Novel variants in GNAI3 associated with auriculocondylar syndrome strengthen a common dominant negative effect

Auriculocondylar syndrome is a rare craniofacial disorder comprising core features of micrognathia, condyle dysplasia and question mark ear. Causative variants have been identified in PLCB4, GNAI3 and EDN1, which are predicted to function within the EDN1-EDNRA pathway during early pharyngeal arch patterning. To date, two GNAI3 variants in three families have been reported. Here we report three novel GNAI3 variants, one segregating with affected members in a family previously linked to 1p21.1-q23.3 and two de novo variants in simplex cases. Two variants occur in known functional motifs, the G1 and G4 boxes, and the third variant is one amino acid outside of the G1 box. Structural modeling shows that all five altered GNAI3 residues identified to date cluster in a region involved in GDP/GTP binding. We hypothesize that all GNAI3 variants lead to dominant negative effects.CRANIRAREUniversite Paris Descartes-Sorbonne Paris Cite Pole de Recherche et d'Enseignement SuperieurAgence Nationale de la Recherche (project EvoDevoMut)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)National Health and Medical Research Council of AustraliaUniv São Paulo, Inst Biociencias, Dept Genet & Biol Evolut, Ctr Pesquisas Genoma Humano & Celulas Tronco, BR-05508090 São Paulo, BrazilUniv Paris 05, Sorbonne Paris Cite, INSERM, U1163, Paris, FranceUniv São Paulo, HRCA, Dept Clin Genet, Bauru, BrazilUniv Melbourne, Royal Childrens Hosp, Murdoch Childrens Res Inst, Victorian Clin Genet Serv, Melbourne, Vic, AustraliaUniv Melbourne, Dept Paediat, Melbourne, Vic, AustraliaRoyal Childrens Hosp, Dept Plast & Maxillofacial Surg, Melbourne, Vic, AustraliaHosp Sick Children, Dept Otolaryngol Head & Neck Surg, Toronto, ON M5G 1X8, CanadaUniv São Paulo, Inst Biosci, BR-05508090 São Paulo, BrazilLeiden Univ, Med Ctr, Leiden Genome Technol Ctr, Leiden, NetherlandsUniversidade Federal de São Paulo, Inst Ciencia & Tecnol, Sao Jose Dos Campos, BrazilHop Necker Enfants Malad, AP HP, Dept Genet, Paris, FranceUniversidade Federal de São Paulo, Inst Ciencia & Tecnol, Sao Jose Dos Campos, BrazilUniversite Paris Descartes-Sorbonne Paris Cite Pole de Recherche et d'Enseignement Superieur: SPC/JFG/2013-031National Health and Medical Research Council of Australia: 607431Web of Scienc

Radiological and ct scan evaluation of mandible in patients with first and second pharingeal arches

Introdução: O 1º e 2º arcos faríngeos contribuem com o desenvolvimento craniofacial e interferências no seu desenvolvimento podem resultar em alterações de gravidade variável, envolvendo maxila, mandíbula e orelha. Das anomalias associadas à malformação de orelha externa, a hipoplasia mandibular, o dermóide epibulbar e a anomalia de coluna cervical são as mais freqüentes e, este conjunto de sinais tem sido denominado espectro oculoauriculovertebral. O EOAV é uma condição heterogênea e complexa e o espectro de anomalias inclui desde microtia isolada até outras anomalias cranianas e extracranianas. Objetivo: analisar e descrever a morfologia da mandíbula, com ênfase na articulação temporomandibular (ATM) e investigar orelha média e interna em indivíduos com anomalias de 1º e 2º arcos faríngeos cadastrados no Serviço de Genética Clinica do HRAC USP. Indivíduos estudados e métodos: avaliação genética-clínica e avaliação por imagem enfocando orelha média, interna e côndilo mandibular foram realizadas em 56 indivíduos, cadastrados no Serviço de Genética Clínica do Hospital de Reabilitação de Anomalias Craniofaciais USP. O critério mínimo utilizado foi a presença de microtia isolada ou de microssomia hemifacial com malformação auricular leve, como apêndices pré-auriculares. Resultados e conclusão: anomalias envolvendo côndilo mandibular e/ou mandíbula e anomalias de orelha média mostraram alta freqüência (87.5% e 96.1%, respectivamente) nos indivíduos da presente casuística. Relação preditiva entre a ocorrência e a gravidade das anomalias de côndilo mandibular e/ou mandíbula com o acometimento da orelha externa e, relação preditiva para a ocorrência do acometimento do côndilo mandibular com a ocorrência de anomalias estruturais de orelha média e orelha interna foram observadas. Para a avaliação da ATM, a tomografia computadorizada foi considerada o exame de eleição. A investigação das estruturas do côndilo mandibular, da orelha média e interna deve fazer parte do protocolo de avaliação dos indivíduos com anomalias de 1º e 2º arcos faríngeos.Introduction: The first and second pharingeal arches contribute to craniofacial development and interferences in normal development of these structures can result in maxillary, mandibular, and ear abnormalities. Mandible hypoplasia, epibulbar dermoids, and spinal vertebral defects are the most frequent anomalies combined with ear anomalies and this group has been called oculoauriculovertebral spectrum. This is a heterogeneous and complex condition that includes isolated microtia until other cranial and extracranial anomalies. Purpose: To analyze and describe the morphology of the mandible, with special approach to the temporomandibular joint and to investigate the middle and inner ear in patients with first and second pharyngeal arches involvement. Methods: Clinical genetics evaluation, radiological and CT scan evaluation with main focus in middle and inner ear structures as well as in mandible. This study was performed in fifty six patients at the Hospital of the Rehabilitation of the craniofacial anomalies USP. Minimal diagnostic criteria were the presence of preauricular tags or mild external ear anomaly associated to facial asymmetry. Results and Conclusions: Condyle and/or mandible and middle ear anomalies showed high frequency (87.5% and 96.1%) for the patients of the present study. Predictive relation between the occurrence and the gravity for condyle anomalies and/or mandible with involvement of the external ear was observed. Other predictive relation was observed between the occurrence of condyle anomalies with involvement of structural anomalies of middle and inner ear. CT scan proved to be the most appropriated tool for temporomandibular joint evaluation. Evaluation of condyle structures, middle and inner ear should be included in protocols for evaluation of conditions with first and second pharingeal arches involvement

Oculoauriculovertebral spectrum: report of nine familial cases with evidence of autosomal dominant inheritance and review of the literature

Oculoauriculovertebral spectrum (OAVS; OMIM 164210) is a complex condition characterized by defects of aural, oral, mandibular and vertebral development. The aetiology of this condition is likely to be heterogeneous; most cases are sporadic, however, familial cases suggesting autosomal recessive end autosomal dominant inheritance have been reported. In this study, we describe the clinical aspects of nine familial cases with evidence of autosomal dominant inheritance and compare them with reports in the literature. Interfamilial and intrafamilial clinical variabilities were observed in this study (reinforcing the necessity of careful examination of familial members). We suggest that oculoauriculovertebral spectrum with autosomal dominant inheritance is characterized mainly by bilateral auricular involvement and rarely presents extracranial anomalies. Clin Dysmorphol 18:67-77 (C) 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins

Mandibulofacial Syndrome With Growth and Mental Retardation, Microcephaly, Ear Anomalies With Skin Tags, and Cleft Palate in a Mother and Her Son: Autosomal Dominant or X-Linked Syndrome?

We report on a Brazilian mother and her son affected with mandibulofacial dysostosis, growth and mental retardation, microcephaly, first branchial arch anomalies, and cleft palate. To date only three males and one female, all sporadic cases, with a similar condition have been reported. This article describes the first familial case with this rare condition indicating autosomal dominant or X-linked inheritance

Analysis of MLL2 gene in the first Brazilian family with Kabuki syndrome

Most patients with Kabuki syndrome (KS) are the only person in their family with the condition. However, familial cases of KS have been described showing evidence that this syndrome can be inherited as a dominant trait with variable expressivity. We report on two related individuals with facial findings characteristic of KS. The proposita had arched eyebrows, long and upward slanting palpebral fissures, cleft lip and palate, retromicrognathia, brachydactyly of hands and feet, stubby fingers, nail hypoplasia, and prominent finger pads. Her mother had eyebrows with dispersed lateral half, long and upward slanting palpebral fissures, retrognathia, abnormal and posteriorly rotated ears, prominent finger pads, brachydactyly of feet, learning difficulties, and psychomotor development delay. DNA sequencing revealed a novel missense mutation in the MLL2 gene in both the proposita and her mother. The mutation (p.R5432Q) was found in the exon 51, within the SET domain of the gene, which confers methyltransferase activity on the protein. Therefore, the epigenetic and transcriptional regulatory properties of this protein may be altered and this suggests that the mutation is the cause of phenotype observed in both the patient and her mother. The clinical signs and the molecular evidence in this family further support the notion that KS is an autosomal dominant condition with variable expressivity. To our knowledge this is the first report of a Brazilian family with recurrence of this syndrome. (C) 2012 Wiley Periodicals, Inc.NIH [DE08559]NI