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Expanding the spectrum of SMAD3-related phenotypes to agnathia-otocephaly.
Meier, Nicole; Bruder, Elisabeth; Miny, Peter; Tercanli, Sevgi; Filges, Isabel.
Afiliación
  • Meier N; Medical Genetics, Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel, Basel, Switzerland.
  • Bruder E; Department of Clinical Research, University Hospital Basel, Basel, Switzerland.
  • Miny P; Pathology, Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel, Basel, Switzerland.
  • Tercanli S; Medical Genetics, Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel, Basel, Switzerland.
  • Filges I; Centre for Prenatal Ultrasound, Basel, Switzerland.
Mol Genet Genomic Med ; 8(4): e1178, 2020 04.
Article en En | MEDLINE | ID: mdl-32100971
BACKGROUND: Agnathia-otocephaly is a rare and lethal anomaly affecting craniofacial structures derived from the first pharyngeal arch. It is characterized by agnathia, microstomia, aglossia, and abnormally positioned auricles with or without associated anomalies. Variants affecting function of OTX2 and PRRX1, which together regulate the neural crest cells and the patterning of the first pharyngeal arch as well as skeletal and limb development, were identified to be causal for the anomaly in a few patients. METHODS: Family-based exome sequencing (ES) on a fetus with severe agnathia-otocephaly, cheilognathopalatoschisis, laryngeal hypoplasia, fused lung lobes and other organ abnormalities and mRNA expression analysis were performed. RESULTS: Exome sequencing detected a de novo SMAD3 missense variant in exon 6 (c.860G>A) associated with decreased mRNA expression. Variants in SMAD3 cause Loeys-Dietz syndrome 3 presenting with craniofacial anomalies such as mandibular hypoplasia, micro- or retro-gnathia, bifid uvula and cleft palate as well as skeletal anomalies and arterial tortuosity. The SMAD3 protein acts as a transcriptional regulator in the transforming growth factor ß (TGFB) and bone morphogenetic (BMP) signaling pathways, which play a key role in the development of craniofacial structures originating from the pharyngeal arches. CONCLUSION: Agnathia-otocephaly with or without associated anomalies may represent the severe end of a phenotypic spectrum related to variants in genes in the interacting SMAD/TGFB/BMP/SHH/FGF developmental pathways.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fenotipo / Anomalías Craneofaciales / Proteína smad3 / Feto Tipo de estudio: Diagnostic_studies / Prognostic_studies Límite: Humans Idioma: En Revista: Mol Genet Genomic Med Año: 2020 Tipo del documento: Article País de afiliación: Suiza Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fenotipo / Anomalías Craneofaciales / Proteína smad3 / Feto Tipo de estudio: Diagnostic_studies / Prognostic_studies Límite: Humans Idioma: En Revista: Mol Genet Genomic Med Año: 2020 Tipo del documento: Article País de afiliación: Suiza Pais de publicación: Estados Unidos