Lin Bichen, Liu Yang, Su Lanxin, Liu Hangbo, Feng Hailan, Yu Miao, Liu Haochen
First Clinical Division, Peking University School and Hospital of Stomatology & National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing 100081, China.
Department of Prosthodontics, Peking University School and Hospital of Stomatology & National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing 100081, China.
Diagnostics (Basel). 2022 Nov 24;12(12):2936. doi: 10.3390/diagnostics12122936.
The goal of the current study was to identify the pathogenic gene variant in a Chinese family with Blepharocheilodontic (BCD) syndrome. Whole-exome sequencing (WES) and Sanger sequencing were used to identify the pathogenic gene variant. The harmfulness of the variant was predicted by bioinformatics. We identified a novel heterozygous missense variant c.1198G>A (p.Asp400Asn) in the CDH1 gene in the proband and his mother with BCD syndrome. The sequencing results of three healthy individuals in this family are wild type. This result is consistent with familial co-segregation. According to ReVe, REVEL, CADD, gnomAD, dbSNP, and the classification of pathogenic variants with the standards of the 2015 American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG), c.1198G>A (p.Asp400Asn) is predicted to be a likely pathogenic. We observed that variant c.1198G>A (p.Asp400Asn) was located in the extracellular cadherin-type repeats in CDH1. Amino acid sequence alignment of the CDH1 protein among multiple species showed that Asp400 was highly evolutionarily conserved. The conformational analysis showed that this variant might cause structural damage to the CDH1 protein. Phenotypic analysis revealed unique dental phenotypes in patients with BCD syndrome, such as oligodontia, conical-shaped teeth, and notching of the incisal edges. Our results broaden the variation spectrum of BCD syndrome and phenotype spectrum of CDH1, which can help with the clinical diagnosis, treatment, and genetic counseling in relation to BCD syndrome.
本研究的目的是在一个患有唇裂、腭裂和牙列异常（BCD）综合征的中国家庭中鉴定致病基因变异。采用全外显子组测序（WES）和桑格测序来鉴定致病基因变异。通过生物信息学预测该变异的有害性。我们在先证者及其患有BCD综合征的母亲中鉴定出CDH1基因中的一个新的杂合错义变异c.1198G>A（p.Asp400Asn）。该家族中三名健康个体的测序结果为野生型。这一结果与家族共分离情况一致。根据ReVe、REVEL、CADD、gnomAD、dbSNP以及按照2015年美国医学遗传学与基因组学学会和分子病理学协会（ACMG）的标准对致病变异进行的分类，c.1198G>A（p.Asp400Asn）被预测为可能致病。我们观察到变异c.1198G>A（p.Asp400Asn）位于CDH1的细胞外钙黏蛋白型重复序列中。多种物种间CDH1蛋白的氨基酸序列比对显示，Asp400在进化上高度保守。构象分析表明，该变异可能会对CDH1蛋白造成结构损伤。表型分析揭示了BCD综合征患者独特的牙齿表型，如少牙症、锥形牙和切缘切迹。我们的结果拓宽了BCD综合征的变异谱以及CDH1的表型谱，这有助于BCD综合征的临床诊断、治疗和遗传咨询。
