Deletion 17q12 is a recurrent copy number variant that confers high risk of autism and schizophrenia.
Autism spectrum disorders (ASD) and schizophrenia are neurodevelopmental disorders for which recent evidence indicates an important etiologic role for rare copy number variants (CNVs) and suggests common genetic mechanisms. We performed cytogenomic array analysis in a discovery sample of patients with neurodevelopmental disorders referred for clinical testing. We detected a recurrent 1.4 Mb deletion at 17q12, which harbors HNF1B, the gene responsible for renal cysts and diabetes syndrome (RCAD), in 18/15,749 patients, including several with ASD, but 0/4,519 controls. We identified additional shared phenotypic features among nine patients available for clinical assessment, including macrocephaly, characteristic facial features, renal anomalies, and neurocognitive impairments. In a large follow-up sample, the same deletion was identified in 2/1,182 ASD/neurocognitive impairment and in 4/6,340 schizophrenia patients, but in 0/47,929 controls (corrected p = 7.37 × 10⁻⁵). These data demonstrate that deletion 17q12 is a recurrent, pathogenic CNV that confers a very high risk for ASD and schizophrenia and show that one or more of the 15 genes in the deleted interval is dosage sensitive and essential for normal brain development and function. In addition, the phenotypic features of patients with this CNV are consistent with a contiguous gene syndrome that extends beyond RCAD, which is caused by HNF1B mutations only.
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA. daniel.morenodeluca@emory.edu
Daniel
D
Moreno-De-Luca
Jennifer G
JG
Mulle
Erin B
EB
Kaminsky
Stephan J
SJ
Sanders
Scott M
SM
Myers
Margaret P
MP
Adam
Amy T
AT
Pakula
Nancy J
NJ
Eisenhauer
Kim
K
Uhas
LuAnn
L
Weik
Lisa
L
Guy
Melanie E
ME
Care
Chantal F
CF
Morel
Charlotte
C
Boni
Bonnie Anne
BA
Salbert
Ashadeep
A
Chandrareddy
Laurie A
LA
Demmer
Eva W C
EW
Chow
Urvashi
U
Surti
Swaroop
S
Aradhya
Diane L
DL
Pickering
Denae M
DM
Golden
Warren G
WG
Sanger
Emily
E
Aston
Arthur R
AR
Brothman
Troy J
TJ
Gliem
Erik C
EC
Thorland
Todd
T
Ackley
Ram
R
Iyer
Shuwen
S
Huang
John C
JC
Barber
John A
JA
Crolla
Stephen T
ST
Warren
Christa L
CL
Martin
David H
DH
Ledbetter
D002648:Child; D002659:Child Development Disorders, Pervasive / Q000235:genetics; D002675:Child, Preschool; D002886:Chromosomes, Human, Pair 17; D056915:DNA Copy Number Variations; D019066:Facies; D005260:Female; D006801:Humans; D008297:Male; D010641:Phenotype; D012559:Schizophrenia / Q000235:genetics*; D017384:Sequence Deletion