OculoDentoDigital Dysplasia (ODDD) via the GJA1 Gene

OculoDentoDigital Dysplasia (ODDD) is a autosomal dominant (AD) disorder. Rarely, autosomal recessive (AR) transmission also been reported. ODDD is characterized by pleiotropic malformations of the eyes, face, limbs, and dentition. High penetrance and marked intra- and inter-familial phenotypic variability has been reported in ODDD (Paznekas et al. 2009). Glaucoma is the main cause of vision loss in ODDD. Other ocular malformations include microphthalmia, microcornea, fine porous spongy iris abnormalities, and cataracts (Musa et al. 2008). Characteristic facial appearance includes a long narrow nose, hypoplastic alae nasi, anteverted nostrils, and a prominent columella and nasal bridge. Dental abnormalities include microdontia, hypodontia, and enamel hypoplasia. Digital abnormalities include syndactyly of finger 4/5, and hypoplastic phalanges (Frasson et al. 2004; Musa et al. 2008; Jamsheer et al. 2014). Less common symptoms include hypotrichosis, intracranial calcifications, and conductive deafness secondary to recurrent otitis media (Frasson et al. 2004).

ODDD is caused by mutations in the GJA1 (gap junction alpha 1) gene, which is located on chromosome 6q21–q23.2. ODDD is mainly an AD disorder due to mutations in GJA1. However, rarely AR inheritance has also been reported. The AD mutations in GJA1 have been reported to reduce channel function and act in dominant-negative manner (Richardson 2005). The two AR mutations that have been reported so far are p.R33* and p.Arg76His. The homozygous carriers of the p.R33*mutation had severe developmental defects typically associated with ODDD. When the p.Arg76 residue is substituted by serine (p.Arg76Ser), the patients showed the ODDD phenotype with dominant inheritance. A different substitution of the same amino acid (p.Arg76His) exhibited recessive inheritance with a Hallermann-Streiff syndrome (HSS)/ODDD overlapping phenotype. HSS is characterized by typical skull shape, hypotrichosis, congenital cataracts, beaked nose and dental anomalies (Pizzuti et al. 2004; Richardson et al. 2004). Functional studies have shown that the p.Arg76His mutant exhibited no dominant-negative properties and p.R33* showed modest dominant negative effect (Huang et al. 2013). To date, about 100 causative mutations involved with ODDD have been reported in GJA1. The great majority of these are missense mutations (97%) (Jamsheer et al. 2014; Human Gene Mutation Database).

GJA1 encoded protein connexin 43 (Cx43) is expressed in the most anterior portion of the forebrain and in the developing neural folds. Additionally, it is expressed in the developing and adult eye and also during early limb development (Richardson et al. 2004). Mouse model studies indicated that Cx43 is a major component of the gap junctions between pigmented and non-pigmented cells of the double layered epithelium of the ciliary body and is required for the production of the aqueous humor that is in turn required for the generation of normal intraocular pressure and nourishment of the postnatal lens (Calera et al. 2006).

A GJA1 mutation analysis study detected GJA1 mutations in all ODDD affected patients (177 affected individuals from 54 families) (Paznekas et al. 2003; Paznekas et al. 2009).

No gross deletions or duplications have been reported in the GJA1 gene (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the GJA1 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).