目的 分析6例FBN1基因变异所致的肢端发育不良家系的临床表型及遗传学特征。 方法 选取2018年2月至2020年10月就诊于青岛大学附属医院的6例患者作为研究对象，收集患者的临床资料进行回顾性分析。患者进行高通量测序，并用Sanger测序对候选致病变异进行验证。 结果 6例患者均表现为严重的身材矮小(<-3s)、短指，手足短宽。其他的表现还包括关节僵硬、特殊面容、骨龄落后、肝脏肿大、喙状股骨头、腰椎前凸等。基因检测显示6例患者均携带FBN1基因杂合变异：患者1存在第42外显子c.5183C>T(p.A1728V)错义变异，遗传自父亲(患者2)；患者3存在第43外显子c.5284G>A(p.G1762S)错义变异，遗传自母亲(患者4)；患者5存在第42外显子c.5156G>T(p.C1719F)错义变异，考虑为新发变异；患者6存在第43外显子c.5272G>T(p.D1758Y)错义变异，考虑为新发变异。患者1、3、6携带变异均为已报道致病性变异。根据美国医学遗传学与基因组学学会(ACMG)相关指南，患者5携带的c.5156G>T被评级为致病性变异(PS2＋PM1＋PM2_Supporting ＋PM5＋PP3)。 结论 肢端发育不良6例患者均存在重度矮小，其他的临床表现存在异质性。FBN1基因变异考虑为6例患儿的遗传学病因。 Objective To retrospectively analyze the clinical and genetic characteristics of six patients with Acromicric dysplasia due to variants of the FBN1 gene. Methods Six patients who had visited the Affiliated Hospital of Qingdao University between February 2018 and October 2020 were selected as the study subjects. Clinical data of the patients were collected. High-throughput sequencing was carried out. And candidate variants were verified by Sanger sequencing. Results All of the six patients had presented with severe short stature (< 3s), brachydactyly, short and broad hands and feet. Other manifestations included joint stiffness, facial dysmorphism, delayed bone age, liver enlargement, coracoid femoral head, and lumbar lordosis. Genetic testing revealed that all had harbored heterozygous variants of the FBN1 gene. Patient 1 had harbored a c. 5183C>T (p.A1728V) missense variant in exon 42, which had derived from his father (patient 2). Patient 3 had harbored a c. 5284G>A (p.G1762S) missense variant in exon 43, which had derived from her mother (patient 4). Patient 5 had harbored a c. 5156G>T (p.C1719F) missense variant in exon 42, which wasde novo in origin. Patient 6 had harbored a c. 5272G>T (p.D1758Y) missense variant in exon 43, which was alsode novo in origin. The variants carried by patients 1, 3 and 6 were known to be pathogenic. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the FBN1: c. 5156G>T was rated as a pathogenic variant (PS2+ PM1+ PM2_Supporting + PM5+ PP3). Conclusion All of the six patients had severe short stature and a variety of other clinical manifestations, which may be attributed to the variants of the FBN1 gene.
Clinical phenotype and genetic analysis of six Chinese patients affected with Acromicric dysplasia due to variants ofFBN1 gene
Objective To retrospectively analyze the clinical and genetic characteristics of six patients with Acromicric dysplasia due to variants of the FBN1 gene. Methods Six patients who had visited the Affiliated Hospital of Qingdao University between February 2018 and October 2020 were selected as the study subjects. Clinical data of the patients were collected. High-throughput sequencing was carried out. And candidate variants were verified by Sanger sequencing. Results All of the six patients had presented with severe short stature (< 3s), brachydactyly, short and broad hands and feet. Other manifestations included joint stiffness, facial dysmorphism, delayed bone age, liver enlargement, coracoid femoral head, and lumbar lordosis. Genetic testing revealed that all had harbored heterozygous variants of the FBN1 gene. Patient 1 had harbored a c. 5183C>T (p.A1728V) missense variant in exon 42, which had derived from his father (patient 2). Patient 3 had harbored a c. 5284G>A (p.G1762S) missense variant in exon 43, which had derived from her mother (patient 4). Patient 5 had harbored a c. 5156G>T (p.C1719F) missense variant in exon 42, which wasde novo in origin. Patient 6 had harbored a c. 5272G>T (p.D1758Y) missense variant in exon 43, which was alsode novo in origin. The variants carried by patients 1, 3 and 6 were known to be pathogenic. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the FBN1: c. 5156G>T was rated as a pathogenic variant (PS2+ PM1+ PM2_Supporting + PM5+ PP3). Conclusion All of the six patients had severe short stature and a variety of other clinical manifestations, which may be attributed to the variants of the FBN1 gene.
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