Expression of Gja1 correlates with the phenotype observed in oculodentodigital syndrome/type III syndactyly

culodentodigital syndrome (ODD; OMIM 164200) is a congenital disorder characterised by developmental abnormalities of the face, eyes, limbs, and dentition. ODD is inherited in an autosomal dominant fashion and displays high penetrance but variable expression. Facially, affected patients exhibit a long, narrow nose with hypoplastic alae, thin, anteverted nostrils and a prominent nasal bridge, short palpebral fissures, and bilateral microcornea often with anomalies of the iris. 3 4 Secondary glaucoma occurs in a number of patients. 5 Bilateral complete syndactyly of the fourth and fifth fingers (type III syndactyly) is the characteristic digital malformation. The third finger may occasionally also be involved and associated camptodactyly is a common finding. 2 In addition, microdontia and generalised hypoplasia of the enamel, which tends to affect both the primary and secondary dentitions, are frequently observed. 2 6 ] Spastic paraparesis or lower limb weakness in association with ODD has been reported in a number of sporadic and familial cases. 2 6 9-11 In two of these reports, magnetic resonance imaging demonstrated an underlying leukodystrophy and it has, therefore, been proposed that the definition of ODD be widened to include these features. 10 11 Type III syndactyly has also been reported to occur as an isolated entity in several autosomal dominant pedigrees and it is uncertain whether this anomaly and ODD are separate genetic entities or part of the same disease spectrum. 12-15 However, a family has been reported who, while not exhibiting the usual ocular or dental anomalies associated with ODD, did have a facial appearance that appeared to bridge the gap between the two conditions. he ODD locus was initially mapped to a 28 cM region of human chromosome 6q22-q24, 17 which was subsequently refined to the 1.9 cM genetic interval delineated by the polymorphic markers D6S261, proximally, and D6S1639, distally. 18 This study further indicated that ODD with associated neurological defects maps to this same interval. Recently, Paznekas and coworkers reported that the pleiotropic phenotype of ODD arises as the result of mutation of GJA1, the gene encoding the gap junction protein, connexin 43. In the current paper, we report nine different missense mutations, seven of which have not been described previously, in 10 unrelated families and confirm that type III syndactyly, at least in a subset of cases, is allelic with ODD. Using whole mount in situ hybridisation to analyse a developmental series of morphologically-staged embryos, we further demonstrate that there is a strong correlation between the sites of Gja1 expression and the clinical phenotype.