney HM, Thorland EC, Brown KK, Quintero-Rivera F, South ST, Working Group of the American College of Medical Genetics Laboratory Quality Assurance Committee. American College of Medical Genetics standards and guidelines for interpretation and reporting of postnatal constitutional copy number variants. Genet Med. 2011;13:680–85.
Flirth HV, Richards SM, Bevan AP, Clayton S, Corpas M, Rajan D, et al. DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources. Am J Hum Genet. 2009;84:524–33.
Kirkpatrick BE, Riggs ER, Azzariti DR, Miller VR, Ledbetter DH, Miller DT, et al. GenomeConnect: matchmaking between patients, clinical laboratories, and researchers to improve genomic knowledge. Hum Mutat. 2015;36:974–78.
MacDonald JR, Ziman R, Yuen RK, Feuk L, Scherer SW. The Database of Genomic Variants: a curated collection of structural variation in the human genome. Nucleic Acids Res. 2014;42:986–92.
Lupiáñez DG, Kraft K, Heinrich V, Krawitz P, Brancati F, Klopocki E, et al. Disruptions of topological chromatin domains cause pathogenic rewiring of gene-enhancer interactions. Cell. 2015;161:1012–25.
Franke M, Ibrahim DM, Andrey G, Schwarzer W, Heinrich V, Schöpflin R, et al. Formation of new chromatin domains determines pathogenicity of genomic duplications. Nature. 2016;538:265–69.
Dixon JR, Selvaraj S, Yue F, Kim A, Li Y, Shen Y, et al. Topological domains in mammalian genomes identified by analysis of chromatin interactions. Nature. 2012;485:376–80.
Spielmann M, Lupiáñez DG, Mundlos S. Structural variation in the 3D genome. Nat Rev Genet. 2018;19:453–67.
Ibn-Salem J, Köhler S, Love MI, Chung HR, Huang N, Hurles ME. Deletions of chromosomal regulatory boundaries are associated with congenital disease. Genome Biol. 2014;15:423.
Cooper GM, Coe BP, Girirajan S, Rosenfeld JA, Vu TH, Baker C, et al. A copy number variation morbidity map of developmental delay. Nat Genet. 2011;43:838–46.
Köhler S, Vasilevsky NA, Engelstad M, Foster E, McMurry J, Aymé S, et al. The Human Phenotype Ontology in 2017. Nucleic Acids Res. 2017;45:865–76.
Dixon JR, Jung I, Selvaraj S, Shen Y, Antosiewicz-Bourget JE, Lee AY, et al. Chromatin architecture reorganization during stem cell differentiation. Nature. 2015;518:331–36.
Assembling the Genome [Internet]. [Place unknown]. Genome Reference Consortium; Human Genome Assembly GRCh37. 2013. https://www.ncbi.nlm.nih.gov/grc/human/data?asm=GRCh37. Accessed 13 Sep 2017.
Köhler S, Carmody L, Vasilevsky N, Jacobsen JO, Danis D, Gourdine JP. et al. Expansion of the Human Phenotype Ontology (HPO) knowledge base and resources. Nucleic Acids Res. 2019;47:D1018–27.
Human Phenotype Ontology. Human Phenotype Ontology [Internet]. Berlin: Human Phenotype Ontology; 2008. https://hpo.jax.org/app/. Accessed 13 Sep 2017.
Ensembl. Ensembl Genome Browser [Internet]. Hinxton: Ensembl; 2000. http://grch37.ensembl.org. Accessed 25 Sep 2018.
Zerbino DR, Achuthan P, Akanni W, Amode MR, Barrell D, Bhai J, et al. Ensembl 2018. Nucleic Acids Res. 2018;46:754–61.
Visel A, Minovitsky S, Dubchak I, Pennacchio LA. VISTA Enhancer Browser--a database of tissue-specific human enhancers. Nucleic Acids Res. 2007;35:88–92.
Son JH, Xie G, Yuan C, Ena L, Li Z, Goldstein A, et al. Deep phenotyping on electronic health records facilitates genetic diagnosis by clinical exomes. Am J Hum Genet. 2018;103:58–73.
Flöttmann R, Kragesteen BK, Geuer S, Socha M, Allou L, Sowińska-Seidler A, et al. Noncoding copy-number variations are associated with congenital limb malformation. Genet Med. 2018;20:599–607.
Bianco S, Lupiáñez DG, Chiariello AM, Annunziatella C, Kraft K, Schöpflin R. Polymer physics predicts the effects of structural variants on chromatin architecture. Nat Genet. 2018;50:662–67.
We thank the staff of the UCSF Clinical Cytogenetics Laboratory for obtaining microarray data. We thank Drs. Jingwei Yu and Zhongxia Qi for insightful discussions. This work was supported by the UCSF Department of Laboratory Medicine (to JDS), a Clinical Scientist Development Award from the Doris Duke Charitable Foundation (to APW), and NIH Clinical Scientist Development Award K08CA184116 (to APW).
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Spector, J.D., Wiita, A.P. ClinTAD: a tool for copy number variant interpretation in the context of topologically associated domains. J Hum Genet 64, 437–443 (2019). https://doi.org/10.1038/s10038-019-0573-9
European Journal of Human Genetics (2021)