Molecular analysis of the CHD7 gene in CHARGE syndrome: identification of 22 novel mutations and evidence for a low contribution of large CHD7 deletions.
OBJECTIVE
Autosomal dominant CHARGE syndrome (OMIM no. 214800) is characterized by choanal atresia or cleft lip or palate, ocular colobomas, cardiovascular malformations, retardation of growth, ear anomalies, and deafness, and is caused by mutations in the CHD7 gene. Here, we describe the outcome of a molecular genetic analysis in 18 Finnish and 56 German patients referred for molecular confirmation of the clinical diagnosis of suspected CHARGE syndrome.


METHODS
Quantitative real-time polymerase chain reaction or multiplex ligation-dependent probe amplification assays did not reveal deletions in mutation negative cases, suggesting that larger CHD7 deletions are not a major cause of CHARGE syndrome.


RESULTS
In this group of 74 patients, we found mutations in 30 cases. 22 mutations were novel, including 11 frameshift, 5 nonsense, 3 splice-site, and 3 missense mutations. One de novo frameshift mutation was found in the last exon and is expected to result in a minimally shortened CHD7 polypeptide. Because the mutation is associated with a typical CHARGE syndrome phenotype, it may indicate the presence of an as yet unknown functional domain in the very carboxyterminal end of CHD7.


CONCLUSIONS
Our mutation detection rate of 40.5% is reflective of screening an unselected sample population referred for CHD7 testing based on suspected clinical diagnosis of CHARGE syndrome and not for having met strict clinical criteria for this disorder.
Vuorela
Pia
P
Department of Medical Genetics, University of Turku, Turku, Finland.
Ala-Mello
Sirpa
S
Saloranta
Carola
C
Penttinen
Maila
M
Pöyhönen
Minna
M
Huoponen
Kirsi
K
Borozdin
Wiktor
W
Bausch
Birke
B
Botzenhart
Elke M
EM
Wilhelm
Christian
C
Kääriäinen
Helena
H
Kohlhase
Jürgen
J
D000015:Abnormalities, Multiple / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D004265:DNA Helicases / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D017353:Gene Deletion; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D009154:Mutation; D016133:Polymerase Chain Reaction; D013577:Syndrome
D004268:DNA-Binding Proteins; D004265:DNA Helicases; C491434:CHD7 protein, human