Identification of a novel TGFBR2 gene mutation in a Korean patient with Loeys–Dietz aortic aneurysm syndrome; no mutation in TGFBR2 gene in 30 patients with classic Marfan's syndrome

To the Editor: Recently, Mizuguchi and colleagues (1) reported that heterozygous loss-of-function mutations in the gene encoding type II transforming growth factor b receptor (TGFBR2) are responsible for Marfan’s syndrome type II (MFS2; OMIM 154705). Immediately after the discovery, Loeys et al. (2) described a novel aortic aneurysm syndrome (Loeys–Dietz syndrome or LDS; OMIM 609192), which is caused by mutations in the TGFBR1 or TGFBR2 gene. The clinical manifestations of LDS include altered cardiovascular, craniofacial, neurocognitive, and skeletal development such as craniosynostosis, structural brain abnormalities, mental retardation, and congenital heart disease (2). Although some individuals with mutations in TGFBR1 or TGFBR2 have phenotypes that overlap with MFS, none met the diagnostic criteria for MFS. Here, we investigated mutations of the TGFBR2 gene in a cohort of 30 Korean patients initially diagnosed as having MFS according to the Ghent nosology. A 7-year-old Korean boy with initial diagnosis of MFS variant but later found to have LDS was also included. Twentyfive MFS patients had previously been screened but were negative for a mutation in the FBN1 gene by polymerase chain reaction (PCR) and single-strand conformation polymorphism (SSCP) (3). Actually, MFS patients included in the present study might have mutations in the FBN1 gene because PCR-SSCP is a screening method, a yield could be much lower than a comprehensive sequencing method. In addition, remaining five MFS patients were not screened for the FBN1 mutation. All patients were evaluated clinically and genetically after obtaining informed consents from the patients or parents. To calculate the allele frequency of the Thr315Met and Arg356Pro variations of TGFBR2 gene, genomic DNAs from 497 normal controls were used. The study design was reviewed and approved by the Institutional Review Board. All coding exons and flanking intron regions of the TGFBR2 gene were amplified using primer sets designed by the authors (available on request). Haplotype analysis for the TGFBR2 gene region was performed using four short tandem repeat (STR) markers flanking the TGFBR2 gene (D3S3659, D3S1266, D3S3567, and D3S3521). We identified a total of six (one synonymous, three missense, and two intronic) variations in the TGFBR2 gene (Table 1). Of these, two intronic and one synonymous variations (Asn389Asn) were known polymorphisms listed in the singlenucleotide polymorphism database (dbSNP; http://www.ncbi.nlm.nih.gov/projects/SNP/). The Val191Ile variation was supposed to be a novel polymorphism because it was found in two of 30 MFS patients and in three of the 20 normal controls. The Thr315Met variation, which was found in familial non-polyposis colorectal cancer (4), was observed in two patients with MFS and in nine of 497 controls giving an estimated allele frequency of 0.01. Therefore, this variation is presumed to be a rare polymorphism in the Korean population. The Arg356Pro variation, located in the highly conserved serine–threonine kinase domain of TGFBR2, was identified only in the patient with LDS but not in MFS patients (Fig. 1). The patient’s parents did not have the mutation, and Clin Genet 2005: 68: 561–563 Copyright # Blackwell Munksgaard 2005 Printed in Singapore. All rights reserved CLINICAL GENETICS doi: 10.1111/j.1399-0004.2005. 00535.x