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CHARGE SYNDROME

CHARGE SYNDROME

Alternative titles; symbolsCHARGE ASSOCIATION--COLOBOMA, HEART ANOMALY, CHOANAL ATRESIA, RETARDATION, GENITAL AND EAR ANOMALIESHALL-HITTNER SYNDROME; HHSThere is...

Alternative titles; symbols

  • CHARGE ASSOCIATION--COLOBOMA, HEART ANOMALY, CHOANAL ATRESIA, RETARDATION, GENITAL AND EAR ANOMALIES
  • HALL-HITTNER SYNDROME; HHS

There is also evidence that the phenotype is caused by mutation in the semaphorin-3E gene (SEMA3E; 608166) on chromosome 7q21. One such patient has been reported.

Kallmann syndrome (HH5; 612370) is an allelic disorder with a less severe but overlapping phenotype.

▼ Description
CHARGE syndrome is characterized by a pattern of congenital anomalies including choanal atresia and malformations of the heart, inner ear, and retina (summary by Kallen et al., 1999).

▼ Clinical Features
Choanal atresia (see 608911) is a feature of the CHARGE association: coloboma of the eye; heart anomaly; atresia, choanal; retardation of mental and somatic development; microphallus; ear abnormalities and/or deafness (Pagon et al., 1981). Facial palsy, cleft palate, and dysphagia are commonly associated. The first descriptions of this syndrome were provided by Hall (1979) and Hittner et al. (1979). Hall (1979) reported a constellation of nonrandomly associated malformations occurring with choanal atresia. Hittner et al. (1979) reported 10 individuals, including a mother and child, with colobomatous microphthalmia, heart disease, abnormalities of the external ear with associated hearing loss, and mental retardation. They noted that multiple other anomalies may be associated.

Koletzko and Majewski (1984) described 6 patients with choanal atresia and additional malformations and reviewed 11 previously reported cases. Their findings validated the CHARGE association but suggested the inclusion of orofacial clefts and esophageal atresia as main features. A certain degree of dysmorphism (low-set and dysplastic ears, retrogenia, antimongoloid slant of palpebral fissures, anteverted nares) was observed in each of their 6 patients. Infants with bilateral choanal atresia plus cardiac defects and those with choanal atresia plus renal malformations had a high mortality rate. Recurrence risk is low.

Davenport et al. (1986) described 15 cases, 9 sporadic and 6 familial. They concluded that CHARGE is a recognizable pattern of malformations and a true syndrome rather than an association. They pointed to external ear malformations (see their photographs) and a 'wedge-shaped' audiogram that may be unique features valuable in diagnosis. Mixed conductive and sensorineural deafness causes an audiogram with a descending bone conduction curve intersecting at low frequencies with a flat curve for air conduction. Congenital facial paralysis occurs in few other conditions. Feeding difficulties are striking even in the absence of cleft palate or tracheoesophageal fistula.

Metlay et al. (1987) reported a patient with CHARGE syndrome as manifested by coloboma of the optic nerve head, congenital heart defect (ASD, VSD, and parachute mitral valve), choanal atresia, severe growth retardation, genital hypoplasia, abnormal ears, cleft lip and palate, and pectus carinatum. He died at 19 months of age. His mother was short and had hearing impairment, choanal atresia, and a coloboma of the left iris. Reported familial cases were tabulated. Tetralogy of Fallot is the most frequent type of heart defect reported in the CHARGE association (Cyran et al., 1987). Ivarsson et al. (1988) reported supravalvular and peripheral pulmonary stenosis in a patient with CHARGE association who also had an atrial septal defect.

Oley et al. (1988) described 14 boys and 6 girls, including monozygotic twins, who all had at least 4 of the 7 major features included in the mnemonic CHARGE. All had ear anomalies or deafness or both and either coloboma or choanal atresia or both. All the boys had evidence of hypogonadism. Many had a characteristic facial appearance: unusually shaped ears, unilateral facial palsy, square face, malar flattening, and pinched nostrils. All were sporadic cases.

Hurst et al. (1989) reported a brother and sister who had atrial septal defect and ventricular septal defect, short stature, microcephaly, developmental delay, and similar dysmorphic facial appearance. The boy had bilateral choanal hypoplasia and stenosis, and Hurst et al. (1989) suspected that the girl had mild choanal stenosis because she had problems in feeding and sucking in the first few months of life. Bialer and Brown (1990) argued that the diagnosis was indeed the CHARGE association in the case of the sibs reported by Hurst et al. (1989).

Meinecke et al. (1989) described the rare association of cutaneous syndactyly and nail hypoplasia with the more frequent features of the CHARGE syndrome.

Blake et al. (1990) reviewed the clinical experience of 50 patients with CHARGE syndrome. Lin et al. (1990) reviewed 136 patients from the literature and added 8 more. In 47 of these, either a postmortem examination or a computerized axial tomography of the head had been performed. Of the 47, 26 (55%) had definite central nervous system malformations, predominantly forebrain anomalies, particularly arhinencephaly and holoprosencephaly. The presence of CNS malformation was most strongly associated with choanal atresia.

Van Meter and Weaver (1996) reported 2 infants (a male and a female) with significant overlap of symptoms of CHARGE association and Goldenhar anomaly (164210). In addition, both infants had plagiocephaly and torticollis, and the boy had cleft lip, heminostril, and tracheoesophageal fistula. The authors suggested that deficiency in migration of neural crest cells, deficiency of mesodermal formation, or defective interaction between neural crest cells and mesoderm may explain the pathogenesis of these defects of blastogenesis.

Tellier et al. (1998) evaluated 47 CHARGE patients for the frequency of major anomalies, namely, coloboma (79%), heart malformation (85%), choanal atresia (57%), growth and/or mental retardation (100%), genital anomalies (34%), ear anomalies (91%), and/or deafness (62%). In addition, they commented on anomalies observed frequently in neonates and infants with the CHARGE syndrome, including minor facial anomalies, neonatal brainstem dysfunction with cranial nerve palsy, and internal ear anomalies such as semicircular canal hypoplasia, which was found in each patient that could be tested. Criteria for poor survival were thought to include male gender, central nervous system and/or esophageal malformations, and bilateral choanal atresia. A significantly higher mean paternal age at conception together with concordance in monozygotic twins and the existence of rare familial cases supported the role of genetic factors such as de novo dominant mutation or subtle submicroscopic chromosome rearrangement.

The G of the CHARGE association represents genital hypoplasia, which is typically recognized only in males (micropenis/cryptorchidism). On the basis of 9 individuals with CHARGE association, Wheeler et al. (2000) identified hypogonadotropic hypogonadism, manifested by hypogenitalism and gonadotropins at or below minimal detectable levels at ages when these hormones should be readily measurable. The authors suggested that central hypogonadism is responsible not only for the genital hypoplasia in male patients but also for the lack of secondary sexual development in patients of both sexes. Measurement of serum luteinizing hormone (see 152780) and follicle-stimulating hormone (see 136530) in infants may help establish the diagnosis; these determinations in teenagers with CHARGE association can result in early diagnosis of hypogonadotropic hypogonadism, allowing for treatment of hormonal deficiencies and minimization of potential secondary psychosocial and medical problems.

Sanlaville et al. (2006) examined 10 fetuses from pregnancies that were terminated due to severe malformations seen on ultrasound; all of the fetuses had truncating mutations of the CHD7 gene. They identified 3 constant features: anomalies of the external ear, agenesis or hypoplasia of the semicircular canals, and arhinencephaly. Features occurring in at least 7 of 10 cases included genital anomalies, thymic hypoplasia, ocular coloboma, CNS anomalies other than arhinencephaly, choanal atresia or cleft palate, and heart defects. Sanlaville et al. (2006) concluded that semicircular canal agenesis and arhinencephaly are highly predictive diagnostic criteria for CHARGE syndrome, and suggested that they be added to the major diagnostic criteria for the disorder.

Vervloed et al. (2006) studied associations between behavior and medical problems in 27 patients with CHARGE syndrome and found that of all medical conditions, only the presence or absence of heart defects and cardiac surgery could differentiate between the patients with regard to the number of behavioral problems. Long hospital stays were associated with less problem behavior. Cerebral and heart problems did not result in longer hospital stays, whereas esophageal reflux did. The study did not confirm a significant association between medical conditions and autism found in previous studies. Vervloed et al. (2006) noted that while heart surgery and hospitalization may be protective factors, related variables such as reduced vitality or altered parent-child interactions after heart surgery may be the actual cause.

Delahaye et al. (2007) reported 2 unrelated families with dominant transmission of CHARGE syndrome due to pathogenic CHD7 mutations. In both families, the syndrome was phenotypically identified in 1 parent with very mild signs only after the diagnosis of their affected children, who had severe manifestations. Although detailed studies were not performed, the authors suggested that somatic mosaicism may have occurred in the parents. The report emphasized the intrafamilial variability of the syndrome.

By analyzing physician-completed questionnaires based on 99 CHARGE patients in Canada, Blake et al. (2008) found that 92% of patients exhibited symptoms of at least 1 cranial nerve anomaly, and 72% had involvement of more than 1. Involvement of CN IX and X was the most common (68.7%), followed by CN VIII auditory (56.6%), CN V (55.6%), CN VII (31.3%), and CN VIII vestibular (22.2%). Blake et al. (2008) suggested that involvement of some of these nerves may underlie the sucking, chewing, and swallowing difficulties often observed in patients with CHARGE syndrome.

In 3 of 36 patients with an initial clinical diagnosis of Kallmann syndrome, Jongmans et al. (2009) identified de novo heterozygous mutations in the CHD7 gene. Further evaluation of the 3 patients showed that each had additional clinical features consistent with CHARGE syndrome, including deafness, tooth agenesis, dysmorphic ears, coloboma, and short stature. Jongmans et al. (2009) concluded that patients with anosmia and/or hypogonadotropic hypogonadism should be screened for additional clinical features of CHARGE syndrome.

Layman et al. (2009) noted that olfactory defects and olfactory bulb hypoplasia have been previously reported in individuals with CHARGE syndrome. In 5 of 8 individuals with CHARGE due to confirmed CHD7 mutations, they found severe defects in olfaction on the Brief Smell Identification Test (BSIT). Of note, 3 CHARGE patients with mutation in exon 33 of the CHD7 gene did well on the olfaction test, scoring at or near normal.

In 3 members of a Finnish family with CHARGE syndrome, Vuorela et al. (2008) identified a nonsense mutation in the CHD7 gene (608892.0017). The male infant proband and a male fetus from a second pregnancy both had absence of the olfactory bulbs in addition to other features consistent with CHARGE syndrome. The male infant, who died at 3 months of age, also had marked isomerism of the liver with significant symmetry of the right side-appearing lobes and a midline gallbladder, as well as extrahepatic bile duct obstruction and significant hyporotation of the intestines. Their father, in whom the mutation was found in peripheral blood lymphocytes and in buccal cells, had minimal findings, with left-sided conductive hearing loss, a dysplastic, cup-shaped right external ear, slightly asymmetric face, and nonspecific degenerative retinal lesion of the right eye. Vuorela et al. (2008) concluded that a healthy or nearly healthy parent of a CHARGE child may carry a CHD7 mutation, which has implications for genetic counseling.

▼ Other Features
Writzl et al. (2007) reported 2 unrelated infants with genetically confirmed CHARGE syndrome who also had lymphopenia with almost absent T cells. Studies in 1 patient showed no proliferative response to phytohemagglutinin. Both patients also had hypocalcemia and hypothyroidism, and 1 had a hypoplastic thymus. Both patients died within the first month of life. A literature review found 15 patients with features of CHARGE syndrome who also had immune defects. Most of these patients had a T cell-specific defect and thymic aplasia or hypoplasia with poor proliferative response; some had low Ig levels, indicating a humoral defect. Writzl et al. (2007) concluded that newborns with CHARGE syndrome may have severe T-cell abnormalities.

Van de Laar et al. (2007) reported 3 unrelated patients with several major features of CHARGE syndrome, 1 of whom fulfilled the diagnostic criteria proposed by Verloes (2005), who also presented severe limb anomalies, including monodactyly, tibia aplasia, and bifid femora. Van de Laar et al. (2007) suggested that limb defects should be added to the spectrum of manifestations of CHARGE syndrome.

Alazami et al. (2008) reported a girl, born of consanguineous Saudi Arabian parents, with CHARGE syndrome confirmed by genetic analysis of the CHD7 gene. The patient had typical features of the disorder, including coloboma, patent ductus arteriosus, choanal atresia, growth and psychomotor retardation, and hearing loss with cup-shaped ears. She had dysmorphic facial features. In addition, she had right clubfoot deformity, agenesis of the right tibia, and near bifurcation of the right distal femur. The mother had been exposed to ciprofloxacin for 2 weeks before realizing she was pregnant, which may have contributed to the severity of the phenotype. However, Alazami et al. (2008) concluded that anomalies of the extremities should be included as another feature of the disorder, and suggested that the 'E' in CHARGE syndrome reflect this involvement.

Burkitt Wright et al. (2009) reported an infant girl diagnosed with CHARGE syndrome on the basis of choanal atresia, ventricular and atrial septal defects, coarctation of the aorta, facial asymmetry, ear abnormalities, and retinal colobomata. She later manifested severe global developmental delay. At delivery, she was noted to have right radial aplasia and absent thumb. The left arm was of normal length, but the left thumb had a stiff distal interphalangeal joint, suggesting mild abnormalities. Radiographs of the right arm showed absent radius and pollux, severely bowed ulna, and radial club hand. Molecular analysis identified a de novo heterozygous frameshift mutation in the CHD7 gene, resulting in haploinsufficiency. Burkitt Wright et al. (2009) noted that their report and that of Van de Laar et al. (2007), who described CHARGE syndrome patients with severe limb anomalies including monodactyly, tibia aplasia, and bifid femora, suggested that limb defects should be added to the spectrum of manifestations of CHARGE syndrome.

▼ Population Genetics
With an estimated birth incidence of 1 in 12,000, CHARGE syndrome is a common cause of congenital anomalies (Kallen et al., 1999).

In a national surveillance study in Canada, Issekutz et al. (2005) found that the national incidence of CHARGE syndrome was 3.5 in 100,000 live births, but the incidence in the Atlantic provinces of Newfoundland, Labrador, and the Maritime Provinces, was as high as 1 in 8,500 live births.

▼ Pathogenesis
Bajpai et al. (2010) demonstrated that, in both humans and Xenopus, CHD7 (608892) is essential for the formation of multipotent migratory neural crest, a transient cell population that is ectodermal in origin but undergoes a major transcriptional reprogramming event to acquire a remarkably broad differentiation potential and ability to migrate throughout the body, giving rise to craniofacial bones and cartilages, the peripheral nervous system, pigmentation, and cardiac structures. Bajpai et al. (2010) demonstrated that CHD7 is essential for activation of the neural crest transcriptional circuitry, including SOX9 (608160), TWIST (601622), and SLUG (602150). In Xenopus embryos, knockdown of Chd7 or overexpression of its catalytically inactive form recapitulates all major features of CHARGE syndrome. In human neural crest cells, CHD7 associates with PBAF (see 606083) and both remodelers occupy a neural crest-specific distal SOX9 enhancer and a conserved genomic element located upstream of the TWIST1 gene. Consistently, during embryogenesis CHD7 and PBAF cooperate to promote neural crest gene expression and cell migration. Bajpai et al. (2010) concluded that their work identified an evolutionarily conserved role for CHD7 in orchestrating neural crest gene expression programs, provided insights into the synergistic control of distal elements by chromatin remodelers, illuminated the pathoembryology of CHARGE syndrome, and suggested a broader function for CHD7 in the regulation of cell motility.

Van Nostrand et al. (2014) found that a knockin mutant mouse strain expressing a stabilized and transcriptionally dead variant of the tumor suppressor protein p53 (TP53; 191170), p53(25,26,53,54), along with a wildtype allele of p53, revealed late gestational embryonic lethality associated with a host of phenotypes characteristic of CHARGE syndrome (214800), including coloboma, inner and outer ear malformations, heart outflow tract defects, and craniofacial defects. Van Nostrand et al. (2014) also found that the p53(25,26,53,54) mutant protein stabilized and hyperactivated wildtype p53, which then inappropriately induced its target genes and triggered cell cycle arrest or apoptosis during development. Importantly, these phenotypes were only observed with a wildtype p53 allele, as p53(25,26,53,54)-null embryos were fully viable. Furthermore, Van Nostrand et al. (2014) found that CHD7 can bind to the p53 promoter, thereby negatively regulating p53 expression, and that CHD7 loss in mouse neural crest cells or in samples from patients with CHARGE syndrome results in p53 activation. Strikingly, Van Nostrand et al. (2014) found that p53 heterozygosity partially rescued the phenotypes in Chd7-null mouse embryos, demonstrating that p53 contributes to the phenotypes that result from CHD7 loss. The authors concluded that inappropriate p53 activation during development can promote CHARGE phenotypes, supporting the idea that p53 has a critical role in developmental syndromes and providing insight into the mechanisms underlying CHARGE syndrome.

▼ Diagnosis
An analysis by Harris et al. (1997) of choanal atresia-associated malformations, present in 47% of the infants studied without chromosome anomalies, indicated that a weak, nonrandom association can be demonstrated between the malformations of the CHARGE complex. If the definition of CHARGE is the presence of 3 or more malformations, then of the 444 infants identified, 7% belonged to the CHARGE constellation. Harris et al. (1997) concluded that for the term CHARGE to be meaningful, it should be restricted to infants with multiple malformations and choanal atresia and/or coloboma, combined with other cardinal malformations (heart, ear, and genital), for a total of at least 3 cardinal malformations; growth retardation, especially low birth weight, should not be used in the definition.

Verloes (2005) proposed diagnostic criteria for CHARGE syndrome. The 3 major signs were coloboma, choanal atresia, and semicircular canal anomalies, and the 5 minor signs were rhombencephalic abnormalities, hypothalamo-hypophyseal dysfunction, external/middle ear malformations, mediastinal visceral malformations, and mental retardation.

Blake et al. (2008) stated that cranial nerve involvement is now considered 1 of the 4 major criteria for a clinical diagnosis of CHARGE syndrome. The other 3 key diagnostic indicators are coloboma, choanal atresia, and characteristic ear anomalies.

▼ Cytogenetics
Kushnick et al. (1992) reported an infant girl with the findings of CHARGE association, a 46,XY karyotype, and absence of gonads. Absence of ZFY by DNA probe was also found. Emanuel et al. (1992) found evidence of microdeletion in the 22q11.2 region in 1 of 18 patients with the CHARGE syndrome. This contrasted with microdeletion in 14 of 15 cases of velocardiofacial syndrome (192430) and in 4 of 9 patients with isolated conotruncal cardiac malformations (217095). Devriendt et al. (1998) described the case of a female child with features of the CHARGE association, including iris coloboma, large ventricular septal defect, external ear abnormalities, severe growth retardation, and moderate mental delay, associated with a submicroscopic deletion in 22q11 detected by means of fluorescence in situ hybridization. Since there were features of the velocardiofacial syndrome and cat-eye syndrome, the presence of a more complex rearrangement of 22q, with a deletion duplication, was suspected.

North et al. (1995) described a 4.5-year-old girl with CHARGE association who had a de novo inverted duplication (14)(q22-q24.3). Clinical features included iris colobomas, ventricular septal defect, soft tissue choanal atresia, intellectual impairment, growth retardation, sensorineural deafness, apparently low-set ears, and upslanting palpebral fissures. Family history was unremarkable and parental chromosomes were normal. North et al. (1995) compared the findings in their case with those in 5 reported cases of 14q duplication. Although none of the other cases had choanal atresia, the other findings were such as to suggest that a gene or genes causing some of the anomalies of CHARGE association may reside in the region 14q22-q24.3.

Hurst et al. (1991) reported a girl with CHARGE syndrome and an apparently balanced chromosome 8 translocation. She had bilateral retinal coloboma, tetralogy of Fallot, unilateral choanal atresia, abnormalities of the external ears, bilateral sensorineural deafness, unilateral facial nerve palsy, and tracheoesophageal fistula. Parental karyotypes were normal.

▼ Inheritance
Tellier et al. (1996) found a significant increase in mean paternal age at birth of 41 CHARGE patients (33.7 +/- 8 years) as compared with the control population (30.8 +/- 5 years), suggesting the possible role of a dominant mutation or a subtle chromosomal abnormality. Maternal age was not significantly different in patients and controls.

Lalani et al. (2006) presented 5 pedigrees with CHARGE syndrome illustrating 4 familial cases and an affected pair of monozygotic twins. CHD7 mutations were identified in a family with affected brother and sister, in the monozygotic twins, and in a family with mildly affected mother and daughter. In the case of the affected brother and sister, parental gonadal mosaicism was suspected.

Jongmans et al. (2008) reported 5 unrelated families with CHARGE syndrome confirmed by genetic analysis. Two families with the same mutation (608892.0011) showed clear parent-to-child transmission, with the parent being less severely affected than the children. In a third family, the clinically unaffected father was found to be somatic mosaic for a mutation that was present in both affected children. Two sibs were affected in each of the last 2 families, but no mutations were identified in the parents, suggesting germline mosaicism. There was wide phenotypic variability, even among family members with the same mutation.

To determine the parental origin of CHD7 mutations in sporadic CHARGE syndrome, Pauli et al. (2012) identified an informative exonic or intronic polymorphism near the detected CHD7 mutation in 13 families and performed linkage analysis between the CHD7 mutation and the polymorphism in the affected child. In 12 of the 13 families, the mutation affected the paternal allele (92.3%). The paternal origin of the mutation was found for all mutation types. No paternal age effect was found in their cohort.

▼ Molecular Genetics
Using an improved method of array comparative genomic hybridization (CGH), Vissers et al. (2004) reported a 2.3-Mb de novo overlapping microdeletion on chromosome 8q12 in 2 individuals with CHARGE syndrome. Sequence analysis of genes located in this region detected mutations in CHD7 (see, e.g., 608892.0001-608892.0004) in 10 of 17 individuals with CHARGE syndrome who did not have microdeletions, thus accounting for the disease in most affected persons. An individual with CHARGE syndrome with an apparently balanced chromosome 8 translocation had been reported by Hurst et al. (1991).

Lalani et al. (2006) sequenced the CHD7 gene in 110 individuals who had received a clinical diagnosis of CHARGE syndrome, and detected mutations in 64 (58%). Phenotypically, the mutation-positive group was more likely to exhibit cardiovascular malformations, coloboma of the eye, and facial asymmetry, often caused by seventh cranial nerve abnormalities. Microarray gene expression analysis showed a signature pattern of gene expression differences that distinguished the individuals with CHARGE syndrome with CHD7 mutations from controls.

Jongmans et al. (2006) identified mutations in the CHD7 gene in 69 of 107 patients with clinical features suggestive of CHARGE syndrome. The authors stated that there were no genotype-phenotype correlations in this cohort and noted that there were differences in clinical presentation even in sib pairs with identical mutations (see 608892.0008). Somatic mosaicism was detected in the unaffected mother of a sib pair, supporting the existence of germline mosaicism.

Udaka et al. (2007) assessed exon copy number using multiplex PCR/liquid chromatography (MP/LC) in 13 classic CHARGE patients in whom screening by DHPLC had failed to identify point mutations or small insertions/deletions in the CHD7 gene. They found a de novo deletion in 1 patient (608892.0010); the authors stated that this was the first CHARGE patient to have exonic deletion of CHD7.

Van de Laar et al. (2007) reported 3 unrelated patients with several major features of CHARGE syndrome, 1 of whom fulfilled the diagnostic criteria proposed by Verloes (2005), who also presented severe limb anomalies, including monodactyly, tibia aplasia, and bifid femora. Three different heterozygous truncating mutations in the CHD7 gene were detected, respectively (see, e.g., 608892.0016). Van de Laar et al. (2007) suggested that limb defects should be added to the spectrum of manifestations of CHARGE syndrome.

Kim et al. (2008) analyzed the CHD7 gene in 197 patients with Kallmann syndrome or normosmic hypogonadotropic hypogonadism (see HH5; 612370) and identified 7 sporadic heterozygous mutations in 3 KS patients and 4 IHH patients, respectively (see, e.g., 608892.0012-608892.0015). A missense mutation (608892.0012) that was found in a male patient with IHH, cleft lip, and cryptorchidism had previously been reported by Delahaye et al. (2007) in a mother and 2 sons from a family with both typical and atypical CHARGE syndrome phenotypes, and a splice site mutation (608892.0013) in a female KS patient with cleft lip and palate and hearing loss had previously been reported by Jongmans et al. (2008) in 2 brothers with 'relatively mild' CHARGE syndrome. Kim et al. (2008) concluded that both normosmic IHH and Kallmann syndrome due to CHD7 mutations are mild allelic variants of CHARGE syndrome.

Bergman et al. (2008) excluded copy number alterations of the CHD7 gene as a major cause of CHARGE syndrome. Among 54 patients suspected of having the disorder in whom CHD7 mutations were not found, multiplex ligation-dependent probe amplification (MLPA) analysis detected only 1 (1.9%) who had a large CHD7 gene alteration, which was a partial deletion encompassing exons 13 to 38.

Wincent et al. (2008) identified CHD7 mutations in 18 (64%) of 28 Swedish index patients with CHARGE syndrome. Thirteen of the mutations were novel, and 3 (17%) were large deletions. The changes were de novo in all 15 cases in which parental samples were available for testing. No clear genotype/phenotype correlations were observed.

Mutation in the SEMA3E Gene

In a patient originally described by Martin et al. (2001) with CHARGE syndrome and a de novo balanced translocation involving chromosomes 2 and 7, Lalani et al. (2004) mapped the translocation breakpoints and identified the semaphorin-3E gene within 200 kb of the breakpoint on 7q21.11. Screening of patients with CHARGE syndrome for mutations in the SEMA3E gene revealed a de novo mutation in an unrelated patient (S703L; 608166.0001). The mutation was not found in either parent or in 338 ethnically matched control chromosomes.

Exclusion Studies

Since PAX2 (167409) gene expression occurs in primordia affected in CHARGE association, Tellier et al. (2000) analyzed the PAX2 gene in 34 patients fulfilling diagnostic criteria for CHARGE. The authors used 2 polymorphisms to look for deletions, and SSCP of the 12 exons to look for nucleotide variations. No disease-causing mutations were identified, suggesting that mutation of the PAX2 gene is not a common cause of CHARGE association. The authors suggested that the expression pattern of PAX2 is consistent with the possibility that unidentified PAX2 downstream targets and effectors could be candidate genes for CHARGE.

▼ Animal Model
Bosman et al. (2005) identified Chd7 mutations in 9 mouse lines generated by N-ethyl-N-nitrosourea (ENU) mutagenesis. There was widespread expression of Chd7 in early development of the mouse in organs affected in CHARGE syndrome, including eye, olfactory epithelium, inner ear, and vascular system. Closer inspection of heterozygous mutant mice revealed a range of defects with reduced penetrance, such as cleft palate, choanal atresia, septal defects of the heart, hemorrhages, prenatal death, vulva and clitoral defects, and keratoconjunctivitis sicca. Many of these defects mimic the features of CHARGE syndrome.

Layman et al. (2009) found that Chd7 +/- mice had a loss of odor-evoked electroolfactogram responses, suggesting that reduced olfaction is due to a dysfunctional olfactory epithelium. Chd7 expression was high in basal olfactory epithelial neural stem cells and downregulated in mature olfactory sensory neurons. Chd7-deficient mice exhibited smaller olfactory bulbs, reduced olfactory sensory neurons, and disorganized epithelial ultrastructure, despite apparently normal functional cilia and sustentacular cells. Significant reductions in the proliferation of neural stem cells and regeneration of olfactory sensory neurons in the mature Chd7 +/- olfactory epithelium suggested critical roles for Chd7 in regulating neurogenesis.

Gage et al. (2015) generated conditional tissue-specific Chd7 mouse mutants to determine the relative contributions of CHD7 function in neural versus surface ectoderm during early eye morphogenesis. CHD7 was present in the neural ectoderm and surface ectoderm of the eye. Deletion from neural and surface ectoderm resulted in severely dysmorphic eyes generally lacking recognizable optic cup structures. Deletion from the neural ectoderm resulted in similar defects. Deletion from the surface ectoderm resulted in eyes with smaller lenses. Lens tissue and the major subdivisions of the neural ectoderm were present following conditional deletion of Chd7 from the neural ectoderm. Closure of the optic fissure depended on the Chd7 gene dose within the neural ectoderm.

▼ History
The syndrome reported by Abruzzo and Erickson (1977), and cited as an instance of familial CHARGE syndrome by Davenport et al. (1986) and Metlay et al. (1987), was found to be a distinct X-linked disorder (302905).

Tags: 7q21.11, 8q12.2

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