title: Phenotypic heterogeneity of genomic disorders and rare copy-number variants.
abstract: 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.).
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.
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authors.lastname: Raskin
authors.forename: Kathleen
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authors.lastname: Leppig
authors.forename: Heidi
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authors.lastname: Thiese
authors.forename: Rosemarie
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authors.lastname: Smith
authors.forename: Erika
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authors.lastname: Aberg
authors.forename: Dmitriy M
authors.initials: DM
authors.lastname: Niyazov
authors.forename: Luis F
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authors.lastname: Escobar
authors.forename: Dima
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authors.lastname: El-Khechen
authors.forename: Kisha D
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authors.lastname: Johnson
authors.forename: Robert R
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authors.forename: Kiana
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authors.lastname: Siefkas
authors.forename: Susie
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authors.lastname: Ball
authors.forename: Natasha
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authors.lastname: Shur
authors.forename: Marianne
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authors.lastname: McGuire
authors.forename: Campbell K
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authors.lastname: Brasington
authors.forename: J Edward
authors.initials: JE
authors.lastname: Spence
authors.forename: Laura S
authors.initials: LS
authors.lastname: Martin
authors.forename: Carol
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authors.lastname: Clericuzio
authors.forename: Blake C
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authors.lastname: Shaffer
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mesh_terms: D001321:Autistic Disorder / Q000235:genetics; D002648:Child; D055028:Comparative Genomic Hybridization; D000013:Congenital Abnormalities / Q000235:genetics*; D056915:DNA Copy Number Variations; D002658:Developmental Disabilities / Q000235:genetics*; D005260:Female; D018740:Genetic Heterogeneity; D015894:Genome, Human; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D012737:Sex Factors