Clinical and molecular delineation of the 17q21.31 microdeletion syndrome.
BACKGROUND
The chromosome 17q21.31 microdeletion syndrome is a novel genomic disorder that has originally been identified using high resolution genome analyses in patients with unexplained mental retardation.


OBJECTIVE
We report the molecular and/or clinical characterisation of 22 individuals with the 17q21.31 microdeletion syndrome.


RESULTS
We estimate the prevalence of the syndrome to be 1 in 16,000 and show that it is highly underdiagnosed. Extensive clinical examination reveals that developmental delay, hypotonia, facial dysmorphisms including a long face, a tubular or pear-shaped nose and a bulbous nasal tip, and a friendly/amiable behaviour are the most characteristic features. Other clinically important features include epilepsy, heart defects and kidney/urologic anomalies. Using high resolution oligonucleotide arrays we narrow the 17q21.31 critical region to a 424 kb genomic segment (chr17: 41046729-41470954, hg17) encompassing at least six genes, among which is the gene encoding microtubule associated protein tau (MAPT). Mutation screening of MAPT in 122 individuals with a phenotype suggestive of 17q21.31 deletion carriers, but who do not carry the recurrent deletion, failed to identify any disease associated variants. In five deletion carriers we identify a <500 bp rearrangement hotspot at the proximal breakpoint contained within an L2 LINE motif and show that in every case examined the parent originating the deletion carries a common 900 kb 17q21.31 inversion polymorphism, indicating that this inversion is a necessary factor for deletion to occur (p<10(-5)).


CONCLUSIONS
Our data establish the 17q21.31 microdeletion syndrome as a clinically and molecularly well recognisable genomic disorder.
Koolen
D A
DA
Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Sharp
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AJ
Hurst
J A
JA
Firth
H V
HV
Knight
S J L
SJ
Goldenberg
A
A
Saugier-Veber
P
P
Pfundt
R
R
Vissers
L E L M
LE
Destrée
A
A
Grisart
B
B
Rooms
L
L
Van der Aa
N
N
Field
M
M
Hackett
A
A
Bell
K
K
Nowaczyk
M J M
MJ
Mancini
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GM
Poddighe
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PJ
Schwartz
C E
CE
Rossi
E
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De Gregori
M
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Antonacci-Fulton
L L
LL
McLellan
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MD
Garrett
J M
JM
Wiechert
M A
MA
Miner
T L
TL
Crosby
S
S
Ciccone
R
R
Willatt
L
L
Rauch
A
A
Zenker
M
M
Aradhya
S
S
Manning
M A
MA
Strom
T M
TM
Wagenstaller
J
J
Krepischi-Santos
A C
AC
Vianna-Morgante
A M
AM
Rosenberg
C
C
Price
S M
SM
Stewart
H
H
Shaw-Smith
C
C
Brunner
H G
HG
Wilkie
A O M
AO
Veltman
J A
JA
Zuffardi
O
O
Eichler
E E
EE
de Vries
B B A
BB
D000015:Abnormalities, Multiple / Q000453:epidemiology / Q000235:genetics / Q000503:physiopathology; D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D002872:Chromosome Deletion; D007446:Chromosome Inversion; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics*; D002658:Developmental Disabilities / Q000453:epidemiology / Q000235:genetics / Q000503:physiopathology; D005145:Face / Q000473:pathology; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D009123:Muscle Hypotonia / Q000453:epidemiology / Q000235:genetics / Q000503:physiopathology; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D015995:Prevalence; D055815:Young Adult; D016875:tau Proteins
C054369:MAPT protein, human; D016875:tau Proteins