Mutation spectrum of the fibrillin‐1 (FBN1) gene in Taiwanese patients with Marfan syndrome

Abstract

SUMMARYThe aim of this study was to establish a national database of mutations in the fibrillin-1 (FBN1) gene that cause Marfan syndrome (MFS) in the Taiwanese population. In this study, we screened 294 patients from 157 families for the presence of FBN1 mutations using polymerase chain reaction/ denaturing high performance liquid chromatography (PCR/DHPLC). We identified 56 mutations in 62 of the 157 (40%) families including 49 single-base substitutions (36 missense mutations, seven nonsense mutations, and six splicing sites), one small insertion, four small deletions, one small indel (insertion and deletion), and one exonic deletion (Exon 36). When family history was taken into consideration, the mutation detection rate rose to 91% (29 of 32). We further investigated the phenotypic data and found that one third (47 of 157) of the families fit the Ghent criteria for MFS. Based on that data, the mutation rate was 98% (46/47). That finding implies that family history and the Ghent criteria play a more important role than clinical manifestations in establishing a clinical diagnosis of Marfan syndrome. Among the 56 mutations found in this study, 40 (71%) have not been registered in the Human Gene Mutation Database (HGMD) or in the Universal Mutation Database (UMD). This is the first study of the mutation spectrum of MFS in a cohort of patients in Taiwan. The database is expected to considerably improve genetic counseling for and medical care of MFS families.

Autosomal dominant Marfan syndrome caused by a previously reported recessive FBN1 variant

“…reported two cousins with MFS caused by the homozygous c.1453C>T FBN1 variant, while the four heterozygous parents (ages 37–43 years) did not fulfill the original Ghent criteria for MFS at that time (Loeys et al, ). This variant has not been identified in large population databases (ExAC, gnomAD, and GoNL) and has, to our knowledge, only been published in one additional patient from a Taiwanese MFS cohort (Hung et al, ).…”

“…Homozygosity for this variant was previously reported to cause autosomal recessive MFS in a consanguineous family (Vries et al, ). In addition, this variant was reported in a heterozygous state in one patient in a Taiwanese MFS cohort (Hung et al, ). Only limited clinical information was provided in this publication.…”

Molecular pathogenesis of Marfan syndrome

“…Despite the recently revised Ghent Nosology [11], early and accurate diagnosis of MFS is still challenging, primarily due to the fact that not all FBN1 mutations result in MFS (Table 1) and not all TAAs are associated with MFS (Table 2). Moreover, report of unique FBN1 mutations [12] and indication of more severe and differing manifestation of MFS phenotypes in the Asian population [13] further confound management strategy for afflicted patients. Significant obstacles further complicate MFS diagnosis in children whereby an enlarging aorta may be due to natural growth towards adulthood or in pregnancy, where risk of aortic dissection increases significantly postpartum [4].…”

Whole exome sequencing is an efficient, sensitive and specific method of mutation detection in osteogenesis imperfecta and Marfan syndrome

“…30 Conversely, 10-15% of families tested because of a Marfanoid-like phenotype and found to carry FBN1 mutations do not fulfill diagnostic criteria for MFS. 40,41 The importance of a genetic diagnosis in MFS has recently been emphasized. 23 However, genetic screening in individuals with a Marfanoid phenotype is challenging, time-consuming and expensive (B$A1500) due to the size of FBN1 (65 exons, 4257 kb) and wide distribution and diversity of mutations.…”