Abstract
BackgroundOculodentodigital dysplasia (ODDD) is a rare disorder with pleiotropic effects involving multiple body systems, caused by mutations in the gap junction protein alpha 1 (GJA1) gene. GJA1 gene encodes a polytopic connexin membrane protein, Cx43, that is a component of connexon membrane channels.MethodsWe describe two unrelated female probands referred for a genetic review in view of a dysmorphic clinical phenotype.ResultsTwo novel missense mutations in GJA1 that substitute conserved amino acids in the first and second transmembrane domains (NM_000165.5: c.77T>C p.Leu26Pro and NM_000165.5:c.287T>G p.Val96Gly) were detected through targeted sequencing of GJA1. These variants were detected in the heterozygous state in the two Maltese probands and segregated with the disease phenotype.ConclusionThis report further expands the mutational spectrum of ODDD.
Highlights
Oculodentodigital dysplasia (ODDD) (OMIM#164200) is a rare disorder characterized by various ophthalmic, dental, skeletal, and craniofacial anomalies
ODDD is primarily an autosomal dominant disorder caused by mutations in the gap junction protein alpha 1 (GJA1, OMIM#121014, HGNC ID: 4274, NM_000165.5) gene, which encodes the connexin 43 (Cx43) transmembrane protein (Paznekas et al, 2003)
Sanger sequencing of GJA1 gene in the probands and family members identified two novel variants that segregate with the phenotype, suggestive of causality
Summary
Oculodentodigital dysplasia (ODDD) (OMIM#164200) is a rare disorder characterized by various ophthalmic, dental, skeletal, and craniofacial anomalies. ODDD is primarily an autosomal dominant disorder caused by mutations in the gap junction protein alpha 1 (GJA1, OMIM#121014, HGNC ID: 4274, NM_000165.5) gene, which encodes the connexin 43 (Cx43) transmembrane protein (Paznekas et al, 2003). Typical ophthalmologic abnormalities include microphthalmia, microcornea, and various anomalies that involve the iris, which can lead to glaucoma, cataracts, and optic neuropathy. A variety of neurological manifestations have been reported, including lower limb spastic paraparesis, ataxic gait, seizures, neurogenic bladder, and uncommonly, psychomotor retardation These neurological features of ODDD involve 30%. A wide array of human pathologies are caused by mutations in connexin genes, including peripheral neuropathies, skin disorders, non‐syndromic hearing loss and congenital cataract (Abrams & Scherer, 2012; Krutovskikh & Yamasaki, 2000; Lee & White, 2009). Sanger sequencing of GJA1 gene in the probands and family members identified two novel variants that segregate with the phenotype, suggestive of causality
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