Exon copy number alterations of the CHD7 gene are not a major cause of CHARGE syndrome and CHARGE-like syndrome

Department of Genetics, University Medical Center Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands.
European Journal of Medical Genetics (Impact Factor: 1.47). 05/2008; 51(5):417-25. DOI: 10.1016/j.ejmg.2008.03.003
Source: PubMed

ABSTRACT

CHARGE syndrome is a multiple congenital anomaly syndrome caused by mutations in the CHD7 gene. Mutations in this gene are found in 60-70% of patients suspected of having CHARGE syndrome. However, if only typical CHARGE patients are taken into account, mutations in the CHD7 gene are found in over 90% of cases. The remaining 10% might be caused by hitherto undetected alterations of the CHD7 gene, including whole exon duplications and deletions that are missed by the currently used diagnostic procedures. Therefore we looked for these kinds of alterations by multiplex ligation-dependent probe amplification in 54 patients suspected of having CHARGE syndrome without a CHD7 mutation. In one patient a partial deletion of the CHD7 gene (exons 13-38) was identified, while in the other patients no abnormalities were found. The frequency of exon deletions in our cohort was 1.9% (1/54) and 5.6% (1/18) in all patients and in typical CHARGE patients, respectively. We conclude that exon copy number alterations of the CHD7 gene are not a major cause of CHARGE and CHARGE-like syndrome.

Original article
Exon copy number alterations of the CHD7 gene
are not a major cause of CHARGE and
CHARGE-like syndrome
Jorieke E.H. Bergman
a,
*
, Ilse de Wijs
b
, Marjolijn C.J. Jongmans
b
,
Ronald J. Admiraal
c
, Lies H. Hoefsloot
b
,
Conny M.A. van Ravenswaaij-Arts
a
a
Department of Genetics, University Medical Center Groningen, P.O. Box 30.001,
9700 RB Groningen, The Netherlands
b
Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
c
Department of Otorhinolaryngology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
Received 18 December 2007; accepted 27 March 2008
Available online 4 April 2008
Abstract
CHARGE syndrome is a multiple congenital anomaly syndrome caused by mutations in the CHD7
gene. Mutations in this gene are found in 60e70% of patients suspected of having CHARGE syndrome.
However, if only typical CHARGE patients are taken into account, mutations in the CHD7 gene are found
in over 90% of cases. The remaining 10% might be caused by hitherto undetected alterations of the CHD7
gene, including whole exon duplications and deletions that are missed by the currently used diagnostic
procedures. Therefore we looked for these kinds of alterations by multiplex ligation-dependent probe am-
plification in 54 patients suspected of having CHARGE syndrome without a CHD7 mutation. In one pa-
tient a partial deletion of the CHD7 gene (exons 13e38) was identified, while in the other patients no
abnormalities were found. The frequency of exon deletions in our cohort was 1.9% (1/54) and 5.6%
(1/18) in all patients and in typical CHARGE patients, respectively. We conclude that exon copy number
alterations of the CHD7 gene are not a major cause of CHARGE and CHARGE-like syndrome.
Ó 2008 Elsevier Masson SAS. All rights reserved.
Keywords: CHARGE syndrome; CHD7; MLPA; Whole exon deletion; Whole exon duplication
* Corresponding author. Tel.: þ31 (0) 50 3617229; fax: þ31 (0) 50 3617231.
E-mail address: j.e.h.bergman@medgen.umcg.nl (J.E.H. Bergman).
1769-7212/$ - see front matter Ó 2008 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmg.2008.03.003
A
vailable online at www.sciencedirect.com
European Journal of Medical Genetics 51 (2008) 417e425
http://www.elsevier.com/locate/ejmg
+ MODEL
Page 1
1. Introduction
In 2004 the underlying gene defect for CHARGE syndrome (the CHD7 gene, OMIM
#214800) was identified on chromosome 8 (8q12.1) [16]. This multiple congenital anomaly
syndrome was originally described as a combination of coloboma, h eart defects, atresia of
choanae, retardation of growth and/or development, genital hypoplasia and ear anomalies
and/or deafness [12]. Later, additional congenital malformations were recognised, of which
agenesis of the semicircular canals and arhinencephaly were found to be present in nearly
all patients [1,2,13]. The prevalence is approximately 1 in 10,000. CHARGE syndrome is di-
agnosed on clinical grounds according to two different sets of criteria as proposed by Blake
et al. [5] and Verloes [15] , and/or analysis of the CHD7 (chromodomain helicase DNA binding
protein 7) gene. Three large, independent studies found heterozygous mutations in the CHD7
gene in 60e70% of patient s suspected of having CHARGE syndrome [3,8,10]. However, if the
clinical criteria for CHARGE syndrome [5,15] are strictly applied, mutations in CHD7 are pres-
ent in over 90% of the typical CHARGE patient s.
The two sets of criteria used for diagnosing CHARGE syndrome, consist of phenotypic fea-
tures that do not fully overlap (Table 1). Blake et al. consider a patient as having typical
CHARGE syndrome if four major, or three major and three minor, criteria are present [5].
Based on new diagnostic insights, Verloes refined the criteria and included abnor malities of
the semicircular canals [15]. Besides, Verloes distinguished three categories of CHARGE syn-
drome patients: typical, partial and atypical. Verloes considered typical CHARGE patients to
present with three major, or two major and two minor, criteria. Patients were considered to
have partial CHARGE syndrome when two major and one minor criteria were present, while
atypical CHARGE patients have two major and no minor criteria, or one major and two minor
criteria.
Table 1
Clinical criteria for identifying CHARGE syndrome patients
Major criteria Minor criteria Inclusion rule
Blake et al. [5] 1. Ocular coloboma or
microphthalmia
2. Choanal atresia or stenosis
3. Characteristic external ear
anomaly, or middle ear mal-
formations or mixed deafness
4. Cranial nerve dysfunction
1. Congenital cardiovascular
malformations
2. Tracheoesophageal defect
3. Genital hypoplasia or delayed
pubertal development
4. Cleft lip and/or palate
5. Developmental delay
6. Growth retardation
7. Characteristic face
Typical CHARGE: 4 majors,
OR 3 majors þ 3 minors
Verloes [15] 1. Ocular coloboma
2. Choanal atresia or stenosis
3. Hypoplasia of semicircular
canals
1. Heart or oesophagus
malformation
2. Malformation of the inner or
external ear
3. Rhombencephalic dysfunction
including sensorineural
deafness
4. Hypothalamo-hypophyseal
dysfunction
5. Mental retardation
Typical CHARGE: 3 majors,
OR 2 majors þ 2 minors
Partial CHARGE:2
majors þ 1 minor
Atypical CHARGE: 2 majors,
but no minors, OR 1
major þ 2 minors
418 J.E.H. Bergman et al. / European Journal of Medical Genetics 51 (2008) 417e425
Page 2
Most of the CHD7 mutations that have been described in CHARGE syndrome are truncating
(nonsense and frameshift), but missense mutations have also been found. Most mutations are
unique, although some recurrent de novo mutations have been found. There seem to be no
real mutation hot spots, but some exons (2, 3, 31 and 34) are more frequently mutated than
others (own unpublished data). The higher mutation frequency of these exons appears to be re-
lated to their size, with the largest exon 2 most frequently mutated. Until now, only one intra-
genic deletion has been reported in a CHARGE patient [14]. Whole gene deletions of CHD7,
although present in the two patients who contributed to the discovery of the CHD7 gene [16],
were not found in two large cohorts of CHARGE patients [8,10]. However, single exon deletion
or duplication would have been missed with the techniques used in these studies. Since the un-
derlying defect in the remaining 10% of typical CHARGE patients has not yet been discovered,
we hypothesised that exon copy number alterations of the CHD7 gene might cont ribute to
CHARGE syndrome. We identified a cohort of 54 patients (suspected of) having CHARGE
syndrome who did not have a CHD7 mutation. We screened for single exon deletion or dupli-
cation in the CHD7 gene using multiplex ligation-dependent probe amplification (MLPA).
2. Materials and methods
Fifty-four patients were selected from a group of patients who were referred for mutation
analysis of CHD7 because of clinical features suggestive of CHARGE syndrome. Mutation
screening performed by polymerase chain reaction (PCR) followed by direct sequencing had
not revealed any CHD7 alterations in these patients [8]. The DNA samples were subsequently
screened for exon deletions and/or duplications of the CHD7 gene by MLPA analysis. Half of
the patients (see Table 2) were analysed using home-designed synthetic oligonucleotides, cov-
ering all the coding exons of the CHD7 gene in four probe sets as described before [9]. The
other patients were screened with a commercially available set of probes, the SALSA P201
kit (MRC-Holland, Amsterdam, The Netherlands; http://www.mrc-holland.com). This set in-
cludes the usual control probes located on different chromosomes, together with probes for
most exons of the CHD7 gene (27 of 38 exons). When exons were located clos ely together,
one representative exon was chosen for the region. Because probes for both the first non-coding
exon (exon 1) and the last exon (exon 38, containing the stop codon) were included, both kits
would also have detected whole gene deletions.
The MLPA analysis as well as the statistical analysis was performed as described previously
[9]. A patient with a known heterozygous deletion of the whole gene was used as a positive
control, and we included two negative controls in each analysis.
Clinical information on the 54 index patients was obtained from our investigations at the
outpatient clinic for children with CHARGE syndrome or through the referring clinicians,
by means of a written questionnaire submitted prior to DNA analysis. Additional information
was requested whe n necessary. We scored patients for CHARGE features according to the two
sets of criteria (Bla ke et al. [5] and Verloes [15]) as summarised in Table 1. Patients were clas-
sified as typical CHARGE syndrome when they fulfilled the criteria for typical CHARGE of at
least one of the two scoring sets.
3. Results
In our cohort of 54 patients we found a deletion of exons 13e38 in patient no. 1 (Fig. 1). In
all o ther patient s no exon copy number changes in the CHD7 gene were found.
419J.E.H. Bergman et al. / European Journal of Medical Genetics 51 (2008) 417e425
Page 3
Table 2
Clinical features of 54 patients suspected of having CHARGE syndrome but with no mutation in the CHD7 gene
Case Sex
a
Age
b
(yr) Diagnostic criteria Major criteria Minor criteria
h
Blake Verloes
c
Eye anomaly
d
Atresia of choanae
e
Cranial nerve
dysfunction
f
Ear anomaly SSC
g
1M12 LD C VII, VIII, IX, X DDAN, B, CF, GH
2M2 þþ C, Mi (CLP) VIII þþMR, S
3* F 10 þþ C S VIII H, MR, RG, S
4* F 21 þþ C A VII, VIII þB, H, HHD, GH, MR, R
5* M 2 d þþ C, Mi (CLP) U þ U CF, H, S, TE
6F 3 þþ C S VIII þ UMR
7F 1 þþ e (CP) VIII þþCF,H,RG
8M10 þ aC VIII þ U B, CF, GH, MR
9F 7 þ a Mi A VIII þ UB,CF,MR,S
10* F 14 þ a e A VIII þ U H, MR, RG, S
11* M 3 þ a e A (CP) VIII þ UB,H,MR
12* F 4 þ aC VI, VII, VIII, IX, XII þ U CF,GH,H,MR
13* F 29 þ C, Mi A e þ UMR
14* F 6 þ C e þþH, MR, R, S
15 M 1 þ CA U þ UH
16 F 28 þ C, Mi A VIII U U H, MR, S
17 F 1/2 þ C, Mi
(CP) U þ UTE
18* M 3 þ C, Mi (CP) VIII U GH, MR
19 M 7 pC,Mi (CP) e þ U
20 F 4 p Mi S VIII þB
21 F 16 pC,Mi (CP) U U U H, RG
22 F 13 p C, Mi A U U U MR, RG
23* M 46 aC VIII þ UMR
24* M 1 a e A e þ U B, GH, H, R, S
25* F 3 a e A VIII þ UB,CF,MR
26* M 1/2 a e A VIII þ UH,S
27* M 2 aC e þ UH,MR,RG
28* M 36 aC VIII U B, GH, H, HHD
29* F 11 aC e U H, MR, R, S
30 M 39 aC,Mi e U H, MR, RG, S
31 M 11 d a e A e þ UB,CF,H
32* F 2 aMi (CLP)
e þ UB,H
420 J.E.H. Bergman et al. / European Journal of Medical Genetics 51 (2008) 417e425
Page 4
33* F 12 aC,Mi e þ U B, MR, RG
34* M 1/4 a e A e þ UB,H,R
35* F 29 a e A VII, VIII S, TE
36 F 4 a e A e þ U B, MR, RG
37* M 2 aC e H, MR
38* F 3 a e A e H, MR
39 M 4 a e A e þ U H, MR, RG
40 M 3 aC,Mi VIII U B, CF, H, R, RG
41 F 5 aC,Mi VIII U GH, H, MR, S
42 F 1 aC VIII U H, MR, S
43 F 11 aC,Mi e þ U GH, H, R, RG
44 F 8 aC e UH,MR
45 F 3 a e A VIII þH, MR, S
46 F 4 a e A (CP) e
þ UCF,H,MR,S
47 F 11 aC e þ UMR,RG
48 F 3 a e - (CP) e þ UH
49* F 22  e VIII þ U H, HHD, S
50* F 6  e VII, VIII þB, H, MR, TE
51* M 8  C, Mi e UH,R,RG
52* M 9  e A e UH
53 F 10  e VIII þ UCF,MR,R,S,TE
54 M 4  e (CLP) e UH,R
The patient with the partial CHD7 deletion is depicted in bold.
The patients that were screened with home-designed synthetic oligonucleotides are indicated with an asterisk. The other patients were analysed with the SALSA P201 MLPA
kit.
a
F: female; M: male.
b
d: day; yr: year.
c
a: atypical; p: partial.
d
C: coloboma; Mi: microphthalmia.
e
A: atresia of choanae; CLP: cleft lip and palate; CP: cleft palate; S: stenosis of choanae. Presence of CLP or CP was counted as a major criterion, because this rarely occurs
together with atresia of choanae [5].
f
U: unknown.
g
SSC: semicircular canal hypoplasia or vestibular dysfunction.
h
AN: anosmia; B: brain abnormalities; CF: characteristic face; H: heart defect; GH: genital hypoplasia; HHD: hypothalamo-hypophyseal dysfunction; MR: mental retar-
dation; R: renal abnormality; RG: retarded growth; S: skeletal abnormality; and TE: tracheoesophageal abnormalities.
421J.E.H. Bergman et al. / European Journal of Medical Genetics 51 (2008) 417e425
Page 5
An overview of the clinical features of patient no. 1 is given in Table 2 (see also Fig. 2). The
patient was born at 42 weeks of gestation with a birth weight of 3.685 kg. At birth right facial
nerve palsy and dysmorphic ears were noted. In addition he had partial palsy of cranial nerves
IX and X, for which he required tube feeding for 1 year. Choroid colobomas, hypoplasia of the
Normalised MLPA values
MLPA
p
robes
0
0.5
1
1.5
2
01-ex1
02-ex1
03-ex2
04-ex2
05-ex3
06-ex4
07-ex5
08-ex7
09-ex8
10-ex9
11-ex11
12-ex13
13-ex14
14-ex15
15-ex16
16-ex17
17-ex18
18-ex21
18-ex23
20-ex24
21-ex28
22-ex30
23-ex26
24-ex32
25-ex33
26-ex35
27-ex36
28-ex38
29-C5q31
30-C17p123
31-C15q21
32-C17q11
33-C17p13
34-C12p13
35-C1p36
36-C22q13
Fig. 1. Example of an MLPA analysis (SALSA P201 kit) with 13 different DNA samples from (suspected) CHARGE
patients. On the X-axis the probes of the different exons are named (01- till 28-, representing exon 1 till 38 of the CHD7
gene, and 29- till 36-, control probes that have two genomic copies in the normal population). On the Y-axis are the
normalised values (see Koolen et al. for details [9]), 1 means that two copies are present, 0.5 means that only one
copy is present. The sample marked with triangles is patient no. 1 with the partial deletion of the CHD7 gene involving
exon 13 till 38.
Fig. 2. Photographs of patient no. 1 with partial deletion of the CHD7 gene at 12 years and 3 months of age. Note square
face with facial palsy and microcornea (both right-sided), dysplastic ear with typical triangular concha and absence of
the ear lobe, and a flat midface.
422 J.E.H. Bergman et al. / European Journal of Medical Genetics 51 (2008) 417e425
Page 6
pons and vermis of the cerebellum, severe bilateral mixed hearing loss, undescended testes and
micropenis were present as well. At age 12 years, his height was 141.5 cm (2 SD). He had
a square and asymmetric face and proved to be anosmic by the University of Pennsylvania
Smell Identification Test [6]. Unfortunately, imaging of the semicircular canals was not per-
formed, but vestibular dysfunct ion was noted on physical examination.
Our cohort proved to be phenotypically heterogeneous, varying from typical CHARGE pa-
tients to partial and atypical patient s and patients only suspected of having CHARGE syn-
drome. Table 2 gives an overview of their clinical features and scores according to Blake’s
et al. and Verloes’ criteria. Eighteen patients had typical CHARGE syndrome (according to
Blake et al. (n ¼ 5), Verloes (n ¼ 7) or both (n ¼ 6)). Four patients had partial CHARGE, 26
had atypical CHARGE syndrome according to Verloes and six were suspected of having
CHARGE syndrome but did not satisfy either set of criteria.
4. Discussion
A defect in the CHD7 gene is found in 60e70% of all patients suspected of having
CHARGE syndrome and in over 90% of typical CHARGE patients [8]. In the remaining
10% of typical patients the cause of CHARGE syndrome remains elusive. Genetic heterogene-
ity could be present, but the only other gene that has been implicated in CHARGE syndrome,
the SEMA3E gene, was found to be mutated in only one CHARGE patient [11]. So far, muta-
tions in this gene have not been reported in other CHARGE patients. It seems therefore more
plausible to assume that CHD7 is the major causative gene, consi dering the small percentage of
typical patients in whom no mutation is found.
CHARGE patients normally undergo only a routine sequence analysis, which would miss
any mutations located deep in the introns or in the promoter region of the CHD7 gene. In ad-
dition, whole exon deletions or duplications would not be detected. Hitherto, only three
CHARGE patients have been described with a genomic rearrangement leading to a deletion
of the whole CHD7 gene [4,7,16]. Whole gene duplications are not likely to cause CHARGE
syndrome. Based on the mutat ions found so far (predominantly leading to a truncated protein)
and on the presumed function of CHD7, the identified mutations most likely have a loss-of-
function effect. This, however, does not rule out single exon duplication, which would result
in a distortion of the reading frame, as a cause of CHARGE syndrome.
So far no intragenic duplications and only one patient with an intragenic deletion of exons
8e12 has been reported [14]. The described intragenic deletion was detected by multiplex
PCR/liquid chromatography assay and appeared to have arisen through an Alu-mediated re-
placement event. This patient was one of a cohort of 13 typical CHARGE patients studied
by Udaka et al., which leads to an exon deletion frequency of 7.7% (1/13). Another study,
by Vuorela et al., did not find CHD7 deletions with quantitative real-time PCR and MLPA anal-
ysis in 44 CHD7 mutation negative patients [17]. Unfortunately they did not supply the clinical
characteristics of their patients and therefore it is no t known how many typical CHARGE pa-
tients were include d in their cohort.
In our cohort of 54 patients suspected of having CHARGE syndrome without CHD7 alter-
ations on routine sequencing, we found one patient with a deletion of exons 13e38. In the other
patients no exon copy number changes of the CHD7 gene were found by MLPA analysis. Our
patient with the partial CHD7 deletion could clinically not be distinguished from the patients
with normal MLPA results. One of the used MLPA kits (SALSA P201) did not cover all exons
of the CHD7 gene directly. However, exons missing in this MLPA kit are located close to exons
423J.E.H. Bergman et al. / European Journal of Medical Genetics 51 (2008) 417e425
Page 7
that are represented in the kit. Very small deletions or duplications (within exons) will be
missed using MLPA analysis in general, but bigger copy number variations are detectable
with both MLPA kits.
The frequency of exon deletions in our cohort was 1.9% (1/54) and 5.6% (1/18) in all pa-
tients and in typical CHARGE patients, respectively. The latter figure is in accordance with
the finding of Udaka et al. However, it should be noted that the classification of our CHARGE
patients is based on the available clinical information. Unfortunately in 42 patients imaging of
the semicircular canals has not been performed. This means that the 25 patients who satisfied
the Verloes’ criteria for atypical or partial CHARGE could in theory have typical CHARGE in
the presence of semicircular canal anomalies. If we take this precaution into account, the fre-
quency of partial CHD7 deletions in typical CHARGE patients without a mutation in CHD7 is
2.3e5.6% (1/43e1/18) according to our study.
Since we did not detect any exon copy number alterat ions in the 36 non-typical patients, it
seems that MLPA analysis of the CHD7 gene does not significantly improve the mutation anal-
ysis for this group of patients. In typical CHARGE patients however, we do recommend MLPA
analysis of the CHD7 gene, even though the frequency of partial CHD7 deletions is low. A thor-
ough clinical work-up is essential (e.g. imaging of semicircular canals) in order to classify pa-
tients as typical or non-typical CHARGE patients.
Acknowledgements
We thank Jackie Senior for her help in preparing this manuscript. Dr. Bergman was sup-
ported by a grant from the Nether lands Organisation for Health Research.
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    • "t al. [2008]); wg = whole gene; 0 = not mentioned in the online database. a Gennery et al., 2008. b Writzl et al., 2007. c Inoue et al., 2010. d Wincent et al., 2008. e Kaliakatsos et al., 2010. f Vuorela et al., 2007. g Vuorela et al., 2008. h Van de Laar et al., 2007. i Jongmans et al., 2006. j Hoover-Fong et al., 2009. k Vissers et al., 2004. l Bergman et al., 2011a. m Sanka et al., 2007. n Randall et al., 2009. o Chopra et al., 2008. * Atresia or stenosis of choanae. ** Only if necessitating tube feeding."
    [Show abstract] [Hide abstract] ABSTRACT: CHARGE (coloboma, heart defects, atresia of choanae, retardation of growth and development, genital hypoplasia, and ear abnormalities) and 22q11.2 deletion syndromes are variable, congenital malformation syndromes that show considerable phenotypic overlap. We further explored this clinical overlap and proposed recommendations for the genetic diagnosis of both syndromes. We described 2 patients clinically diagnosed with CHARGE syndrome, who were found to carry a 22q11.2 deletion, and searched the literature for more cases. In addition, we screened our cohort of CHD7 mutation carriers (n = 802) for typical 22q11.2 deletion features and studied CHD7 in 20 patients with phenotypically 22q11.2 deletion syndrome but without haploinsufficiency of TBX1. In total, we identified 5 patients with a clinical diagnosis of CHARGE syndrome and a proven 22q11.2 deletion. Typical 22q11.2 deletion features were found in 30 patients (30/802, 3.7%) of our CHD7 mutation-positive cohort. We found truncating CHD7 mutations in 5/20 patients with phenotypically 22q11.2 deletion syndrome. Differentiating between CHARGE and 22q11.2 deletion syndromes can be challenging. CHD7 and TBX1 probably share a molecular pathway or have common target genes in affected organs. We strongly recommend performing CHD7 analysis in patients with a 22q11.2 deletion phenotype without TBX1 haploinsufficiency and conversely, performing a genome-wide array in CHARGE syndrome patients without a CHD7 mutation.
    Full-text · Article · Jun 2013 · Molecular syndromology
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    • "CHD7 analysis was performed as previously described [Jongmans et al., 2006] and multiplex ligation-dependent probe amplification (MLPA) was performed if CHD7 sequence analysis did not identify a mutation [Bergman et al., 2008]. The GenBank accession number NM_017780.2 was used as reference sequence for the CHD7 gene. "
    [Show abstract] [Hide abstract] ABSTRACT: CHARGE syndrome is characterized by the variable occurrence of multisensory impairment, congenital anomalies, and developmental delay, and is caused by heterozygous mutations in the CHD7 gene. Correct interpretation of CHD7 variants is essential for genetic counseling. This is particularly difficult for missense variants because most variants in the CHD7 gene are private and a functional assay is not yet available. We have therefore developed a novel classification system to predict the pathogenic effects of CHD7 missense variants that can be used in a diagnostic setting. Our classification system combines the results from two computational algorithms (PolyPhen-2 and Align-GVGD) and the prediction of a newly developed structural model of the chromo- and helicase domains of CHD7 with segregation and phenotypic data. The combination of different variables will lead to a more confident prediction of pathogenicity than was previously possible. We have used our system to classify 145 CHD7 missense variants. Our data show that pathogenic missense mutations are mainly present in the middle of the CHD7 gene, whereas benign variants are mainly clustered in the 5' and 3' regions. Finally, we show that CHD7 missense mutations are, in general, associated with a milder phenotype than truncating mutations.
    Full-text · Article · Aug 2012 · Human Mutation
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    • "Seventeen families with multiple affected members due to a segregating CHD7 mutation have been reported to date [Bergman et al., 2011b; Delahaye et al., 2007; Jongmans et al., 2006, 2008; Lalani et al., 2006; Pauli et al., 2009; Vuorela et al., 2008; Wincent et al., 2008]. In addition, we identified a presumed pathogenic missense mutation (c.6221T>C; p.Leu2074Pro) in two sisters with KS, whose clinical features were previously reported by Levy and Knudtzon (1993). "
    [Show abstract] [Hide abstract] ABSTRACT: CHD7 is a member of the chromodomain helicase DNA-binding (CHD) protein family that plays a role in transcription regulation by chromatin remodeling. Loss-of-function mutations in CHD7 are known to cause CHARGE syndrome, an autosomal-dominant malformation syndrome in which several organ systems, for example, the central nervous system, eye, ear, nose, and mediastinal organs, are variably involved. In this article, we review all the currently described CHD7 variants, including 183 new pathogenic mutations found by our laboratories. In total, we compiled 528 different pathogenic CHD7 alterations from 508 previously published patients with CHARGE syndrome and 294 unpublished patients analyzed by our laboratories. The mutations are equally distributed along the coding region of CHD7 and most are nonsense or frameshift mutations. Most mutations are unique, but we identified 94 recurrent mutations, predominantly arginine to stop codon mutations. We built a locus-specific database listing all the variants that is easily accessible at www.CHD7.org. In addition, we summarize the latest data on CHD7 expression studies, animal models, and functional studies, and we discuss the latest clinical insights into CHARGE syndrome.
    Full-text · Article · Aug 2012 · Human Mutation
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