Chromosomal microarray analysis in clinical evaluation of neurodevelopmental disorders-reporting a novel deletion of SETDB1 and illustration of counseling challenge.
The pathogenicity of copy number variations (CNV) in neurodevelopmental disorders is supported by research literature. However, few studies have evaluated the utility and counseling challenges of CNV analysis in clinic.



We analyzed the findings of CNV studies from a cohort referred for genetics evaluation of autism spectrum disorders (ASD), developmental disability (DD), and intellectual disability (ID).



Twenty-two CNV in 21 out of 115 probands are considered to be pathogenic (18.3%). Five CNV are likely pathogenic and 22 CNV are variants of unknown significance (VUS). We have found seven cases with more than two CNV and two with a complex rearrangement of the 22q13.3 Phelan-McDermid syndrome region. We identified a new and de novo 1q21.3 deletion that encompasses SETDB1, a gene encoding methylates histone H3 on lysine-9 (H3K9) methyltransferase, in a case with ASD.



We provide evidence to support the value of CNV analysis in etiological evaluation of neurodevelopmental disorders in autism genetics clinic. However, interpretation of the clinical significance and counseling families are still challenging because of the variable penetrance and pleotropic expressivity of CNV. In addition, the identification of a 1q21.3 deletion encompassing SETDB1 provides further support for the role of chromatin modifiers in the etiology of ASD.
Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina.|Children's Hospital of Fudan University, Shanghai, China.
Qiong
Q
Xu
Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina.
Jennifer
J
Goldstein
Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina.
Ping
P
Wang
LabCorp., Research Triangle Park, North Carolina.
Inder K
IK
Gadi
Department of Pathology, Duke University School of Medicine, Durham, North Carolina.
Heather
H
Labreche
Department of Pathology, Duke University School of Medicine, Durham, North Carolina.
Catherine
C
Rehder
Children's Hospital of Fudan University, Shanghai, China.
Wei-Ping
WP
Wang
Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina.
Allyn
A
McConkie
Children's Hospital of Fudan University, Shanghai, China.
Xiu
X
Xu
Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina.|Department of Neurobiology, Duke University School of Medicine, Durham, North Carolina.|Duke University Program in Genomics and Genetics, Durham, North Carolina.
Yong-Hui
YH
Jiang
D000293:Adolescent; D000465:Algorithms; D001321:Autistic Disorder / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D002843:Chromatin / Q000378:metabolism; D055028:Comparative Genomic Hybridization; D003376:Counseling; D056915:DNA Copy Number Variations; D002658:Developmental Disabilities / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D015321:Gene Rearrangement; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000235:genetics; D008297:Male; D046228:Microarray Analysis; D065886:Neurodevelopmental Disorders / Q000235:genetics*; D010375:Pedigree; D011496:Protein Methyltransferases / Q000235:genetics*
D002843:Chromatin; D011496:Protein Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C454062:SETDB1 protein, human