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Identification of two novel splice‐site mutations in CHD7 gene in two patients with classical and atypical CHARGE syndrome phenotype
Author(s) -
Cappuccio G.,
Ginocchio V.M.,
Maffè A.,
Ungari S.,
Andria G.,
Melis D.
Publication year - 2014
Publication title -
clinical genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.543
H-Index - 102
eISSN - 1399-0004
pISSN - 0009-9163
DOI - 10.1111/cge.12115
Subject(s) - molecular genetics , identification (biology) , genetics , medicine , biology , gene , library science , computer science , botany
To the Editor : CHARGE syndrome (CS) is an autosomal dominant disorder with involvement of several organs and systems (central nervous system, eye, ear, nose and mediastinal organs). Two sets of consensus criteria, that do not fully overlap, were proposed by Blake and Verloes, respectively (1). The causative gene for CS is CHD7 (located on chromosome 8q12.1), mutated in 60% of case series; splice-site mutations are detected in 11% of patients (2). We describe two patients, sharing some features of CHARGE phenotypic spectrum, with new, de novo, intronic mutations in CHD7. Patient 1, a male, born from first cousins parents. Clinical features included: left optic nerve coloboma, gum-cheilo-palate clefting, sensorineural hearing loss, pulmonar stenosis, esophageal atresia with tracheoesophageal fistula, psychomotor delay (Griffiths developmental quotient – DQ of 40), scoliosis and congenital fusion of lumbar vertebrae. A genetic evaluation, performed at 2 years of age, revealed dysmorphic ear, square-shaped face with asymmetry and short stature (Fig. 1a). Renal ultrasound and brain magnetic resonance imaging were normal. According to Blake and Verloes criteria, a diagnosis of CS (3/4 major and 3/7 minor criteria) and atypical CS (1/3 major and 4/5 minor signs) was hypothesized, respectively. Patient 2, a female, born from non-consanguineous parents. Clinical features included: atrio-ventricular septal defect and aortic coarctation, chorioretinal atrophy, bilateral progressive sensorineural hearing loss, and left kidney agenesis. Choanal atresia/stenosis (mild or unilateral type included) was excluded. Wechsler Intelligence Scale for Children (WISC-III) test revealed a DQ of 83. Clinical genetic examination detected: prominent nasal bridge, squared-shaped asymmetric face and crowded teeth, external ear anomalies (Fig. 1b). This patient shared two major and two minor criteria according to Blake, and three minor criteria using Verloes’ score, not sufficient for a CS diagnosis; Fig. 1. (a) Clinical features of patient 1: note squared asymmetric face, broad nasal bridge, small mouth and V-shaped upper lip, anteverted nostrils, and short neck. (b) Clinical features of patient 2: note squared asymmetric face, narrow bifrontal diameter, low set and cup shape of outer ears.