Comprehensive genetic analysis of relevant four genes in 49 patients with Marfan syndrome or Marfan‐related phenotypes

Sakai, Haruko; Visser, Remco; Ikegawa, Shiro; Ito, Etsuro; Numabe, Hironao; Watanabe, Yoriko; Mikami, Haruo; Kondoh, Tatsuro; Kitoh, Hiroshi; Sugiyama, Ryusuke; Okamoto, Nobuhiko; Ogata, Tsutomu; Fodde, Riccardo; Mizuno, Seiji; Takamura, Kyoko; Egashira, Masayuki; Sasaki, Nozomu; Watanabe, Shozo; Nishimaki, Shigeru; Takada, Fumio; Nagai, Toshiro; Okada, Yasushi; Aoka, Yoshikazu; Yasuda, Kazushi; Iwasa, Mitsuji; Kogaki, Shigetoyo; Harada, Naoki; Mizuguchi, Takeshi; Matsumoto, Naomichi

doi:10.1002/ajmg.a.31353

Cited by 63 publications

(49 citation statements)

References 24 publications

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“…(Singh et al 2006). However, it should be noted that arterial tortuosity, a cardinal feature of LDS, was not systematically evaluated in any of the four studies (Disabella et al 2006;Matyas et al 2006;Sakai et al 2006;Singh et al 2006). Moreover, two research groups were unable to identify TGFBR2 mutations in 29 MFS patients (FBN1 was normal in 24 and unknown in five) (Ki et al 2005) and seven patients (FBN1 was normal) with MFS compatible with the Ghent criteria (Loeys et al 2005).…”

Section: Germline Tgfbr Mutations and Connective Tissue Disordersmentioning

confidence: 99%

“…At least six TGFBR2 mutations (R356P, N384S, R460H, R460C, S449F, and R537C) and two TGFBR1 mutations (S241L and R487Q) were recognized in two or three conditions (i.e., R460H found in MFS, LDS, and TAAD) (Ades et al 2006;Disabella et al 2006;Ki et al 2005;Loeys et al 2006;Matyas et al 2006;Mizuguchi et al 2004;Pannu et al 2005a;Sakai et al 2006;Singh et al 2006) (Fig. 1, Table 2), implying that TGFBR mutations may cause various clinical consequences or that appropriate diagnosis is rather difficult for these disorders.…”

Section: Germline Tgfbr Mutations and Connective Tissue Disordersmentioning

confidence: 99%

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Recent progress in genetics of Marfan syndrome and Marfan-associated disorders

2006

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Marfan syndrome (MFS, OMIM #154700) is a hereditary connective tissue disorder, clinically presenting with cardinal features of skeletal, ocular, and cardiovascular systems. In classical MFS, changes in connective tissue integrity can be explained by defects in fibrillin-1, a major component of extracellular microfibrils. However, some of the clinical manifestations of MFS cannot be explained by mechanical properties alone. Recent studies manipulating mouse Fbn1 have provided new insights into the molecular pathogenesis of MFS. Dysregulation of transforming growth factor beta (TGFb) signaling in lung, mitral valve and aortic tissues has been implicated in mouse models of MFS. TGFBR2 and TGFBR1 mutations were identified in a subset of patients with MFS (MFS2, OMIM #154705) and other MFS-related disorders, including LoeysDietz syndrome (LDS, #OMIM 609192) and familial thoracic aortic aneurysms and dissections (TAAD2, #OMIM 608987). These data indicate that genetic heterogeneity exists in MFS and its related conditions and that regulation of TGFb signaling plays a significant role in these disorders.

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Section: Germline Tgfbr Mutations and Connective Tissue Disordersmentioning

confidence: 99%

Section: Germline Tgfbr Mutations and Connective Tissue Disordersmentioning

confidence: 99%

Recent progress in genetics of Marfan syndrome and Marfan-associated disorders

2006

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“…11,16 In our study, although 10 patients with the TGFBR mutations had phenotypic variability, genetic analysis can be used to differentiate LDS from Marfan syndrome or from familial thoracic aortic aneurysm and dissection. Prior studies have suggested that some TGFBR2 mutations are present in families whose members have not only LDS (p.Arg495X), 2 but also classic Marfan syndrome (p.Ser449Phe), 5 or incomplete Marfan syndrome (p.Trp504X) 6 and TGFBR1 mutations are present in patients with familial thoracic aortic aneurysm and dissection (p.Arg487Gln).…”

Section: Genetic Analysismentioning

confidence: 79%

“…3,8 To our knowledge, in previous studies of Oriental populations, patients with LDS type II were not identified. [9][10][11][12][13] Accordingly, a large-scale clinical study is needed to identify whether differences in the frequencies of LDS type I and II can be attributed to racial differences.…”

Section: Clinical Findingsmentioning

confidence: 99%

Clinical features and genetic analysis of Korean patients with Loeys–Dietz syndrome

Yang

Han

et al. 2011

J Hum Genet

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Loeys-Dietz syndrome (LDS) is an inherited disorder that is characterized by the triad of arterial tortuosity and aneurysms, hypertelorism and a bifid uvula or cleft palate. The disease is caused by heterozygous mutations in the genes encoding transforming growth factor b receptors 1 and 2 (TGFBR1 and TGFBR2, respectively). However, studies of patients with LDS are limited in Korea. From June 2000 to December 2010, 13 patients (10 probands) diagnosed with LDS were enrolled. The multidisciplinary data of the patients were reviewed retrospectively. The frequency of each clinical manifestation in Korean patients with LDS was compared with Western populations as described in the report by Loeys et al. Twelve (92%) of the 13 LDS patients had arterial tortuosity, 9 (69%) patients had hypertelorism and 11 (85%) patients had bifid uvula or cleft palate. Mutations in either TGFBR1 or TGFBR2 were detected in nine probands (90%). Of the mutations, five novel mutations were detected; three in TGFBR2 and two in TGFBR1. Blue sclera and atrial septal defect were not observed in the Korean patients, and the frequency of blue sclera was significantly lower in our Korean population than previously-described Western population (0 vs 40%; P¼0.005). Despite the restricted number of patients in our study, we identified five novel mutations in the TGFBR1 and TGFBR2 genes and, except for blue sclera, no differences in phenotype are apparent between Korean patients and Western patients. Keywords: arterial tortuosity; bifid uvula; hypertelorism; Loeys-Dietz syndrome; transforming growth factor b receptors INTRODUCTION Loeys-Dietz syndrome (LDS), a genetic disorder affecting the connective tissue, is caused by mutations in the genes encoding transforming growth factor b receptors 1 and 2 (TGFBR1 and TGFBR2, respectively). 1 LDS is characterized by the triad of hypertelorism, a bifid uvula or cleft palate and generalized arterial tortuosity with widespread vascular aneurysm and dissection. 2 The diagnosis of LDS is made according to clinical presentations in the proband and family members, and molecular genetic testing of the TGFBR1 and TGFBR2 genes. 3 Early and accurate diagnosis is essential to patients with LDS because they are at increased risk for aortic dissection or rupture at an early age. To date, most studies related to LDS are based on data obtained from the European and American populations. There are few data regarding the clinical and genetic characteristics of the Korean patients with LDS, leaving doubt as to whether or not there are racial differences in the physical presentation of LDS between the Oriental and Western populations.Therefore, we investigated the clinical and genetic characteristics in the Korean patients with LDS, and compared clinical manifestations between Korean patients and Western populations as reported by Loeys et al. 2 MATERIALS AND METHODS SubjectsWe reviewed 22 consecutive patients who were suspicious of having LDS from June 2000 to December 2010. All had undergone genetic analysis of the TGFBR1 an...

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“…This study identified FBN1 mutations in 91% of MFS patients (Loeys et al 2004). A study of direct DNA sequencing of the exons and flanking introns of FBN1, FBN2, TGFBR1, and TGFBR2 on 49 MFS or MFS-suspected patients identified FBN1 mutations in 55% of patients and TGFBR1 and TGFBR2 mutations in 6% of patients [Sakai et al 2006]. The MFS patients in these studies in whom no mutations were detected could have cryptic FBN1 mutations or locus heterogeneity for MFS (Boileau et al 1993).…”

Section: Discussionmentioning

confidence: 85%

An FBN1 pseudoexon mutation in a patient with Marfan syndrome: confirmation of cryptic mutations leading to disease

Guo¹,

Gupta²,

Tran-Fadulu³

et al. 2008

J Hum Genet

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Marfan syndrome (MFS) results from heterozygous mutations in FBN1. However, genetic analyses of deoxyribonucleic acid (DNA) from approximately 10-30% of MFS patients who meet diagnostic criteria do not reveal an identifiable FBN1 mutation. In a patient who met the diagnostic criteria for MFS, bidirectional DNA sequencing of exons and intron-exon boundaries of FBN1 failed to reveal a mutation. Assessment of the FBN1 message in dermal fibroblasts from the patient revealed insertion of a pseudoexon between exons 63 and 64. Sequencing of intron 63 identified a point mutation, IVS63?373, located near the middle of intron 63 of FBN1 that created a donor splice site in intron 63, leading to inclusion of a 93-bp fragment of intronic sequence in the FBN1 message. Identification of a novel pseudoexon mutation in FBN1, in association with a clinical diagnosis of MFS, confirms that cryptic mutations that are missed by the current DNAbased diagnostic methods have a causative role.

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Comprehensive genetic analysis of relevant four genes in 49 patients with Marfan syndrome or Marfan‐related phenotypes

Cited by 63 publications

References 24 publications

Recent progress in genetics of Marfan syndrome and Marfan-associated disorders

Recent progress in genetics of Marfan syndrome and Marfan-associated disorders

Clinical features and genetic analysis of Korean patients with Loeys–Dietz syndrome

An FBN1 pseudoexon mutation in a patient with Marfan syndrome: confirmation of cryptic mutations leading to disease

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