RESUMO
BACKGROUND: In 1993, Chitayat et al., reported a newborn with hyperphalangism, facial anomalies, and bronchomalacia. We identified three additional families with similar findings. Features include bilateral accessory phalanx resulting in shortened index fingers; hallux valgus; distinctive face; respiratory compromise. OBJECTIVES: To identify the genetic aetiology of Chitayat syndrome and identify a unifying cause for this specific form of hyperphalangism. METHODS: Through ongoing collaboration, we had collected patients with strikingly-similar phenotype. Trio-based exome sequencing was first performed in Patient 2 through Deciphering Developmental Disorders study. Proband-only exome sequencing had previously been independently performed in Patient 4. Following identification of a candidate gene variant in Patient 2, the same variant was subsequently confirmed from exome data in Patient 4. Sanger sequencing was used to validate this variant in Patients 1, 3; confirm paternal inheritance in Patient 5. RESULTS: A recurrent, novel variant NM_006494.2:c.266A>G p.(Tyr89Cys) in ERF was identified in five affected individuals: de novo (patient 1, 2 and 3) and inherited from an affected father (patient 4 and 5). p.Tyr89Cys is an aromatic polar neutral to polar neutral amino acid substitution, at a highly conserved position and lies within the functionally important ETS-domain of the protein. The recurrent ERF c.266A>C p.(Tyr89Cys) variant causes Chitayat syndrome. DISCUSSION: ERF variants have previously been associated with complex craniosynostosis. In contrast, none of the patients with the c.266A>G p.(Tyr89Cys) variant have craniosynostosis. CONCLUSIONS: We report the molecular aetiology of Chitayat syndrome and discuss potential mechanisms for this distinctive phenotype associated with the p.Tyr89Cys substitution in ERF.
Assuntos
Anormalidades Múltiplas/genética , Síndrome de Dandy-Walker/genética , Deficiências do Desenvolvimento/genética , Ossos Faciais/anormalidades , Proteínas Repressoras/genética , Anormalidades Múltiplas/fisiopatologia , Broncomalácia/genética , Broncomalácia/fisiopatologia , Síndrome de Dandy-Walker/fisiopatologia , Deficiências do Desenvolvimento/fisiopatologia , Exoma/genética , Face/fisiopatologia , Ossos Faciais/fisiopatologia , Feminino , Hallux Valgus/genética , Hallux Valgus/fisiopatologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Recém-Nascido , Masculino , FenótipoRESUMO
BACKGROUND: This paper presents the results of an exploratory qualitative study that assesses Canadian pediatric researchers' perceptions of a pre-selected group of ethical issues raised by pharmacogenomics research with children. METHODS: As a pilot study, we conducted semi-structured telephone interviews with Canadian pediatric pharmacogenomic researchers. The interviews were guided by the following themes: (1) benefits and risks of inclusion, (2) the consent/assent process, and (3) the return of research results. RESULTS: Issues about assent, consent, risks and benefits, as well as the communication of results were addressed by the respondents. Some issues, such as the unique vulnerability of children, the long term privacy concerns associated with biobanking, additional core elements that need to be discussed and included in the consent/assent forms, as well as the challenges of communicating research results in a pediatric research were not explicitly identified by the respondents. CONCLUSION: Further consideration should be given to address the ethical challenges of including children in pharmacogenomics research. This exploratory study indicates that further guidance is needed if children are to be protected and yet benefit from such research.