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.
Girirajan
Santhosh
S
Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington, USA.
Rosenfeld
Jill A
JA
Cooper
Gregory M
GM
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Francesca
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Siswara
Priscillia
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Andy
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Walsh
Tom
T
McCarthy
Shane E
SE
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Carl
C
Mefford
Heather C
HC
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Jeffrey M
JM
Browning
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SR
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Brian L
BL
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Diane E
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Levy
Deborah L
DL
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BC
Platky
Kathryn
K
Farber
Darren M
DM
Gowans
Gordon C
GC
Wetherbee
Jessica J
JJ
Asamoah
Alexander
A
Weaver
David D
DD
Mark
Paul R
PR
Dickerson
Jennifer
J
Garg
Bhuwan P
BP
Ellingwood
Sara A
SA
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R
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VC
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Wendy
W
McDonald
Marie T
MT
Hoo
Joe J
JJ
French
Beatrice N
BN
Hudson
Cindy
C
Johnson
John P
JP
Ozmore
Jillian R
JR
Moeschler
John B
JB
Surti
Urvashi
U
Escobar
Luis F
LF
El-Khechen
Dima
D
Gorski
Jerome L
JL
Kussmann
Jennifer
J
Salbert
Bonnie
B
Lacassie
Yves
Y
Biser
Alisha
A
McDonald-McGinn
Donna M
DM
Zackai
Elaine H
EH
Deardorff
Matthew A
MA
Shaikh
Tamim H
TH
Haan
Eric
E
Friend
Kathryn L
KL
Fichera
Marco
M
Romano
Corrado
C
Gécz
Jozef
J
DeLisi
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LE
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King
Mary-Claire
MC
Shaffer
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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