Alternative titles; symbols
HGNC Approved Gene Symbol: CHD7
SNOMEDCT: 47535005;
Cytogenetic location: 8q12.2 Genomic coordinates (GRCh38) : 8:60,678,740-60,868,028 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 8q12.2 | CHARGE syndrome | 214800 | Autosomal dominant | 3 |
| Hypogonadotropic hypogonadism 5 with or without anosmia | 612370 | Autosomal dominant | 3 |
CHD7 is a transcriptional regulator that binds to enhancer elements in the nucleoplasm. CHD7 also functions as a positive regulator of ribosomal RNA (rRNA) biogenesis in the nucleolus (summary by Zentner et al., 2010).
By sequencing clones obtained from an adult brain cDNA library, Nagase et al. (2000) cloned CHD7, which they designated KIAA1416. The deduced protein contains 1,967 amino acids. RT-PCR ELISA detected intermediate to low expression in all tissues and specific brain regions examined. Highest expression was in brain, kidney, and skeletal muscle.
Using in situ hybridization, Sanlaville et al. (2006) analyzed the expression pattern of the CHD7 gene during early human development in normal human embryos and fetal tissues obtained after elective termination of pregnancy and found that CHD7 is widely expressed in undifferentiated neuroepithelium and in mesenchyme of neural crest origin. Towards the end of the first trimester it is expressed in dorsal root ganglia, cranial nerves and ganglia, and auditory, pituitary, and nasal tissues as well as in the neural retina. Sanlaville et al. (2006) noted that there was good correlation between the CHD7 expression pattern and the developmental anomalies observed in CHARGE syndrome (214800).
By immunofluorescence analysis and subcellular fractionation of DLD1 human colorectal cancer cells, Zentner et al. (2010) found that CHD7 localized to both the nucleolus and nucleoplasm.
Bajpai et al. (2010) demonstrated that, in both humans and Xenopus, CHD7 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.
Hundreds of tandemly duplicated rRNA genes are clustered into repeated arrays known as nucleolar organizer regions on the p arms of chromosomes 13, 14, 15, 21, and 22. Zentner et al. (2010) found that CHD7 specifically associated with hypomethylated, active rDNA at multiple sites along the rDNA loci in both DLD1 human colorectal cancer cells and mouse embryonic stem cells. Small interfering RNA-mediated depletion of CHD7 resulted in hypermethylation of the rDNA promoter and concomitant reduction of 45S pre-rRNA (see 180450), as well as reduced protein synthesis and cell proliferation. In contrast, overexpression of CHD7 caused increased levels of 45S pre-rRNA compared with controls. Levels of 45S pre-rRNA were also reduced in both Chd7 +/- and Chd7 -/- mouse embryonic stem cells and in Chd7 -/- embryos and tissues dissected from Chd7 +/- embryos. In Chd7 -/- cells, absence of Chd7 impaired the ability of Tcof1 (606847) to bind rDNA. Zentner et al. (2010) concluded that CHD7 functions as positive regulator of both nucleoplasmic and nuclear genes.
Using immunoprecipitation and mass spectrometry, Engelen et al. (2011) identified Chd7 among 50 proteins that interacted with epitope-tagged Sox2 (184429) in mouse neural stem cells. Reverse immunoprecipitation and protein pull-down experiments confirmed direct interaction between Sox2 and Chd7. Knockdown of Sox2 or Chd7 via short hairpin RNA revealed an overlapping set of target genes. Sequencing of DNA bound by Sox2 and Chd7 in chromatin immunoprecipitation experiments and analysis of genes disrupted by knockdown of Sox2 or Chd7 revealed that the 2 proteins cooperated in gene activation. Engelen et al. (2011) concluded that Chd7 is an important Sox2 cofactor.
Using a yeast 2-hybrid library screen, Batsukh et al. (2010) identified CHD8 (610528) as an interacting partner of CHD7. In a direct yeast 2-hybrid system, the CHD7-CHD8 interaction was disrupted by CHD7 missense mutations found in CHARGE patients, including gly2108 to arg (608892.0011), whereas in coimmunoprecipitation studies disruption of the CHD7-CHD8 interaction by the mutations could not be observed. The authors hypothesized that CHD7 and CHD8 proteins interact directly and indirectly via additional linker proteins. Disruption of the direct CHD7-CHD8 interaction may change the conformation of a putative large CHD7-CHD8 complex and could be a disease mechanism in CHARGE syndrome.
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.
Vissers et al. (2004) determined that the CHD7 gene consists of 38 exons and has a genomic size of 188 kb.
By radiation hybrid analysis, Nagase et al. (2000) mapped the CHD7 gene to chromosome 8.
CHARGE Syndrome
Using an improved method of genome scan by comparative genomic hybridization (CGH), Vissers et al. (2004) identified a 2.3-Mb de novo overlapping microdeletion on 8q12 in 2 individuals with CHARGE syndrome (214800). Sequence analysis of genes located in this region detected mutations in CHD7 in 10 of 17 individuals with CHARGE syndrome without microdeletions, accounting for the disease in most affected individuals. The 10 heterozygous mutations identified by Vissers et al. (2004) (see, e.g., 608892.0001-608892.0004) included 7 stop codon mutations, 2 missense mutations, and 1 mutation at an intron-exon boundary. The stop codon mutations were scattered throughout the gene.
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%) (see, e.g., 608892.0005-608892.0007). Mutations were distributed throughout the coding exons and conserved splice sites of CHD7. Of the 64 mutations, 47 (73%) predicted premature termination of the protein. These included nonsense and frameshift mutations, which most likely lead to haploinsufficiency. Phenotypically, the mutation-positive group was more likely to exhibit cardiovascular malformations (54 of 59 in the mutation-positive group vs 30 of 42 in the mutation-negative group; p = 0.014), coloboma of the eye (55 of 62 in the mutation-positive group vs 30 of 43 in the mutation-negative group; p = 0.022), and facial asymmetry, often caused by seventh cranial nerve abnormalities (36 of 56 in the mutation-positive group vs 13 of 39 in the mutation-negative group; p = 0.004). Mouse embryo whole-mount and section in situ hybridization showed the expression of Chd7 in the outflow tract of the heart, optic vesicle, facioacoustic preganglion complex, brain, olfactory pit, and mandibular component of the first branchial arch.
Jongmans et al. (2006) identified mutations in the CHD7 gene in 69 (65%) 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, 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).
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 no CHD7 mutation was found, multiplex ligation-dependent probe amplification (MLPA) analysis detected only 1 (1.9%) had a large CHD7 gene alteration, which was a partial deletion encompassing exons 13 to 38.
In 3 members of a 2-generation Finnish family with CHARGE syndrome, Vuorela et al. (2008) identified a nonsense mutation in the CHD7 gene (608892.0017).
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.
Hypogonadotropic Hypogonadism 5 with or without Anosmia
Kim et al. (2008) analyzed the CHD7 gene in 197 patients with Kallmann syndrome or normosmic hypogonadotropic hypogonadism (HH5; 612370) and identified 7 heterozygous mutations in 7 sporadic patients, 3 with KS and 4 with nIHH, respectively (see, e.g., 608892.0012-608892.0015). Two of the mutations had previously been found in patients with CHARGE syndrome (see 608892.0012 and 608892.0013). Kim et al. (2008) concluded that both normosmic IHH and Kallmann syndrome due to mutation in CHD7 are mild allelic variants of CHARGE syndrome.
Possible Association with Susceptibility to Idiopathic Scoliosis
For discussion of a possible association between variation in the CHD7 gene and idiopathic scoliosis (see IS3, 608765), see 608892.0009.
Possible Association with Susceptibility to Small Cell Lung Cancer
Pleasance et al. (2010) sequenced a small-cell lung cancer cell line, NCI-H209, to explore the mutational burden associated with tobacco smoking. A total of 22,910 somatic substitutions were identified, including 134 in coding exons. Multiple mutation signatures testify to the cocktail of carcinogens in tobacco smoke and their proclivities for particular bases and surrounding sequence context. Effects of transcription-coupled repair and a second, more general, expression-linked repair pathway were evident. Pleasance et al. (2010) identified a tandem duplication that duplicates exons 3 through 8 of CHD7 in frame, and another 2 lines carrying PVT1 (165140)-CHD7 fusion genes, indicating that CHD7 may be recurrently rearranged in this disease.
Possible Association with Cleft Lip/Palate
Felix et al. (2006) analyzed the coding region of CHD7 in 9 CHARGE cases and identified 5 mutations, 4 of which were novel. They sequenced selected CHD7 exons in nonsyndromic clefting cases from Iowa and Philippines populations, as well as matched controls. No variants that appeared to be significant were found among the cases of nonsyndromic cleft lip/palate. Association analysis of 3 SNPs in the CHD7 gene using 878 nonsyndromic cleft lip/palate case-parent triads from Iowa and Philippines populations showed no significant overtransmission. Felix et al. (2006) concluded that mutations in CHD7 are not common in isolated clefting, and minimal evidence was found that CHD7 can act as a modifier for nonsyndromic clefting.
Associations Pending Confirmation
D'Alessandro et al. (2016) performed whole-exome sequencing in 81 unrelated probands with atrioventricular septal defect (AVSD; see 606215) to identify potential causal variants in a comprehensive set of 112 genes with strong biological relevance to AVSD. A significant enrichment of rare and rare damaging variants was identified in the gene set, compared with controls (odds ratio (OR) 1.52; 95% confidence interval (CI), 1.35-1.71; p = 4.8 x 10(-11)). The enrichment was specific to AVSD probands, compared with a cohort without AVSD with tetralogy of Fallot (OR 2.25; 95% CI, 1.84-2.76; p = 2.2 x 10(-16)). Six genes, including the syndrome-associated gene CHD7, were enriched for rare variants in AVSD. Nine AVSD probands (11.1%) had rare nonsynonymous variants in CHD7 compared with 5.0% of controls from the Exome Variant Server (EVS) (OR 2.3; p = 0.04). Several missense mutations were either novel or exceptionally rare. All were conserved and predicted to be damaging. D'Alessandro et al. (2016) concluded that mutations in genes with strong biological relevance to AVSD, including syndrome-associated genes, can contribute to AVSD, even in those with isolated heart disease.
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 mimicked 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 +/- 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.
Melicharek et al. (2010) showed that the Drosophila homolog of Chd7, 'kismet,' is required for proper axonal pruning, guidance, and extension in the developing fly's central nervous system. In addition to defects in neuroanatomy, flies with reduced kismet expression showed defects in memory and motor function, phenotypes consistent with symptoms observed in CHARGE syndrome patients.
The 'whirligig' (whi) mouse was obtained in an ENU screen and carries a heterozygous c.2918G-A transition in exon 11 of the Chd7 gene, resulting in a premature stop codon (trp973 to ter; W973X). Heterozygous whi/+ mice present a phenotype similar to that of CHARGE syndrome patients, whereas homozygous whi/whi embryos die shortly after embryonic day 10.5 (E10.5) (Bosman et al., 2005). Using genomewide microarray expression analysis, Schulz et al. (2014) identified 98 genes that showed greater than 2-fold difference in expression between whi/whi and wildtype embryos. Many of the misregulated genes were involved in neural crest cell and axon guidance, including semaphorins (e.g., Sema3a, 603961) and ephrin receptors (e.g., Epha3, 179611).
In a female patient with CHARGE syndrome (214800), Vissers et al. (2004) described a heterozygous 3082A-G transition in exon 12 of the CHD7 gene that resulted in an ile1028-to-val (I1028V) mutation. The patient had coloboma, retardation of growth and development, and semicircular canal agenesis. The mutation was de novo.
In a female patient with CHARGE syndrome (214800), Vissers et al. (2004) described a heterozygous 3770T-G transversion in exon 15 of the CHD7 gene that caused a leu1257-to-arg (L1257R) mutation. The patient had coloboma, retardation of growth and development, genital hypoplasia, ear abnormalities including deafness, and semicircular canal agenesis. It was shown to be a de novo mutation.
In a female patient with CHARGE syndrome (214800), Vissers et al. (2004) found a heterozygous de novo mutation, tyr1806-to-ter (Y1806X), caused by a 5418C-G transversion in exon 26 of the CHD7 gene. The patient had heart malformation and atresia of choanae, retardation of growth and development, genital hypoplasia, and ear anomalies but no coloboma or cleft lip/palate.
In a male patient with CHARGE syndrome (214800), Vissers et al. (2004) found a de novo heterozygous splice site mutation, IVS26-7G-A, in the CHD7 gene. The patient had coloboma, heart malformation, retardation of growth and development, genital hypoplasia, ear abnormalities, and cleft lip/palate, but no choanal atresia.
In a mildly affected girl with CHARGE syndrome (214800), Lalani et al. (2006) found a trp2332-to-stop (W2332X) mutation in exon 33 of the CHD7 gene. This child had a brother who died at age 6 months from complications of CHARGE and from whom tissue samples were not available. The parents were unaffected. Parental germline mosaicism was suspected.
Lalani et al. (2006) described a family in which mother and daughter had mild CHARGE syndrome (214800) and carried an arg2319-to-ser (R2319S) mutation in exon 33 of the CHD7 gene.
Lalani et al. (2006) described an instance of monozygotic twins with CHARGE syndrome (214800) caused by a glu1271-to-stop (E1271X) mutation in exon 16 of the CHD7 gene.
In monozygotic twin sisters, Jongmans et al. (2006) identified a 1-bp insertion (5752dupA) in exon 29 of the CHD7 gene, predicted to cause a frameshift at thr1918. One sib died 29 hours after birth due to a combination of hypoplastic left heart syndrome and bilateral choanal atresia; she also had tracheoesophageal fistula and typical CHARGE ears but no colobomas. The other sib was examined at 12 years of age, at which time she was functioning 4 years behind her chronologic age and was noted to have short stature and an unsteady gait. She was born with a large patent ductus arteriosus that required surgery and needed multiple procedures to correct bilateral choanal atresia. She had a gastrostomy until age 6 years. She had severe bilateral deafness, abnormal external ears, and bilateral chorioretinal colobomas.
This variant, formerly titled SCOLIOSIS, IDIOPATHIC, SUSCEPTIBILITY TO, 3, has been reclassified based on the findings of Tilley et al. (2013).
To search for genes underlying susceptibility to idiopathic scoliosis (see IS3, 608765), Gao et al. (2007) ascertained a cohort of 52 families and conducted a study by genomewide scans, which produced evidence of linkage in association with 8q12 loci (multipoint lod = 2.77; p = 0.0028). Further mapping in the region showed significant evidence of disease-associated haplotypes centering over exons 2 through 4 of the CHD7 gene, which is associated with the CHARGE syndrome of multiple developmental anomalies. In 25 affected probands with idiopathic scoliosis (see IS3, 608765) and 44 parental controls, Gao et al. (2007) identified a single-nucleotide polymorphism, SNP rs4738824, an A-to-G change in intron 2 of the CHD7 gene that was predicted to disrupt a caudal-type (cdx) transcription factor binding site. The A nucleotide of this SNP appears to be perfectly conserved across 9 vertebrate species. In the 27 remaining families in the study, Gao et al. (2007) found significant overtransmission of the G allele, which was predicted to disrupt a caudal-type (cdx) transcription factor binding site, to affected offspring (p = 0.005).
Tilley et al. (2013) performed model-independent linkage analysis and tests of association for 22 single-nucleotide polymorphisms in the CHD7 gene in 244 families of European descent with familial idiopathic scoliosis. Linkage analysis identified 3 marginally significant results. However, their results were not significant for tests of association to the CHD7 gene (p less than 0.01). In addition, no significant results (p less than 0.01) were found from a metaanalysis of the results from the tests of association from their sample and that of Gao et al. (2007).
In a 13-year-old Japanese girl with CHARGE syndrome (214800), Udaka et al. (2007) identified a de novo heterozygous 10.4-kb deletion in the CHD7 gene, encompassing exons 8 to 12 with breakpoints within introns 7 and 12, and predicted to cause a truncated protein lacking the functionally important chromo, SNF2, and helicase domains. The authors stated that this was the first CHARGE patient to have a documented exonic deletion in CHD7.
In affected individuals of 2 unrelated families with a mild form of CHARGE syndrome (214800), Jongmans et al. (2008) identified a heterozygous 6322G-A transition in exon 31 of the CHD7 gene, resulting in a gly2108-to-arg (G2108R) substitution. There was parent-to-child transmission in both families, consistent with autosomal dominant inheritance. In 1 family, the mother had only dysmorphic ears, right-sided hearing loss, hypoplastic semicircular canals, and normal cognitive development, whereas her daughter had ear abnormalities, unilateral deafness, pulmonary stenosis, and right-sided double renal system. In the second family, the mother had only mild structural anomaly of 1 ear, whereas both her sons showed more severe features with other organ involvement. Jongmans et al. (2008) noted the variable intrafamilial phenotype and concluded that the G2108R mutation confers a relatively mild phenotype with normal fertility.
In 2 brothers, one diagnosed with atypical and the other with typical CHARGE syndrome (214800), born of nonconsanguineous French parents, Delahaye et al. (2007) identified heterozygosity for a 2501C-T transition in exon 8 of the CHD7 gene, resulting in a ser834-to-phe (S834F) substitution at a highly conserved residue. The mutation was also found in their mother, who was only investigated after the identification of her children's anomalies and was subsequently diagnosed with atypical CHARGE syndrome. The mutation was not found in 4 unaffected family members or in 300 chromosomes from other patients or parents.
In a male patient with normosmic hypogonadotropic hypogonadism (HH5; 612370), cleft lip, and cryptorchidism, Kim et al. (2008) identified heterozygosity for the S834F mutation in the DNA-binding chromodomain 1 of the CHD7 gene. There were no other affected family members or relatives. The mutation was not found in 180 controls.
In 2 brothers with a 'relatively mild' presentation of CHARGE syndrome (214800), Jongmans et al. (2008) identified heterozygosity for a splice site transversion (2442+5G-C) in IVS6 of the CHD7 gene. The boys, who were 7 years and 4 years old, respectively, had mild mental retardation, micropenis, bilateral cryptorchidism, and, according to their mother, no sense of smell. They had a history of balance disturbances, and both tested positive for autistic spectrum disorders. The older boy had severe bilateral hearing loss; the younger had right-sided severe and left-sided mild hearing loss, and also had bilateral cleft lip/palate. The mutation was not found in the mother, and the father was unavailable for analysis; haplotyping indicated that the mutation occurred on the paternal allele. Neither parent had any clinical features of CHARGE syndrome. The mutation was not found in 600 healthy control alleles.
In a Turkish female with Kallmann syndrome (HH5; 612370) who also had mild sensorineural deafness and cleft lip and palate, Kim et al. (2008) identified a de novo IVS6+5G-C transversion in the CHD7 gene. RT-PCR analysis revealed that the mutation results in an in-frame deletion of 22 of 66 amino acids in chromodomain 1 of CHD7, an evolutionarily conserved region known to interact with histone tails. The mutation was not found in 96 Turkish controls or in 180 other controls.
In a Turkish male with normosmic hypogonadotrophic hypogonadism (HH5; 612370) and no other anomalies, Kim et al. (2008) identified heterozygosity for a splice site transition (IVS8+5G-A) in the CHD7 gene, resulting in skipping of exon 8 and causing a frameshift and subsequent premature termination codon at residue 849. This truncation of more than 70% of the C terminus, including approximately half of the first and all of the second chromodomains, was predicted to render the protein nonfunctional. There were no other affected family members or relatives. The mutation was not found in 96 Turkish controls or 180 other controls.
In a male patient with Kallmann syndrome (HH5; 612370) and no other anomalies, Kim et al. (2008) identified a 164A-G transition in exon 2 of the CDH7 gene, resulting in a his55-to-arg (H55R) substitution at a highly conserved residue. There were no other affected family members or relatives. The mutation was not found in 180 controls.
In an 11-month-old boy with CHARGE syndrome (214800) and right monodactyly, Van de Laar et al. (2007) identified heterozygosity for a 1-bp insertion (8682insT) in exon 38 of the CHD7 gene, predicted to result in premature termination of the protein. The right-sided monodactyly was accompanied by ulnar hypoplasia, and he also had small, square, low-set ears, left cryptorchidism, micropenis, and a congenital heart malformation consisting of double-outlet right ventricle, large-outlet ventricular septal defect, dysplastic tricuspid valve, pulmonary stenosis, and atrial septal defect type II. Severe bilateral hearing loss was detected at 1 week of age, and brain scans revealed bilateral absence of the semicircular canals, hypoplasia of the left vestibulocochlear cranial nerve, right choanal atresia, and a small submucous cleft palate. Motor development was delayed; he could not sit without support at 11 months of age.
In 3 members of a Finnish family with CHARGE syndrome (214800), Vuorela et al. (2008) identified a 4795C-T transition in exon 21 of the CHD7 gene, resulting in a gln1599-to-ter (Q1599X) substitution. 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. The father's parents and brother did not carry the mutation, suggesting the mutation occurred de novo in the father, and his brother also had mild asymmetric hearing loss and a mildly dysplastic left external ear.
Bajpai, R., Chen, D. A., Rada-Iglesias, A., Zhang, J., Xiong, Y., Helms, J., Chang, C.-P., Zhao, Y., Swigut, T., Wysocka, J. CHD7 cooperates with PBAF to control multipotent neural crest formation. Nature 463: 958-962, 2010. [PubMed: 20130577] [Full Text: https://doi.org/10.1038/nature08733]
Batsukh, T., Pieper, L., Koszucka, A. M., von Velsen, N., Hoyer-Fender, S., Elbracht, M., Bergman, J. E. H., Hoefsloot, L. H., Pauli, S. CHD8 interacts with CHD7, a protein which is mutated in CHARGE syndrome. Hum. Molec. Genet. 19: 2858-2866, 2010. [PubMed: 20453063] [Full Text: https://doi.org/10.1093/hmg/ddq189]
Bergman, J. E. H., de Wijs, I., Jongmans, M. C. J., Admiraal, R. J., Hoefsloot, L. H., van Ravenswaaij-Arts, C. M. A. Exon copy number alterations of the CHD7 gene are not a major cause of CHARGE and CHARGE-like syndrome. Europ. J. Med. Genet. 51: 417-425, 2008. [PubMed: 18472328] [Full Text: https://doi.org/10.1016/j.ejmg.2008.03.003]
Bosman, E. A., Penn, A. C., Ambrose, J. C., Kettleborough, R., Stemple, D. L., Steel, K. P. Multiple mutations in mouse Chd7 provide models for CHARGE syndrome. Hum. Molec. Genet. 14: 3463-3476, 2005. [PubMed: 16207732] [Full Text: https://doi.org/10.1093/hmg/ddi375]
D'Alessandro, L. C. A., Al Turki, S., Manickaraj, A. K., Manase, D., Mulder, B. J. M., Bergin, L., Rosenberg, H. C., Mondal, T., Gordon, E., Lougheed, J., Smythe, J., Devriendt, K., UK10K Consortium, Bhattacharya, S., Watkins, H., Bentham, J., Bowdin, S., Hurles, M. E., Mital, S. Exome sequencing identifies rare variants in multiple genes in atrioventricular septal defect. Genet. Med. 18: 189-198, 2016. [PubMed: 25996639] [Full Text: https://doi.org/10.1038/gim.2015.60]
Delahaye, A., Sznajer, Y., Lyonnet, S., Elmaleh-Berges, M., Delpierre, I., Audollent, S., Wiener-Vacher, S., Mansbach, A. L., Amiel, J., Baumann, C., Bremond-Gignac, D., Attie-Bitach, T., Verloes, A., Sanlaville, D. Familial CHARGE syndrome because of CHD7 mutation: clinical intra- and interfamilial variability. Clin. Genet. 72: 112-121, 2007. [PubMed: 17661815] [Full Text: https://doi.org/10.1111/j.1399-0004.2007.00821.x]
Engelen, E., Akinci, U., Bryne, J. C., Hou, J., Gontan, C., Moen, M., Szumska, D., Kockx, C., van IJcken, W., Dekkers, D. H. W., Demmers, J., Rijkers, E.-J., Bhattacharya, S., Philipsen, S., Pevny, L. H., Grosveld, F. G., Rottier, R. J., Lenhard, B., Poot, R. A. Sox2 cooperates with Chd7 to regulate genes that are mutated in human syndromes. Nature Genet. 43: 607-611, 2011. [PubMed: 21532573] [Full Text: https://doi.org/10.1038/ng.825]
Felix, T. M., Hanshaw, B. C., Mueller, R., Bitoun, P., Murray, J. C. CHD7 gene and non-syndromic cleft lip and palate. Am. J. Med. Genet. 140A: 2110-2114, 2006. [PubMed: 16763960] [Full Text: https://doi.org/10.1002/ajmg.a.31308]
Gao, X., Gordon, D., Zhang, D., Browne, R., Helms, C., Gillum, J., Weber, S., Devroy, S., Swaney, S., Dobbs, M., Morcuende, J., Sheffield, V., Lovett, M., Bowcock, A., Herring, J., Wise, C. CHD7 gene polymorphisms are associated with susceptibility to idiopathic scoliosis. Am. J. Hum. Genet. 80: 957-965, 2007. [PubMed: 17436250] [Full Text: https://doi.org/10.1086/513571]
Jongmans, M. C. J., Admiraal, R. J., van der Donk, K. P., Vissers, L. E. L. M., Baas, B. F., Kapusta, L., van Hagen, J. M., Donnai, D., de Ravel, T. J., Veltman, J. A., Geurts van Kessel, A., De Vries, B. B. A., Brunner, H. G., Hoefsloot, L. H., van Ravenswaaij, C. M. A. CHARGE syndrome: the phenotypic spectrum of mutations in the CHD7 gene. J. Med. Genet. 43: 306-314, 2006. [PubMed: 16155193] [Full Text: https://doi.org/10.1136/jmg.2005.036061]
Jongmans, M. C. J., Hoefsloot, L. H., van der Donk, K. P., Admiraal, R. J., Magee, A., van de Laar, I., Hendriks, Y., Verheij, J. B. G. M., Walpole, I., Brunner, H. G., van Ravenswaaij, C. M. A. Familial CHARGE syndrome and the CHD7 gene: a recurrent missense mutation, intrafamilial recurrence and variability. Am. J. Med. Genet. 146A: 43-50, 2008. [PubMed: 18074359] [Full Text: https://doi.org/10.1002/ajmg.a.31921]
Kim, H.-G., Kurth, I., Lan, F., Meliciani, I., Wenzel, W., Eom, S. H., Kang, G. B., Rosenberger, G., Tekin, M., Ozata, M., Bick, D. P., Sherins, R. J., Walker, S. L., Shi, Y., Gusella, J. F., Layman, L. C. Mutations in CHD7, encoding a chromatin-remodeling protein, cause idiopathic hypogonadotropic hypogonadism and Kallmann syndrome. Am. J. Hum. Genet. 83: 511-519, 2008. [PubMed: 18834967] [Full Text: https://doi.org/10.1016/j.ajhg.2008.09.005]
Lalani, S. R., Safiullah, A. M., Fernbach, S. D., Harutyunyan, K. G., Thaller, C., Peterson, L. E., McPherson, J. D., Gibbs, R. A., White, L. D., Hefner, M., Davenport, S. L. H., Graham, J. M., Jr., Bacino, C. A., Glass, N. L., Towbin, J. A., Craigen, W. J., Neish, S. R., Lin, A. E., Belmont, J. W. Spectrum of CHD7 mutations in 110 individuals with CHARGE syndrome and genotype-phenotype correlation. Am. J. Hum. Genet. 78: 303-314, 2006. [PubMed: 16400610] [Full Text: https://doi.org/10.1086/500273]
Layman, W. S., McEwen, D. P., Beyer, L. A., Lalani, S. R., Fernbach, S. D., Oh, E., Swaroop, A., Hegg, C. C., Raphael, Y., Martens, J. R., Martin, D. M. Defects in neural stem cell proliferation and olfaction in Chd7 deficient mice indicate a mechanism for hyposmia in human CHARGE syndrome. Hum. Molec. Genet. 18: 1909-1923, 2009. [PubMed: 19279158] [Full Text: https://doi.org/10.1093/hmg/ddp112]
Melicharek, D. J., Ramirez, L. C,. Singh, S., Thompson, R., Marenda, D. R. Kismet/CHD7 regulates axon morphology, memory and locomotion in a Drosophila model of CHARGE syndrome. Hum. Molec. Genet. 19: 4253-4264, 2010. [PubMed: 20716578] [Full Text: https://doi.org/10.1093/hmg/ddq348]
Nagase, T., Kikuno, R., Ishikawa, K., Hirosawa, M., Ohara, O. Prediction of the coding sequences of unidentified human genes. XVI. The complete sequences of 150 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 7: 65-73, 2000. [PubMed: 10718198] [Full Text: https://doi.org/10.1093/dnares/7.1.65]
Pauli, S., von Velsen, N., Burfeind, P., Steckel, M., Manz, J., Buchholz, A., Borozdin, W., Kohlhase, J. CHD7 mutations causing CHARGE syndrome are predominantly of paternal origin. Clin. Genet. 81: 234-239, 2012. [PubMed: 21554267] [Full Text: https://doi.org/10.1111/j.1399-0004.2011.01701.x]
Pleasance, E. D., Stephens, P. J., O'Meara, S., McBride, D. J., Meynert, A., Jones, D., Lin, M.-L., Beare, D., Lau, K. W., Greenman, C., Varela, I., Nik-Zainal, S., and 28 others. A small-cell lung cancer genome with complex signatures of tobacco exposure. Nature 463: 184-190, 2010. [PubMed: 20016488] [Full Text: https://doi.org/10.1038/nature08629]
Sanlaville, D., Etchevers, H. C., Gonzales, M., Martinovic, J., Clement-Ziza, M., Delezoide, A.-L., Aubry, M.-C., Pelet, A., Chemouny, S., Cruaud, C., Audollent, S., Esculpavit, C., and 13 others. Phenotypic spectrum of CHARGE syndrome in fetuses with CHD7 truncating mutations correlates with expression during human development. J. Med. Genet. 43: 211-217, 2006. [PubMed: 16169932] [Full Text: https://doi.org/10.1136/jmg.2005.036160]
Schulz, Y., Wehner, P., Opitz, L., Salinas-Riester, G., Bongers, E. M. H. F., van Ravenswaaij-Arts, C. M. A., Wincent, J., Schoumans, J., Kohlhase, J., Borchers, A., Pauli, S. CHD7, the gene mutated in CHARGE syndrome, regulates genes involved in neural crest cell guidance. Hum. Genet. 133: 997-1009, 2014. [PubMed: 24728844] [Full Text: https://doi.org/10.1007/s00439-014-1444-2]
Tilley, M. K., Justice, C. M., Swindle, K., Marosy, B., Wilson, A. F., Miller, N. H. CHD7 gene polymorphisms and familial idiopathic scoliosis. Spine 38: E1432-E1436, 2013. Note: Electronic Article. [PubMed: 23883829] [Full Text: https://doi.org/10.1097/BRS.0b013e3182a51781]
Udaka, T., Okamoto, N., Aramaki, M., Torii, C., Kosaki, R., Hosokai, N., Hayakawa, T., Takahata, N., Takahashi, T., Kosaki, K. An Alu retrotransposition-mediated deletion of CHD7 in a patient with CHARGE syndrome. Am. J. Med. Genet. 143A: 721-726, 2007. [PubMed: 17334995] [Full Text: https://doi.org/10.1002/ajmg.a.31441]
Van de Laar, I., Dooijes, D., Hoefsloot, L., Simon, M., Hoogeboom, J., Devriendt, K. Limb anomalies in patients with CHARGE syndrome: an expansion of the phenotype. Am. J. Med. Genet. 143A: 2712-2715, 2007. [PubMed: 17937444] [Full Text: https://doi.org/10.1002/ajmg.a.32008]
Van Nostrand, J. L., Brady, C. A., Jung, H., Fuentes, D. R., Kozak, M. M., Johnson, T. M., Lin, C.-Y., Lin, C.-J., Swiderski, D. L., Vogel, H., Bernstein, J. A., Attie-Bitach, T., Chang, C.-P., Wysocka, J., Martin, D. M., Attardi, L. D. Inappropriate p53 activation during development induces features of CHARGE syndrome. Nature 514: 228-232, 2014. [PubMed: 25119037] [Full Text: https://doi.org/10.1038/nature13585]
Vissers, L. E. L. M., van Ravenswaaij, C. M. A., Admiraal, R., Hurst, J. A., de Vries, B. B. A., Janssen, I. M., van der Vliet, W. A., Huys, E. H. L. P. G., de Jong, P. J., Hamel, B. C. J., Schoenmakers, E. F. P. M., Brunner, H. G., Veltman, J. A., Geurts van Kessel, A. Mutations in a new member of the chromodomain gene family cause CHARGE syndrome. Nature Genet. 36: 955-957, 2004. [PubMed: 15300250] [Full Text: https://doi.org/10.1038/ng1407]
Vuorela, P. E., Penttinen, M. T., Hietala, M. H., Laine, J. O., Huoponen, K. A., Kaariainen, H. A. A familial CHARGE syndrome with a CHD7 nonsense mutation and new clinical features. Clin. Dysmorph. 17: 249-253, 2008. [PubMed: 18978652] [Full Text: https://doi.org/10.1097/MCD.0b013e328306a704]
Zentner, G. E., Hurd, E. A., Schnetz, M. P., Handoko, L., Wang, C., Wang, Z., Wei, C., Tesar, P. J., Hatzoglou, M., Martin, D. M., Scacheri, P. C. CHD7 functions in the nucleolus as a positive regulator of ribosomal RNA biogenesis. Hum. Molec. Genet. 19: 3491-3501, 2010. [PubMed: 20591827] [Full Text: https://doi.org/10.1093/hmg/ddq265]