Clinical and genetic analysis of a patient with Craniofrontonasal syndrome
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目的 探讨1例颅额鼻综合征(CNFS)患者的临床特征及遗传学病因。 方法 选取2021年11月13日于贵阳市妇幼保健院就诊的1例CNFS患者为研究对象。收集患者的临床资料，抽取患者及其父母的外周静脉血样，进行家系全外显子组测序(trio-WES)与Sanger测序验证，并对候选变异进行生物信息学分析。 结果 患者为15岁女性，以前额膨凸、眼距与鼻背过宽、双鼻尖为主要临床表现。基因检测结果提示其携带EFNB1基因c.473T>C(p.M158T)杂合错义变异，其父母均未携带该变异。生物信息学分析：EFNB1基因c.473T>C(p.M158T)变异在HGMD及ClinVar数据库中未见收录，在1000 Genomes、ExAC、gnomAD及神州基因组数据云等数据库中均未见人群携带频率收录；经REVEL在线软件预测，该变异对基因或基因产物可造成有害影响；经UGENE软件分析，该变异位点所编码的氨基酸在不同物种间高度保守；经AlphaFold2软件进行3D建模显示，该变异可能影响Ephrin-B1蛋白的结构与功能。根据美国医学遗传学与基因组学学会(ACMG)指南与临床基因组资源中心(ClinGen)的建议，该变异被评级为致病性变异。 结论 结合患者的临床特征与基因检测结果，确诊其为CNFS，EFNB1基因c.473T>C(p.M158T)杂合错义变异可能为该患者的遗传学病因。上述发现为其家系的遗传咨询和产前诊断提供了依据。 Objective To explore the clinical feature and genetic etiology of a patient with Craniofacial nasal syndrome (CNFS). Methods A patient with CNFS who had presented at the Guiyang Maternal and Child Health Care Hospital on November 13, 2021 was selected as the study subject. Clinical data of the patient were collected. Peripheral venous blood samples were collected from the patient and her parents and subjected to trio-whole exome sequencing (trio-WES). Candidate variants were verified by Sanger sequencing and bioinformatic analysis. Results The patient, a 15-year-old female, had predominantly featured forehead bulging, hypertelorism, wide nasal dorsum and bifid nasal tip. Genetic testing revealed that she has harbored a heterozygous missense c. 473T>C (p.M158T) variant of theEFNB1 gene, which was detected in either of her parents. By bioinformatic analysis, the variant has not been recorded in the HGMD and ClinVar databases, and no population frequency was recorded in the 1000 Genomes, ExAC, gnomAD and Shenzhou Genome Data Cloud databases. As predicted by the REVEL online software, the variant can confer deleterious effects on the gene or its product. Analysis using UGENE software showed the corresponding amino acid to be highly conserved among various species. Analysis with AlphaFold2 software suggested that the variant may affect the 3D structure and function of the Ephrin-B1 protein. Based on the American College of Medical Genetics and Genomics (ACMG) standards and guidelines and recommendation of Clinical Genome Resource (ClinGen), the variant was rated as pathogenic. Conclusion Combining the patient’s clinical features and genetic finding, the diagnosis of CNFS was confirmed. The heterozygous c. 473T>C (p.M158T) missense variant of theEFNB1 gene probably underlay the disease in this patient. Above finding has provided a basis for the genetic counseling and prenatal diagnosis for her family.
Objective To explore the clinical feature and genetic etiology of a patient with Craniofacial nasal syndrome (CNFS). Methods A patient with CNFS who had presented at the Guiyang Maternal and Child Health Care Hospital on November 13, 2021 was selected as the study subject. Clinical data of the patient were collected. Peripheral venous blood samples were collected from the patient and her parents and subjected to trio-whole exome sequencing (trio-WES). Candidate variants were verified by Sanger sequencing and bioinformatic analysis. Results The patient, a 15-year-old female, had predominantly featured forehead bulging, hypertelorism, wide nasal dorsum and bifid nasal tip. Genetic testing revealed that she has harbored a heterozygous missense c. 473T>C (p.M158T) variant of theEFNB1 gene, which was detected in either of her parents. By bioinformatic analysis, the variant has not been recorded in the HGMD and ClinVar databases, and no population frequency was recorded in the 1000 Genomes, ExAC, gnomAD and Shenzhou Genome Data Cloud databases. As predicted by the REVEL online software, the variant can confer deleterious effects on the gene or its product. Analysis using UGENE software showed the corresponding amino acid to be highly conserved among various species. Analysis with AlphaFold2 software suggested that the variant may affect the 3D structure and function of the Ephrin-B1 protein. Based on the American College of Medical Genetics and Genomics (ACMG) standards and guidelines and recommendation of Clinical Genome Resource (ClinGen), the variant was rated as pathogenic. Conclusion Combining the patient’s clinical features and genetic finding, the diagnosis of CNFS was confirmed. The heterozygous c. 473T>C (p.M158T) missense variant of theEFNB1 gene probably underlay the disease in this patient. Above finding has provided a basis for the genetic counseling and prenatal diagnosis for her family.
Craniofacial nasal syndromePremature closure of cranial sutureEFNB1 geneTrio-whole exome sequencing
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