CHARGE association (MIM 214800) is a sporadic disorder, characterised by coloboma of the eye, choanal atresia, cranial nerve dysfunction, characteristic external and inner ear abnormalities, cardiac anomalies, genitourinary abnormalities, and growth retardation. Various chromosomal rearrangements have been reported in rare patients with a CHARGE-like phenotype. These include balanced translocation between chromosomes 6 and 8,¹ unbalanced translocations involving chromosomes 2 and 18, 3 and 22,² partial trisomy of 19q with partial monosomy 21q,³ inverted duplication of chromosome 14 (14q22→q24.3),⁴ and partial trisomy of 2q.⁵ Based in part on the inconsistent chromosomal aberrations in rare patients with CHARGE association, it is most likely that this condition is genetically heterogeneous. Within the group of children with CHARGE association, there is clearly a subgroup with distinctive clinical characteristics that appears to have a recognisable syndrome.⁶ Previously, a systematic scan for loss of heterozygosity using microsatellite markers in 10 such patients failed to identify a discernible submicroscopic deletion.⁷ Although several candidate genes such as PITX2⁸ and PAX2⁹ have been investigated, no mutations have been identified in patients with CHARGE syndrome. Here, we demonstrate a de novo mutation in SEMA3E in an affected patient, identified upon mapping the translocation breakpoints in an unrelated individual with a de novo balanced translocation involving chromosomes 2 and 7: karyotype 46,XY,t(2;7)(p14;q21.11).

METHODS

The study sample includes 72 patients, of whom 43 have either four major criteria for CHARGE (coloboma, choanal atresia, characteristic ear abnormality, and cranial nerve dysfunction) or three major and three minor criteria (genital hypoplasia, developmental delay, cardiovascular malformations, growth deficiency, orofacial cleft, tracheo-oesopageal fistula, and characteristic face) as described by Blake et al.¹⁰ This set of patients was used for all FISH analyses, DHPLC, and candidate gene sequencing. An additional 29 patients with clinical diagnosis of CHARGE, …