Phenotypic Heterogeneity of Genomic Disorders and Rare Copy-Number Variants
Open accessAbstract
BACKGROUND: Some copy-number variants are associated with genomic disorders with extreme phenotypic heterogeneity. The cause of this variation is unknown, which presents challenges in genetic diagnosis, counseling, and management. METHODS: We analyzed the genomes of 2312 children known to carry a copy-number variant associated with intellectual disability and congenital abnormalities, using array comparative genomic hybridization. RESULTS: Among the affected children, 10.1% carried a second large copy-number variant in addition to the primary genetic lesion. We identified seven genomic disorders, each defined by a specific copy-number variant, in which the affected children were more likely to carry multiple copy-number variants than were controls. We found that syndromic disorders could be distinguished from those with extreme phenotypic heterogeneity on the basis of the total number of copy-number variants and whether the variants are inherited or de novo. Children who carried two large copy-number variants of unknown clinical significance were eight times as likely to have developmental delay as were controls (odds ratio, 8.16; 95% confidence interval, 5.33 to 13.07; P=2.11×10(-38)). Among affected children, inherited copy-number variants tended to co-occur with a second-site large copy-number variant (Spearman correlation coefficient, 0.66; P<0.001). Boys were more likely than girls to have disorders of phenotypic heterogeneity (P<0.001), and mothers were more likely than fathers to transmit second-site copy-number variants to their offspring (P=0.02). CONCLUSIONS: Multiple, large copy-number variants, including those of unknown pathogenic significance, compound to result in a severe clinical presentation, and secondary copy-number variants are preferentially transmitted from maternal carriers. (Funded by the Simons Foundation Autism Research Initiative and the National Institutes of Health.).
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In many cases, patients with inherited deletions of 16p or de novo SHANK2 mutations carry additional mutations, and the presence of multiple hits might be the rule rather than the exception in ASD.
“In many cases, patients with inherited deletions of 16p or de novo SHANK2 mutations, for example, carry additional mutations, and the presence of multiple hits might be indeed the rule rather than the exception in ASD 93,94 .”
From Progress toward treatments for synaptic defects in autism (2013) · cites this paper as [93]
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- Authors
- Girirajan, S., Rosenfeld, J. A., Coe, B. P., Parikh, S., Friedman, N., Goldstein, A., Filipink, R. A., McConnell, J. S., Angle, B., Meschino, W. S., Nezarati, M. M., Asamoah, A., Jackson, K. E., Gowans, G. C., Martin, J. A., Carmany, E. P., Stockton, D. W., Schnur, R. E., Penney, L. S., Martin, D. M., Raskin, S., Leppig, K., Thiese, H., Smith, R., Aberg, E., Niyazov, D. M., Escobar, L. F., El-Khechen, D., Johnson, K. D., Lebel, R. R., Siefkas, K., Ball, S., Shur, N., McGuire, M., Brasington, C. K., Spence, J. E., Martin, L. S., Clericuzio, C., Ballif, B. C., Shaffer, L. G., & Eichler, E. E.
- Affiliations
- University of Washington (US)
- Cleveland Clinic (US)
- Lurie Children's Hospital (US)
- North York General Hospital (CA)
- University of Louisville (US)
- Providence Sacred Heart Medical Center (US)
- Children's Hospital of Michigan (US)
- Cooper Medical School of Rowan University (US)
- Dalhousie University (CA)
- University of Michigan (US)
- Pontifícia Universidade Católica do Paraná (BR)
- Group Health Cooperative (US)
- Izaak Walton Killam Health Centre (CA)
- Ochsner Medical Center (US)
- Peyton Manning Children’s Hospital at St.Vincent (US)
- Rush University Medical Center (US)
- SUNY Upstate Medical University (US)
- Virginia Mason Memorial (US)
- Rhode Island Hospital (US)
- University of Pittsburgh (US)
- Carolinas Medical Center (US)
- Nemours Children's Clinic (US)
- University of New Mexico (US)
- Howard Hughes Medical Institute (US)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2012-10-04
- Volume
- 367
- Issue
- 14
- Pages
- 1321-1331
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC3494411
- OpenAlex
- W2063989452
- Cited by
- 621
- References
- 38
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- FWCI
- 43.42
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD065285, R01HD065285)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genome Rearrangement Algorithms
- Keywords
- copy number variation, genomic disorders, phenotypic heterogeneity, intellectual disability, congenital malformations, developmental delay, de novo mutations, inherited mutations, variants of uncertain significance, sex differences in transmission, mother-to-child transmission
- MeSH terms
- Congenital Abnormalities, Autistic Disorder, Child, Developmental Disabilities, Female, Humans, Male, Intellectual Disability, Phenotype, Sex Factors, Genome, Human, Genetic Heterogeneity, Oligonucleotide Array Sequence Analysis, Comparative Genomic Hybridization, DNA Copy Number Variations
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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