Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes.
BACKGROUND
Duplications and deletions in the human genome can cause disease or predispose persons to disease. Advances in technologies to detect these changes allow for the routine identification of submicroscopic imbalances in large numbers of patients.


METHODS
We tested for the presence of microdeletions and microduplications at a specific region of chromosome 1q21.1 in two groups of patients with unexplained mental retardation, autism, or congenital anomalies and in unaffected persons.


RESULTS
We identified 25 persons with a recurrent 1.35-Mb deletion within 1q21.1 from screening 5218 patients. The microdeletions had arisen de novo in eight patients, were inherited from a mildly affected parent in three patients, were inherited from an apparently unaffected parent in six patients, and were of unknown inheritance in eight patients. The deletion was absent in a series of 4737 control persons (P=1.1x10(-7)). We found considerable variability in the level of phenotypic expression of the microdeletion; phenotypes included mild-to-moderate mental retardation, microcephaly, cardiac abnormalities, and cataracts. The reciprocal duplication was enriched in nine children with mental retardation or autism spectrum disorder and other variable features (P=0.02). We identified three deletions and three duplications of the 1q21.1 region in an independent sample of 788 patients with mental retardation and congenital anomalies.


CONCLUSIONS
We have identified recurrent molecular lesions that elude syndromic classification and whose disease manifestations must be considered in a broader context of development as opposed to being assigned to a specific disease. Clinical diagnosis in patients with these lesions may be most readily achieved on the basis of genotype rather than phenotype.
Mefford
Heather C
HC
University of Washington School of Medicine, Seattle 98195, USA.
Sharp
Andrew J
AJ
Baker
Carl
C
Itsara
Andy
A
Jiang
Zhaoshi
Z
Buysse
Karen
K
Huang
Shuwen
S
Maloney
Viv K
VK
Crolla
John A
JA
Baralle
Diana
D
Collins
Amanda
A
Mercer
Catherine
C
Norga
Koen
K
de Ravel
Thomy
T
Devriendt
Koen
K
Bongers
Ernie M H F
EM
de Leeuw
Nicole
N
Reardon
William
W
Gimelli
Stefania
S
Bena
Frederique
F
Hennekam
Raoul C
RC
Male
Alison
A
Gaunt
Lorraine
L
Clayton-Smith
Jill
J
Simonic
Ingrid
I
Park
Soo Mi
SM
Mehta
Sarju G
SG
Nik-Zainal
Serena
S
Woods
C Geoffrey
CG
Firth
Helen V
HV
Parkin
Georgina
G
Fichera
Marco
M
Reitano
Santina
S
Lo Giudice
Mariangela
M
Li
Kelly E
KE
Casuga
Iris
I
Broomer
Adam
A
Conrad
Bernard
B
Schwerzmann
Markus
M
Räber
Lorenz
L
Gallati
Sabina
S
Striano
Pasquale
P
Coppola
Antonietta
A
Tolmie
John L
JL
Tobias
Edward S
ES
Lilley
Chris
C
Armengol
Lluis
L
Spysschaert
Yves
Y
Verloo
Patrick
P
De Coene
Anja
A
Goossens
Linde
L
Mortier
Geert
G
Speleman
Frank
F
van Binsbergen
Ellen
E
Nelen
Marcel R
MR
Hochstenbach
Ron
R
Poot
Martin
M
Gallagher
Louise
L
Gill
Michael
M
McClellan
Jon
J
King
Mary-Claire
MC
Regan
Regina
R
Skinner
Cindy
C
Stevenson
Roger E
RE
Antonarakis
Stylianos E
SE
Chen
Caifu
C
Estivill
Xavier
X
Menten
Björn
B
Gimelli
Giorgio
G
Gribble
Susan
S
Schwartz
Stuart
S
Sutcliffe
James S
JS
Walsh
Tom
T
Knight
Samantha J L
SJ
Sebat
Jonathan
J
Romano
Corrado
C
Schwartz
Charles E
CE
Veltman
Joris A
JA
de Vries
Bert B A
BB
Vermeesch
Joris R
JR
Barber
John C K
JC
Willatt
Lionel
L
Tassabehji
May
M
Eichler
Evan E
EE
D001321:Autistic Disorder / Q000235:genetics*; D002386:Cataract / Q000151:congenital / Q000235:genetics; D002648:Child; D002869:Chromosome Aberrations; D002872:Chromosome Deletion; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D000013:Congenital Abnormalities / Q000235:genetics*; D005260:Female; D020440:Gene Duplication; D015321:Gene Rearrangement; D014644:Genetic Variation; D006330:Heart Defects, Congenital / Q000235:genetics; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D008831:Microcephaly / Q000235:genetics; D010641:Phenotype; D011995:Recombination, Genetic
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