Dataset Information

VAX1 mutation associated with microphthalmia, corpus callosum agenesis, and orofacial clefting: the first description of a VAX1 phenotype in humans.

ABSTRACT: Vax1 and Vax2 have been implicated in eye development and the closure of the choroid fissure in mice and zebrafish. We sequenced the coding exons of VAX1 and VAX2 in 70 patients with anophthalmia/microphthalmia (A/M). In VAX1, we observed homozygosity for two successive nucleotide substitutions c.453G>A and c.454C>A, predicting p.Arg152Ser, in a proband of Egyptian origin with microphthalmia, small optic nerves, cleft lip/palate, and corpus callosum agenesis. This mutation affects an invariant residue in the homeodomain of VAX1 and was absent from 96 Egyptian controls. It is likely that the mutation results in a loss of function, as the mutation results in a phenotype similar to the Vax1 homozygous null mouse. We did not identify any mutations in VAX2. This is the first description of a phenotype associated with a VAX1 mutation in humans and establishes VAX1 as a new causative gene for A/M.

SUBMITTER: Slavotinek AM

PROVIDER: S-EPMC3401628 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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VAX1 mutation associated with microphthalmia, corpus callosum agenesis, and orofacial clefting: the first description of a VAX1 phenotype in humans.

Slavotinek Anne M AM Chao Ryan R Vacik Tomas T Yahyavi Mani M Abouzeid Hana H Bardakjian Tanya T Schneider Adele A Shaw Gary G Sherr Elliott H EH Lemke Greg G Youssef Mohammed M Schorderet Daniel F DF

Human mutation 20111227 2

Vax1 and Vax2 have been implicated in eye development and the closure of the choroid fissure in mice and zebrafish. We sequenced the coding exons of VAX1 and VAX2 in 70 patients with anophthalmia/microphthalmia (A/M). In VAX1, we observed homozygosity for two successive nucleotide substitutions c.453G>A and c.454C>A, predicting p.Arg152Ser, in a proband of Egyptian origin with microphthalmia, small optic nerves, cleft lip/palate, and corpus callosum agenesis. This mutation affects an invariant r ...[more]

PMID: 22095910

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Project description:Although children with oral clefts have a higher risk for dental anomalies when compared with the general population, prior studies have shown conflicting results regarding their dental decay risk. Also, few studies have assessed dental decay risk in unaffected relatives of children with clefts. Thus, the question of increased risk of dental decay in individuals with oral clefts or their unaffected relatives is still open for empirical investigation. This study characterizes dental decay in the largest international cohort to date of children with nonsyndromic clefts and their relatives, as compared with controls, and it addresses whether families with oral clefts have a significantly increased risk for dental decay versus the general population. A total of 3,326 subjects were included: 639 case probands, 1,549 unaffected relatives, and 1,138 controls. Decay was identified from in-person dental examinations or intraoral photographs. Case-control differences were tested with regression analysis. No significant differences were shown in percentage decayed and filled teeth and decayed teeth in the primary dentition (dft, dt) and permanent dentition (DFT, DT) in cases versus controls. In the cleft region, no significant differences were seen in primary or permanent decay (dt, DT) when compared with controls. No difference was found with regard to cleft type and percentage dft, dt, DFT, and DT in case probands. Nonsignificant differences were found in unaffected siblings and parents versus controls (primary and permanent dentitions). Collectively, these findings indicate that individuals with nonsyndromic oral clefts and their families do not have a higher dental decay risk as compared with the general population. These results suggest that either genetic or environmental factors underlying a higher susceptibility for dental anomalies do not increase caries risk or that the seemingly higher risk for dental decay associated with increased dental anomalies in case probands may be superseded by possible greater access to dental care.

Project description:BackgroundImpaired social functioning is a common symptom of individuals with developmental disruptions in callosal connectivity. Among these developmental conditions, agenesis of the corpus callosum provides the most extreme and clearly identifiable example of callosal disconnection. To date, deficits in nonliteral language comprehension, humor, theory of mind, and social reasoning have been documented in agenesis of the corpus callosum. Here, we examined a basic social ability as yet not investigated in this population: recognition of facial emotion and its association with social gaze.MethodsNine individuals with callosal agenesis and nine matched controls completed four tasks involving emotional faces: emotion recognition from upright and inverted faces, gender recognition, and passive viewing. Eye-tracking data were collected concurrently on all four tasks and analyzed according to designated facial regions of interest.ResultsIndividuals with callosal agenesis exhibited impairments in recognizing emotions from upright faces, in particular lower accuracy for fear and anger, and these impairments were directly associated with diminished attention to the eye region. The callosal agenesis group exhibited greater consistency in emotion recognition across conditions (upright vs. inverted), with poorest performance for fear identification in both conditions. The callosal agenesis group also had atypical facial scanning (lower fractional dwell time in the eye region) during gender naming and passive viewing of faces, but they did not differ from controls on gender naming performance. The pattern of results did not differ when taking into account full-scale intelligence quotient or presence of autism spectrum symptoms.ConclusionsAgenesis of the corpus callosum results in a pattern of atypical facial scanning characterized by diminished attention to the eyes. This pattern suggests that reduced callosal connectivity may contribute to the development and maintenance of emotion processing deficits involving reduced attention to others' eyes.

Dataset Information

VAX1 mutation associated with microphthalmia, corpus callosum agenesis, and orofacial clefting: the first description of a VAX1 phenotype in humans.

Publications

VAX1 mutation associated with microphthalmia, corpus callosum agenesis, and orofacial clefting: the first description of a VAX1 phenotype in humans.

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