Clinical and mutational spectrum of Mowat-Wilson syndrome.
Mowat-Wilson Syndrome is a recently delineated mental retardation syndrome usually associated with multiple malformations and a recognizable facial phenotype caused by defects of the transcriptional repressor ZFHX1B. To address the question of clinical and mutational variability, we analysed a large number of patients with suspected Mowat-Wilson Syndrome (MWS). Without prior knowledge of their mutational status, 70 patients were classified into "typical MWS", "ambiguous" and "atypical" groups according to their facial phenotype. Using FISH, qPCR and sequencing, ZFHX1B deletions, splice site or truncating mutations were detected in all 28 patients classified as typical MWS. No ZFHX1B defect was apparent in the remaining 15 cases with ambiguous facial features or in the 27 atypical patients. Genotype-phenotype analysis confirmed that ZFHX1B deletions and stop mutations result in a recognizable facial dysmorphism with associated severe mental retardation and variable malformations such as Hirschsprung disease and congenital heart defects. Our findings indicate that structural eye anomalies such as microphthalmia should be considered as part of the MWS spectrum. We also show that agenesis of the corpus callosum and urogenital anomalies (especially hypospadias) are significant positive predictors of a ZFHX1B defect. Based on our observation of affected siblings and the number of MWS cases previously reported, we suggest a recurrence risk of around 1%. The lack of missense mutations in MWS and MWS-like patients suggests there may be other, as yet unrecognized phenotypes, associated with missense mutations of this transcription factor.
Zweier
Christiane
C
Institute of Human Genetics, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.
Thiel
Christian T
CT
Dufke
Andreas
A
Crow
Yanick J
YJ
Meinecke
Peter
P
Suri
Mohnish
M
Ala-Mello
Sirpa
S
Beemer
Frits
F
Bernasconi
Sergio
S
Bianchi
Paolo
P
Bier
Andrea
A
Devriendt
Koen
K
Dimitrov
Boyan
B
Firth
Helen
H
Gallagher
Renata C
RC
Garavelli
Livia
L
Gillessen-Kaesbach
Gabriele
G
Hudgins
Louanne
L
Kääriäinen
Helena
H
Karstens
Susan
S
Krantz
Ian
I
Mannhardt
Anca
A
Medne
Livija
L
Mücke
Jürgen
J
Kibaek
Maria
M
Krogh
Lotte Nylandsted
LN
Peippo
Maarit
M
Rittinger
Olaf
O
Schulz
Solveig
S
Schelley
Susan L
SL
Temple
I Karen
IK
Dennis
Nick R
NR
Van der Knaap
Marjo S
MS
Wheeler
Patricia
P
Yerushalmi
Baruch
B
Zenker
Martin
M
Seidel
Heide
H
Lachmeijer
A
A
Prescott
Trine
T
Kraus
Cornelia
C
Lowry
R Brian
RB
Rauch
Anita
A
D000015:Abnormalities, Multiple / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D018388:Codon, Terminator / Q000235:genetics; D004247:DNA / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D005838:Genotype; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D012326:RNA Splicing; D012097:Repressor Proteins / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017384:Sequence Deletion; D013577:Syndrome; D000074165:Zinc Finger E-box Binding Homeobox 2
D018388:Codon, Terminator; D018398:Homeodomain Proteins; D012097:Repressor Proteins; C492363:ZEB2 protein, human; D000074165:Zinc Finger E-box Binding Homeobox 2; D004247:DNA