Three novel GJA1 missense substitutions resulting in oculo-dento-digital dysplasia (ODDD) — Further extension of the mutational spectrum

• Published in: Gene 2014-04, Vol.539 (1), p.157-161
• Main Authors: Jamsheer, Aleksander, Sowińska-Seidler, Anna, Socha, Magdalena, Stembalska, Agnieszka, Kiraly-Borri, Cathy, Latos-Bieleńska, Anna
• Format: Article
• Language: English
• Subjects: Abnormalities, Multiple - genetics; Amino Acid Sequence; Amino Acid Substitution - genetics; Child, Preschool; Connexin 43; Connexin 43 - genetics; Craniofacial Abnormalities - genetics; Eye Abnormalities - genetics; Facies; Female; Fingers - abnormalities; Foot Deformities, Congenital - genetics; GJA1; Humans; Limb Deformities, Congenital - genetics; Male; Missense mutation; Mutation, Missense - genetics; Oculo-dento-digital dysplasia; Oculo-dento-osseous syndrome; ODDD; ODDS; Sequence Analysis, DNA; Syndactyly - genetics; Tooth Abnormalities - genetics
• ISSN: 0378-1119; 1879-0038
• DOI: 10.1016/j.gene.2014.01.066

Oculodentodigital dysplasia (ODDD) is a clinically variable genetic disorder caused by mutations of the GJA1 gene, predominantly inherited in an autosomal dominant fashion. In rare cases ODDD can also exhibit autosomal recessive mode of inheritance. The phenotype of ODDD comprises craniofacial (short and narrow palpebral fissure, thin, narrow nose with hypoplastic alae nasi), dental (oligodontia, hypoplastic enamel), and digital abnormalities (syndactyly of finger 4/5, hypoplastic phalanges). Ocular manifestation is typical and involves microphthalmia, microcornea, glaucoma, congenital malformations of iris or vitreous, ectopic pupils or strabismus. To date, only 67 GJA1 mutations have been described to underlie ODDD and most of them (i.e. 97%) represent missense substitutions. In this report, we describe three (two familial and one sporadic) non-consanguineous cases presenting with ODDD features in whom we identified novel missense heterozygous mutations of the GJA1 gene: c.317T>G (p. L106R), c.G139C (p.D47H), and c.C257A (p.S86Y). The first two mutations were inherited from an affected parent, whereas the latter one occurred de novo. The mutations affect highly conserved amino acid residues located in the different portions of the GJA1 protein. Our report broadens the spectrum of probably pathogenic mutations associated with ODDD phenotype and demonstrates that the amino acid substitutions at highly conserved positions 47, 86, 106 may affect protein functioning and lead to the development of this syndrome. Together with molecular data, we provide a brief clinical description of the affected individuals. •We report three novel missense heterozygous GJA1 mutations associated with ODDD.•List of GJA1 mutations: c.G139C (p.D47H), c.C257A (p.S86Y), c.317T>G (p. L106R)•Pictures and clinical symptoms of two families and one sporadic case are provided.•All three missense variants are predicted to be damaging by in silico analyses.