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
page: 65

INTRODUCTION

Coloboma, cardiac defects, choanal atresia/ stenosis, retarded growth and development, genital hypoplasia and ear abnormalities/deafness are seen in CHARGE (Hall-Hittner syndrome) syndrome. In addition to these cardinal findings, dysmorphic facial features such as low set and dysmorphic ears, retrognathia, hypertelorism, microcephaly, facial asymmetry, cleft lip/palate, genital hypoplasia, limb abnormalities, hypogonadotropic hypogonadism and behavioral disorders can be seen [1-4]. Although this rare syndrome has an autosomal dominant pattern of inheritance, usually (97.0%) occurs as the result of a de novo mutation [5,6]. Mutations in the CHD7 gene are responsible for 65.0-70.0% cases of CHARGE syndrome [7-9]. When typical cases who fully meet the formal diagnostic criteria, the incidence rises to 90.0-95.0% [6]. The CHD7 gene is a member of chromodomain helicase DNA-binding (CHD) protein family that regulates transcription by chromatin remodeling [10]. It is suggested that CHD7 has a role in adenosine triphosphate (ATP)-dependent chromatin remodeling in embryonic stem cells [3]. We present two patients with novel mutations in the CHD7 gene, who were clinically diagnosed as typical CHARGE syndrome according to Verloes criteria [11]. Case 1. A 2-month-old girl presented with choanal atresia, bilateral coloboma and hearing loss. She was the first child of non consanguineous parents. The pregnancy was medically followed and prenatal history was uneventful. She was born at term by cesarean delivery and her birth weight was 3190 g. During the first day of life, the patient presented to hospital with respiratory problems and left choana atresia was found. On physical examination at 2 months of age, the patient weighted 4550 g (5 centile), height was 54 cm (29 centile) and head circumference was 37 cm (24 centile). She had characteristic facial findings: square face, unilateral microphthalmia, micrognathia and dysmorphic ears (Figure 1A). A careful ophtalmic examination assessment was performed. There were bilateral coloboma involved the optic disc, retina and choroid. Auditory brainstem response (ABR) audiometry showed bilateral decreased hearing threshold. Abdominal and transfontanelle ultrasonographic examinations were unremarkable. Cranial magnetic resonance imaging (MRI) revealed bilateral frontal hypoplasia (interpreted as a normal variant) with hypoplastic right bulbus oculi. The patient also underwent echocardiography, which revealed an atrial septal defect (ASD) and moderate pulmonary hypertension. Cytogenetic analysis revealed a normal female karyotype. In sequence analysis for the CHD7 gene, we identified two novel mutations in adjacent nucleotides in exon 2: c.1281T>G and c.1282C>G, affecting adjacent codons and resulting in two amino acid changes: tyrosine to stop codon (p.Y427*) and proline to alanine (p.P428A) (Figure 1B). None of these mutations has been described previously. Since neither the mother nor the father was a carrier of either mutation, we concluded that both mutations occurred de novo on one allele. Complex mutations of adjacent codons occur very rarely and to our knowledge, the adjacent CHD7 mutations occurring on the same allele have not been previously reported. Case 2. A 4-month-old girl presented with rightsided choanal atresia, dysmorphic facial features and operated aberrant supraclavicular artery. She was the second child of non consanguineous parents; at birth the mother was 31 and the father was 32 years old. Family history was negative in regard to malformations and development. Right-sided choanal atresia and dysmorphic facial features were recognized after an uncomplicated 42-week pregnancy. Her birth weight was 3210 g. At birth she presented with respiratory problems due to right-sided choanal atresia. Cardiological examination demonstrated aberrant supraclavicular artery that was surgically corrected at the age of 2 months. Physical examination at 4 months of age showed mild hypotonia, epicanthus, flat nasal bridge, smallcurled low-set ears, pili asymmetry and bilateral clinodactyly of the second fingers of feet (Figure 2A). Her head circumference was 37 cm(<3 centile), height was 59 cm (90-95 centile), weight was 3900 g (3-25 centile). Ophtalmologic examination revealed bilateral posterior embryotoxon. A brain MRI was normal. Right-sided choanal atresia was confirmed by paranasal sinus computed tomography (CT), and bilateral semi-circular hypoplasia was noted. Audiological examination showed hearing impairment. Ultrasonographic examination was performed to rule out the suspected hip dislocation. After determining pili asymmetry hip dysplasia, ultrasongraphic examination revealed normal results. Her head circumference was 39.5 cm (<3 centile), height was 61 cm (3-10 centile), weight was 5310 g (<3 centile). Her psychomotor development was delayed. She is now 3 years old and still unable to walk and talk. A clinical suspicion of CHARGE syndrome was raised due to her dysmorphic features. In order to rule out Di George (DG) syndrome, fluorescent in situ hybridization (FISH) studies for 22q11 (for DG) and 8q12.1 (for CHARGE) were planned with routine high resolution cytogenetic analysis. All the results were normal. We discovered a novel de novo c.4103_4104insGC (p.G3169Qfs*4) mutation in the CHD7 gene when we performed sequence analysis (Figure 2B). Molecular analysis of her parents showed normal results. Genetic counseling for future pregnancies was provided to the family.

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