Аutosomal Dominant Oculodental-Digital Dysplasia with Mutation in Gene GJA1 (Clinical Case)

The purpose: to describe clinical cases of oculodental-digital dysplasia (ODDD, OMIM #164200) with mutation in GJA1 (OMIM 121014) with molecular genetic verification of the diagnosis.

Methods. The article describes the clinical case of oculodental-digital dysplasia in a 51 years old patient. Patient underwent full ophthalmic examination including autorefractometry, visual acuity testing with full correction, tonometry, biomicroscopy, fundus examination and photo as well as kinetic perimetry, autofluorescence and optical coherence tomography (OCT) of macula and optic disk were performed. Electrophysiological examination included Visual Evoked Potentials (VEP) to flash and pattern stimulation, ISCEV standard electroretinograms (ERG) and macular ERG. For the verification of the diagnosis and pathologic gene molecular genetic examination was performed with family anamnesis previously attained.

Results. The patient was complaining the deterioration of vision, hearing loss and the sense of smell. Visual deterioration was associated with nyctalopia. Natural history revealed glaucoma 2а which was diagnosed when he was 48 years old. Best corrected visual acuity was 1,0. Peripheral visual field defects were revealed bilaterally. High visual acuity correlated with normal foveal structure on OCTs the retinal nerve fiber layer (RNFL) was thinner than normal in temporal half; deep excavation was visualized in both eyes. Normal MERG and bilateral decrease of scotopic, maximal full-field ERG was recorded which correlated with nyctalopia, as well as subnormal photopic responses indicating cone system involvement. The genetics revealed characteristic features of the face: a small nose with hypoplasia of the wings of the nose, unfolded nostrils and a wide bridge of the nose (pseudohypertelorism). On right-wing the ear sink was detected 2 antitraguses. Changes fingers upper extremities — operated syndactyly IV and V on the background of brachydactyly of the fingers. On the legs on both sides — syndactyly III–IV. 10 years the sense of smell has been dereriorated. In the study of DNA in proband in direct Sanger sequencing of all exons 1–2 and regions of exon-intron compounds of gene GJA1, was found the pathogenic variant in second exon c.412G>A (p.Gly138Ser) in heterozygous state. Was established autosomal dominant type of disease.

Conclusion. We are the first to describe rod-cone dystrophy in oculodental-digital dysplasia.

1. Meyer-Schwickerath G., Gruterich E., Weyers H. Mikrophthalmussyndrome. Klin. Monatsbl. Augenheilkd. 1957;131:18–30.

2. Judisch G.F., Martin-Casals A., Hanson J.W., Olin W.H. Oculodentodigital dysplasia: four new reports and a literature review. Arch. Ophthal. 1979;97:878– 884.

3. Gutmann D.H., Zackai E.H. McDonald-McGinn D.M., Fischbeck K.H., Kamholz J. Oculodentodigital dysplasia syndrome associated with abnormal cerebral white matter. Am. J. Med. Genet. 1991;41:18–20. DOI: 10.1002/ajmg.1320410106

4. De Bock M., Kerrebrouck M., Wang N., Leybaert L. Neurological manifestations of oculodentodigital dysplasia: a Cx43 channelopathy of the central nervous system? Front. Pharm. 2013;4:120. Note: Electronic Article. DOI: 10.3389/fphar.2013.00120

5. Brice G., Ostergaard P., Jeffery S. A novel mutation in GJA1 causing oculodentodigital syndrome and primary lymphoedema in a three generation family. Clin. Genet. 2013;84:378–381. DOI: 10.1111/cge.12158

6. Corcos I.A., Meese E.U., Loch-Caruso R. Human connexin 43 gene locus, GJA1, sublocalized to band 6q21-q23.2. Cytogenet. Cell Genet. 1993;64:31–32. DOI: 10.1159/000133554

7. Gabriel L.A.R., Sachdeva R., Marcotty A. Oculodentodigital dysplasia: new ocular findings and a novel connexin 43 mutation. Arch. Ophthal. 2011;129:781–784. DOI: 10.1001/archophthalmol.2011.113

8. Paznekas W.A., Karczeski B., Vermeer S. GJA1 mutations, variants, and connexin 43 dysfunction as it relates to oculodentodigital dysplasia phenotype. Hum. Mutat. 2009;30:724–733. DOI: 10.1002/humu.20958

9. Paznekas W.A., Boyadjiev S.A., Shapirob R.E. Connexin 43 (GJA1) mutations cause the pleiotropic phenotype of oculodentodigital dysplasia. Am. J. Hum. Genet. 2003;72:408–418. DOI: 10.1086/346090

10. Boyadjiev S.A., Jabs E.W., LaBuda M. Linkage analysis narrows the critical region for oculodentodigital dysplasia to chromosome 6q22-q23. Genomics. 1999;58:34– 40. DOI: 10.1006/geno.1999.5814

11. Dasgupta C., Martinez A.-M., Zuppan C.W. Identification of connexin43 (alpha-1) gap junction gene mutations in patients with hypoplastic left heart syndrome by denaturing gradient gel electrophoresis (DGGE). Mutat. Res. 2001;479:173–186.

12. Hu Y., Chen I., de Almeida S. A novel autosomal recessive GJA1 missense mutation linked to craniometaphyseal dysplasia. PLoS One. 2013;8:e73576. Note: Electronic Article. DOI: 10.1371/journal.pone.0073576

13. Boyden L.M., Craiglow B.G., Zhou J. Dominant de novo mutations in GJA1 cause erythrokeratodermia variabilis et progressiva, without features of oculodentodigital dysplasia. J. Invest. Derm. 2015;135:1540–1547. DOI: 10.1038/jid.2014.485

14. Wang H., Cao X., Lin Z. Exome sequencing reveals mutation in GJA1 as a cause of keratoderma-hypotrichosis-leukonychia totalis syndrome. Hum. Molec. Genet. 2015;24(1):243–250. DOI: 10.1093/hmg/ddu442

15. Richardson R.R., Donnai D., Meire F., Dixon M.J. Expression of Gja1 correlates with the phenotype observed in oculodentodigital syndrome/type III syndactyly. J. Med. Genet. 2004;41:60–67. DOI: 10.1136/jmg.2003.012005

16. Van Steensel M.A.M., Spruijt L., van der Burgt I. A 2-bp deletion in the GJA1 gene is associated with oculo-dento-digital dysplasia with palmoplantar keratoderma. Am. J. Med. Genet. 2005;132A:171–174. DOI: 10.1002/ajmg.a.30412

17. Traboulsi E.I., Parks M.M. Glaucoma in oculo-dento-osseous dysplasia. Am. J. Ophthal. 1990;109:310–313.

18. Himi M., Fujimaki T., Yokoyama T. A case of oculodentodigital dysplasia syndrome with novel GJA1 gene mutation. Japanese Journal of Ophthalmology 2009;53(5):541– 545. DOI: 10.1007/s10384-009-0711-6

19. Tsui E., Hill K.A., Laliberte A.M. Ocular pathology relevant to glaucoma in a Gja1(Jrt/+) mouse model of human oculodentodigital dysplasia. Invest. Ophthal. Vis. Sci. 2011;52:3539–3547. DOI: 10.1167/iovs.10-6399

20. van Genderen M.M., Kinds G.F., Riemslag F.C., Hennekam R.C. Ocular features in Rubinstein-Taybi syndrome: investigation of 24 patients and review of the literature. Br J Ophthalmol. 2000;84(10):1177–1184. DOI: 10.1136/bjo.84.10.1177