Balkan Journal of Medical Genetics

THREE NOVEL MUTATIONS OF CHD7 GENE IN TWO TURKISH PATIENTS WITH CHARGE SYNDROME; A DOUBLE POINT MUTATION AND AN INSERTION
Giray Bozkaya O, Ataman E, Randa C, Onur Cura D, Gürsoy S, Aksel O, Ulgenalp A
*Corresponding Author: Associate Professor Ozlem Giray Bozkaya, Department of Pediatrics, Division of Genetics, Faculty of Medicine, Dokuz Eylul University, Mithatpasa 1606, Inciralti, Izmir 35340, Turkey. Tel: +90-230-412-6122. Fax: +90-230-412-6005. E-mail: ozlem.giray@deu.edu.tr
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DISCUSSION

The CHARGE syndrome occurs approximately 1 in 8,500 to 10,000 live births and shows characteristic clinical manifestations [12]. The diagnosis is primarily based on combinations of clinical findings that were grouped as major and minor characteristics. Three major or two major and two minor features refers to the diagnosis of typical CHARGE syndrome. Two major and one minor features refers to partial/ incomplete CHARGE syndrome. The major characteristics of CHARGE syndrome are more specific to this disorder and relatively rare in other syndromes (Table 1) [11,13]. Coloboma and ophthalmic findings are found in 75.0-90.0% of CHARGE patients [6]. Coloboma may be present in bilateral choroid, retina and the optic nerve. Retinal coloboma is present more often in CHARGE patients. In some cases, retinal coloboma can occur with microphtalmia and this occurrence predicts poor prognosis [14,15]. Typical colobama usually causes field defects in CHARGE syndrome [16]. Choanal atresia or stenosis is found in approximately half of the patients and noticed due to respiratory difficulty during the neonatal period [12,17]. Laryngomalacia, tracheomalacia and subglottic stenosis can be seen [6]. Cleft palate/lip can cooccur occur with coanal atresia [18]. Cardiac malformations are usually present in patients with CHARGE syndrome, and common features are tetralogy of Fallot, ASD and patent ductus arteriosus [16]. Hypoplastic left/right heart and double outlet right ventricle are rarely present in CHARGE syndrome. Almost all patients with CHARGE syndrome have ear malformations, especially semi-circular canal abnormalities and sensorineural hearing loss [15]. Due to the pituitary hormone deficiencies, growth retardation appears during childhood [16]. In addition to growth failure, hypothalamo-hypophyseal dysfunction leads to hypogonadotropic hypogonadism, genital hypoplasia and delayed puberty in patients with CHARGE syndrome [6]. The CHD7 gene consists of 38 exons and only the first exon is non coding [8]. This gene is a member of ATP-dependent chromatin remodeling protein family [19]. The function of the CHD family is not yet clear, but it is known that ATP-dependent chromatin remodeling has a key role in embryonic development [19,20]. In the embryonic period, the CHD7 protein activates several gene expressions that required embryonic stem cell differentiation into the neural progenitors. In CHARGE patients, disruption of CHD7 function during development inhibits gene expression and impairs differentiation of embryonic stem cells. These functional distinctions might partly explain the symptoms of the syndrome [21]. More than 500 pathogenic alterations have been described in the CHD7 gene. Mutational spectrum is reported as follows: nonsense mutations 46.0%, frameshift mutations 24.0%, missense mutations 15.0%, splice site mutations 10.0%, intronic mutations approximately 3.0%, chromosomal rearrangements and deletions, including CHD7 gene locus, approximately 1.0% [8]. The CHD7 protein contains an ATPase domain [helicase C-terminal (HELICc)] and DEXDc domains, a pair of breast tumor kinase (BRK) domains and a SANT (SWI3, ADA2, N-CoR and TFIIIB) domain [21]. Previously, five different pathogenic mutations in the HELICc domain were published [22]. In our article, patient 2 has a novel insertion mutation in exon 17 that seems to disrupt the HELICc domain of the CHD7 protein. The phenotype-genotype correlation is not yet clearly known. Mechanisms of the double nucleotide substitution are not completely understood. One of these is tandem base substitution (TBS) that is described as the presence of at least two successive nucleotide substitutions without any insertion or deletion of bases [23]. The other mechanism may occur as concurrent mutations are considered simultaneously. The ratio of these mutations are seen in 93.9% of human inherited diseases [24]. In the first case, we detected a novel double base mutation that is described for the first time in the literature. The first mutation (c.1281 T>G; p.Y427*) leads to a truncated protein and this may cause typical CHARGE syndrome findings in this case. The majority of patients with CHARGE syndrome have a normal karyotype; rarely can chromosomal abnormalities be seen [8]. Therefore, cytogenetic analysis must be performed to exclude chromosomal abnormalities and other syndromes overlapping CHARGE syndrome. Declaration of Interest. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

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