PDF(Pubmed)
Abstract：
BACKGROUND: Marfan syndrome (MFS) is a hereditary connective tissue disorder involving multiple systems, including ophthalmologic abnormalities. Most cases are due to heterozygous mutations in the fibrillin-1 gene (FBN1). Other associated genes include LTBP2, MYH11, MYLK, and SLC2A10. There is significant clinical overlap between MFS and other Marfan-like disorders.
OBJECTIVE: To expand the mutation spectrum of FBN1 gene and validate the pathogenicity of Marfan-related genes in patients with MFS and ocular manifestations.
METHODS: We recruited 318 participants (195 cases, 123 controls), including 59 sporadic cases and 88 families. All patients had comprehensive ophthalmic examinations showing ocular features of MFS and met Ghent criteria. Additionally, 754 cases with other eye diseases were recruited. Panel-based next-generation sequencing (NGS) screened mutations in 792 genes related to inherited eye diseases.
RESULTS: We detected 181 mutations with an 84.7% detection rate in sporadic cases and 87.5% in familial cases. The overall detection rate was 86.4%, with FBN1 accounting for 74.8%. In cases without FBN1 mutations, 23 mutations from seven Marfan-related genes were identified, including four pathogenic or likely pathogenic mutations in LTBP2. The 181 mutations included 165 missenses, 10 splicings, three frameshifts, and three nonsenses. FBN1 accounted for 53.0% of mutations. The most prevalent pathogenic mutation was FBN1 c.4096G>A. Additionally, 94 novel mutations were detected, with 13 de novo mutations in 14 families.
CONCLUSIONS: We expanded the mutation spectrum of the FBN1 gene and provided evidence for the pathogenicity of other Marfan-related genes. Variants in LTBP2 may contribute to the ocular manifestations in MFS, underscoring its role in phenotypic diversity.
OBJECTIVE: To expand the mutation spectrum of FBN1 gene and validate the pathogenicity of Marfan-related genes in patients with MFS and ocular manifestations.
METHODS: We recruited 318 participants (195 cases, 123 controls), including 59 sporadic cases and 88 families. All patients had comprehensive ophthalmic examinations showing ocular features of MFS and met Ghent criteria. Additionally, 754 cases with other eye diseases were recruited. Panel-based next-generation sequencing (NGS) screened mutations in 792 genes related to inherited eye diseases.
RESULTS: We detected 181 mutations with an 84.7% detection rate in sporadic cases and 87.5% in familial cases. The overall detection rate was 86.4%, with FBN1 accounting for 74.8%. In cases without FBN1 mutations, 23 mutations from seven Marfan-related genes were identified, including four pathogenic or likely pathogenic mutations in LTBP2. The 181 mutations included 165 missenses, 10 splicings, three frameshifts, and three nonsenses. FBN1 accounted for 53.0% of mutations. The most prevalent pathogenic mutation was FBN1 c.4096G>A. Additionally, 94 novel mutations were detected, with 13 de novo mutations in 14 families.
CONCLUSIONS: We expanded the mutation spectrum of the FBN1 gene and provided evidence for the pathogenicity of other Marfan-related genes. Variants in LTBP2 may contribute to the ocular manifestations in MFS, underscoring its role in phenotypic diversity.
摘要：
背景：马凡综合征（MFS）是一种涉及多个系统的遗传性结缔组织疾病，包括眼科异常。大多数病例是由于原纤维蛋白-1基因（FBN1）的杂合突变。其他相关基因包括LTBP2，MYH11，MYLK，和SLC2A10。MFS和其他马凡样疾病之间存在显著的临床重叠。
目的：扩大FBN1基因的突变谱，验证Marfan相关基因在MFS和眼部表现患者中的致病性。
方法：我们招募了318名参与者(195例，123个控件），包括59例零星病例和88个家庭。所有患者均进行了全面的眼科检查，显示了MFS的眼部特征，并符合根特标准。此外,招募了754例其他眼病患者。基于面板的下一代测序（NGS）筛选了与遗传性眼病相关的792个基因的突变。
结果：我们检测到181个突变，散发性病例检出率为84.7%，家族性病例检出率为87.5%。总检出率为86.4%,FBN1占74.8%。在没有FBN1突变的情况下，从7个Marfan相关基因中鉴定出23个突变，包括LTBP2中的四个致病性或可能的致病性突变。181个突变包括165个错觉，10个拼接,三个移相者,和三个无意义。FBN1占突变的53.0%。最普遍的致病突变是FBN1c.4096G>A。此外,检测到94个新的突变，在14个家族中有13个从头突变。
结论：我们扩展了FBN1基因的突变谱，为其他马凡相关基因的致病性提供了证据。LTBP2的变异可能有助于MFS的眼部表现，强调其在表型多样性中的作用。
目的：扩大FBN1基因的突变谱，验证Marfan相关基因在MFS和眼部表现患者中的致病性。
方法：我们招募了318名参与者(195例，123个控件），包括59例零星病例和88个家庭。所有患者均进行了全面的眼科检查，显示了MFS的眼部特征，并符合根特标准。此外,招募了754例其他眼病患者。基于面板的下一代测序（NGS）筛选了与遗传性眼病相关的792个基因的突变。
结果：我们检测到181个突变，散发性病例检出率为84.7%，家族性病例检出率为87.5%。总检出率为86.4%,FBN1占74.8%。在没有FBN1突变的情况下，从7个Marfan相关基因中鉴定出23个突变，包括LTBP2中的四个致病性或可能的致病性突变。181个突变包括165个错觉，10个拼接,三个移相者,和三个无意义。FBN1占突变的53.0%。最普遍的致病突变是FBN1c.4096G>A。此外,检测到94个新的突变，在14个家族中有13个从头突变。
结论：我们扩展了FBN1基因的突变谱，为其他马凡相关基因的致病性提供了证据。LTBP2的变异可能有助于MFS的眼部表现，强调其在表型多样性中的作用。
