A recurrent 16p12.1 microdeletion supports a two-hit model for severe developmental delay.
We report the identification of a recurrent, 520-kb 16p12.1 microdeletion associated with childhood developmental delay. The microdeletion was detected in 20 of 11,873 cases compared with 2 of 8,540 controls (P = 0.0009, OR = 7.2) and replicated in a second series of 22 of 9,254 cases compared with 6 of 6,299 controls (P = 0.028, OR = 2.5). Most deletions were inherited, with carrier parents likely to manifest neuropsychiatric phenotypes compared to non-carrier parents (P = 0.037, OR = 6). Probands were more likely to carry an additional large copy-number variant when compared to matched controls (10 of 42 cases, P = 5.7 x 10(-5), OR = 6.6). The clinical features of individuals with two mutations were distinct from and/or more severe than those of individuals carrying only the co-occurring mutation. Our data support a two-hit model in which the 16p12.1 microdeletion both predisposes to neuropsychiatric phenotypes as a single event and exacerbates neurodevelopmental phenotypes in association with other large deletions or duplications. Analysis of other microdeletions with variable expressivity indicates that this two-hit model might be more generally applicable to neuropsychiatric disease.
Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington, USA.
Santhosh
S
Girirajan
Jill A
JA
Rosenfeld
Gregory M
GM
Cooper
Francesca
F
Antonacci
Priscillia
P
Siswara
Andy
A
Itsara
Laura
L
Vives
Tom
T
Walsh
Shane E
SE
McCarthy
Carl
C
Baker
Heather C
HC
Mefford
Jeffrey M
JM
Kidd
Sharon R
SR
Browning
Brian L
BL
Browning
Diane E
DE
Dickel
Deborah L
DL
Levy
Blake C
BC
Ballif
Kathryn
K
Platky
Darren M
DM
Farber
Gordon C
GC
Gowans
Jessica J
JJ
Wetherbee
Alexander
A
Asamoah
David D
DD
Weaver
Paul R
PR
Mark
Jennifer
J
Dickerson
Bhuwan P
BP
Garg
Sara A
SA
Ellingwood
Rosemarie
R
Smith
Valerie C
VC
Banks
Wendy
W
Smith
Marie T
MT
McDonald
Joe J
JJ
Hoo
Beatrice N
BN
French
Cindy
C
Hudson
John P
JP
Johnson
Jillian R
JR
Ozmore
John B
JB
Moeschler
Urvashi
U
Surti
Luis F
LF
Escobar
Dima
D
El-Khechen
Jerome L
JL
Gorski
Jennifer
J
Kussmann
Bonnie
B
Salbert
Yves
Y
Lacassie
Alisha
A
Biser
Donna M
DM
McDonald-McGinn
Elaine H
EH
Zackai
Matthew A
MA
Deardorff
Tamim H
TH
Shaikh
Eric
E
Haan
Kathryn L
KL
Friend
Marco
M
Fichera
Corrado
C
Romano
Jozef
J
Gécz
Lynn E
LE
DeLisi
Jonathan
J
Sebat
Mary-Claire
MC
King
Lisa G
LG
Shaffer
Evan E
EE
Eichler
D000328:Adult; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D002872:Chromosome Deletion; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics; D055028:Comparative Genomic Hybridization / Q000379:methods; D002658:Developmental Disabilities / Q000235:genetics*; D005190:Family; D005787:Gene Frequency; D006801:Humans; D007223:Infant; D008957:Models, Genetic; D020411:Oligonucleotide Array Sequence Analysis; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012008:Recurrence; D012720:Severity of Illness Index