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. 2019 Dec 5;10(1):5519.
doi: 10.1038/s41467-019-13380-2.

Predictive Impact of Rare Genomic Copy Number Variations in Siblings of Individuals With Autism Spectrum Disorders

Free PMC article

Predictive Impact of Rare Genomic Copy Number Variations in Siblings of Individuals With Autism Spectrum Disorders

L D'Abate et al. Nat Commun. .
Free PMC article


Identification of genetic biomarkers associated with autism spectrum disorders (ASDs) could improve recurrence prediction for families with a child with ASD. Here, we describe clinical microarray findings for 253 longitudinally phenotyped ASD families from the Baby Siblings Research Consortium (BSRC), encompassing 288 infant siblings. By age 3, 103 siblings (35.8%) were diagnosed with ASD and 54 (18.8%) were developing atypically. Thirteen siblings have copy number variants (CNVs) involving ASD-relevant genes: 6 with ASD, 5 atypically developing, and 2 typically developing. Within these families, an ASD-related CNV in a sibling has a positive predictive value (PPV) for ASD or atypical development of 0.83; the Simons Simplex Collection of ASD families shows similar PPVs. Polygenic risk analyses suggest that common genetic variants may also contribute to ASD. CNV findings would have been pre-symptomatically predictive of ASD or atypical development in 11 (7%) of the 157 BSRC siblings who were eventually diagnosed clinically.

Conflict of interest statement

S.W.S. is on Scientific Advisory Committees for Population Bio and Deep Genomics, and his institution, The Hospital for Sick Children, has licensed to Lineagen software code he co-developed: “Method of determining disease causality of genome mutations”.


Fig. 1
Fig. 1
Project flowchart. Families consisting of a proband and at least 1 infant sibling were recruited through the Baby Siblings Research Consortium. The proband was the first in the family to receive an ASD diagnosis. Psychometric data were collected for all siblings at ~36 months of age, at which point an ASD diagnosis was made if the child met clinical criteria (see Methods). All children were also assessed for ASD, cognitive and adaptive behavioral functioning at least once prior to the 36-month time point. We genotyped individuals from 253 families on the Affymetrix CytoScanTM HD Array and whole-genome sequenced 91 of these families using established pipelines. Copy number variants determined to be ASD-relevant were confirmed with secondary methods. We scrutinized the phenotypes of high-risk infant siblings carrying these ASD-relevant CNVs to determine whether they (i) had ASD, (ii) were atypically developing, or (iii) were neurotypical/non-ASD. There were also 34 siblings who did not meet criteria for formal enrollment but for whom phenotype and microarray data were available. Following the general BSRC strategy, a separate CNV analysis was conducted on 2124 probands and 2423 non-ASD sibs from 2110 ASD-affected families part of the Simons Simplex Collection. Fourteen probands were monozygotic twins. Of the unaffected sibs, 288 were atypically developing. This analysis was performed to further assess the predictive value of chromosomal microarray. ASD autism spectrum disorder, CNV copy number variation.
Fig. 2
Fig. 2
ASD-relevant CNVs among infant siblings (n = 288). Summary of ASD-relevant genetic findings in the infant sibling cohort, stratified by family segregation and infant sibling phenotype. ASD autism spectrum disorder, CNV copy number variation.
Fig. 3
Fig. 3
Pedigrees demonstrating ASD-relevant CNVs in infant siblings. a Infant siblings with ASD who shared a CNV with a related index case (arrow). Targeted testing (only) for a pathogenic CNV was performed on sibling 12-8257-005. b Atypically developing infant siblings who shared a CNV with a related index case. Female sibling 4-0062-004 was positive for ASD on the ADOS (24 and 36 months) assessments, but subthreshold on the ADI-R. Clinical impression was that the child did not have ASD. She had subthreshold scores on the MSEL Early Learning Composite (ELC) (SS = 76) and VABS Adaptive Behavior Composite (ABC) (SS = 84). In family 1-0616, the second-born son (1-0616-004) displayed subthreshold ASD symptoms, vulnerabilities in language and verbal reasoning, gross and fine-motor skill delay; the third-born son (1-616-005) (not in the official cohort) experienced fine-motor delay as seen on the VABS at 24 months, and parents reported concerns regarding socialization. In family 4-0027, the female sibling displayed behavioral rigidity and transition difficulties. The male sibling in family 12-8115 was developing typically. c Infant siblings with ASD who did not share a CNV with a related index case. d Infant siblings with a CNV not shared with a related index case. Individual 4-0061-004 had language delay and cognitive regression (ELC = 56). Male sibling 12-4453-005 scored just above threshold on the ADOS (CSS = 5), but the clinical history was not consistent with a diagnosis of ASD. His ELC (SS = 88), and ABC (SS = 90) scores were within 1 standard deviation of the expected mean. The scores of male 14-0376-001 on the ADOS (CSS = 1), MSEL (ELC = 91) and the VABS (ABC = 105) reflected a typical developmental trajectory. Figure includes 5 additional non-infant siblings who were not counted as part of the formal cohort (dotted outline). CNV classification is provided in Supplementary Table 4. ASD autism spectrum disorder, CNV copy number variation, ADOS Autism Diagnostic Observation Schedule, CSS calibrated severity score, ADI-R Autism Diagnostic Interview-Revised, MSEL Mullen Scales of Early Learning, VABS Vineland Adaptive Behavior Scales, SS standard score.

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    1. Falkmer T, Anderson K, Falkmer M, Horlin C. Diagnostic procedures in autism spectrum disorders: a systematic literature review. Eur. Child Adolesc. Psychiatry. 2013;22:329–340. doi: 10.1007/s00787-013-0375-0. - DOI - PubMed
    1. Ozonoff S, et al. Recurrence risk for autism spectrum disorders: a Baby Siblings Research Consortium study. Pediatrics. 2011;128:e488–e495. - PMC - PubMed
    1. Grønborg TK, Schendel DE, Parner ET. Recurrence of autism spectrum disorders in full- and half-siblings and trends over time: a population-based cohort study. JAMA Pediatr. 2013;167:947–953. doi: 10.1001/jamapediatrics.2013.2259. - DOI - PMC - PubMed
    1. Risch N, et al. Familial recurrence of autism spectrum disorder: evaluating genetic and environmental contributions. Am. J. Psychiatry. 2014;171:1206–1213. doi: 10.1176/appi.ajp.2014.13101359. - DOI - PubMed
    1. Messinger DS, et al. Early sex differences are not autism-specific: A Baby Siblings Research Consortium (BSRC) study. Mol. Autism. 2015;6:32. doi: 10.1186/s13229-015-0027-y. - DOI - PMC - PubMed

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