Phenotype and genetic variant analysis of seven pedigrees affected with blepharophimosis syndrome / 中华医学遗传学杂志

OBJECTIVE@#To analyze the clinical manifestations and gene variants of patients with blepharophimosis, ptosis and epicanthus inversus syndrome (BPES).@*METHODS@#Clinical data of 7 pedigrees affected with BPES were collected, and genomic DNA was extracted from peripheral blood samples of the probands and their relatives. All exons of the FOXL2 gene were subjected to Sanger sequencing. Those with negative findings were further screened by targeted capture and next generation sequencing (NGS) and microarray analysis. Pathogenicity of candidate variants were predicted by search of PubMed and related databases, and the impact of the variants was interpreted by protein prediction software. Diagnosis was confirmed by clinical phenotype, medical history and mutation analysis.@*RESULTS@#A pathogenic variant was identified in six of the 7 pedigrees, which included four known pathogenic variants and one novel FOXL2 c.299dupA variant. A heterozygous 3q22.3q23 deletion, which encompassed the FOXL2 gene, was identified in another pedigree.As predicted, the c.299dupA frameshift mutation of FOXL2 gene can lead to the premature termination of protein translation, which is pathogenic.@*CONCLUSION@#A novel and 5 known pathogenic variants have been identified in six pedigrees affected with BPES by the combined Sanger sequencing, target capture NGS and microarray analysis. Above findings have enabled genetic counseling and prenatal diagnosis for these pedigrees.

Estudos moleculares em anomalias craniofaciais raras: sindrome blefaroqueilodontica e efeitos de linha media facial com hipertelorismo / Molecular biological studies in rare craniofacial anomalies

A Síndrome Blefaroqueilodôntica (BCD) e os Defeitos de Linha Média Facial com Hipertelorismo (DLMFH) são defeitos craniofaciais raros. Por esse motivo, os estudos de grandes casuísticas têm sido limitados. Contribuição científica significativa neste assunto tem sido dada por nosso grupo, que delineou características clínicas e diretrizes para seguimento de longo prazo e evidenciou achados neuroradiológicos em ambas as anomalias. Embasado nesses achados preliminares e evidências recentes da literatura pertinente, foi possível estabelecer uma estratégia inicial para investigação etiológica da BCD e dos DLMFH, sendo os objetivos desse projeto: investigar a etiologia da BCD nos indivíduos afetados pela síndrome, por meio de estudo dos genes candidatos IRF6, P63, OSR2, TBX10, FOXE1, SHH, FGF8 e PAX3; pesquisar, nos indivíduos com DLMFH, a presença de mutações nos genes candidatos SHH, FGF8 e PAX3; identificar, em ambas as malformações, possíveis alterações cromossômicas; e, por último, associar os achados clínicos detectados nas investigações anteriores aos possíveis achados moleculares. Foram utilizadas técnicas de sequenciamento direto, array-CGH, genotipagem automática e hibridação in situ por fluorescência. Não foi possível relacionar nenhuma mutação pontual nos genes estudados associadas às malformações em questão, pois não foram encontradas alterações gênicas patogênicas. Entretanto foram detectadas em pacientes com DLFMH três aberrações cromossômicas em regiões distintas do genoma, tratando-se de um caso de duplicação no cromossomo...

The Blepharocheilodontic Syndrome (BCD) and Midline Facial Defects with Ocular Hypertelorism (MFDH) are rare craniofacial anomalies. Considering the rarity of these two groups of congenital defects, studies with large casuistry have been limited. Our group has significantly contributed to the scientific knowledge about both anomalies, delineating clinical characteristics, evidencing neurological findings and designing protocols for long term follow-up. Based in these preliminary findings and recent evidences of pertinent literature, it was possible to determine an initial etiologic investigation strategy for the BCD and the MFDH. The objectives of this project are to investigate the etiology of the BCD in affected individuals through IRF6, P63, OSR2, TBX10, FOXE1, SHH, FGF8 and PAX3 candidate genes study; to search MFDH patients for mutations in the SHH, FGF8 and PAX3 candidate genes; to identify, in both syndromes...