Hemizygous deletion of COL3A1, COL5A2, and MSTN causes a complex phenotype with aortic dissection: a lesson for and from true haploinsufficiency

• Published in: European journal of human genetics : EJHG 2010-12, Vol.18 (12), p.1315-1321
• Main Authors: Meienberg, Janine, Rohrbach, Marianne, Neuenschwander, Stefan, Spanaus, Katharina, Giunta, Cecilia, Alonso, Sira, Arnold, Eliane, Henggeler, Caroline, Regenass, Stephan, Patrignani, Andrea, Azzarello-Burri, Silvia, Steiner, Bernhard, Nygren, Anders OH, Carrel, Thierry, Steinmann, Beat, Mátyás, Gábor
• Format: Article
• Language: English
• Subjects: 631/208/2489/144; 692/699/75/593/1301; Aorta; Aortic Diseases - genetics; Aortic Diseases - pathology; Base Pairing - genetics; Base Sequence; Bioinformatics; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Blood and lymphatic vessels; Breakpoints; Cardiology. Vascular system; Chromosome Breakage; Clonal deletion; Collagen; Collagen Type III - genetics; Collagen Type III - ultrastructure; Collagen Type V - genetics; Collagen Type V - ultrastructure; Cytogenetics; Diseases of the aorta; Dissection; DNA microarrays; DNA Probes - metabolism; Ehlers-Danlos syndrome; Etiology; Female; Fundamental and applied biological sciences. Psychology; Gene deletion; Gene Expression; General aspects. Genetic counseling; Genes; Genetic screening; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Genomics; Haploinsufficiency; Haploinsufficiency - genetics; Hemizygote; Hemochromatosis; Hereditary diseases; Human Genetics; Humans; Hypertrophy; Male; Marfan syndrome; Marfan's syndrome; Medical genetics; Medical sciences; Molecular and cellular biology; Molecular Sequence Data; Mutation; Myostatin - genetics; Pedigree; Phenotype; Phenotypes; Polymerase Chain Reaction; Sequence Deletion - genetics; Stat1 protein; Stat4 protein
• ISSN: 1018-4813; 1476-5438
• DOI: 10.1038/ejhg.2010.105

Aortic dilatation/dissection (AD) can occur spontaneously or in association with genetic syndromes, such as Marfan syndrome (MFS; caused by FBN1 mutations), MFS type 2 and Loeys–Dietz syndrome (associated with TGFBR1 / TGFBR2 mutations), and Ehlers–Danlos syndrome (EDS) vascular type (caused by COL3A1 mutations). Although mutations in FBN1 and TGFBR1 / TGFBR2 account for the majority of AD cases referred to us for molecular genetic testing, we have obtained negative results for these genes in a large cohort of AD patients, suggesting the involvement of additional genes or acquired factors. In this study we assessed the effect of COL3A1 deletions/duplications in this cohort. Multiplex ligation-dependent probe amplification (MLPA) analysis of 100 unrelated patients identified one hemizygous deletion of the entire COL3A1 gene. Subsequent microarray analyses and sequencing of breakpoints revealed the deletion size of 3 408 306 bp at 2q32.1q32.3. This deletion affects not only COL3A1 but also 21 other known genes ( GULP1 , DIRC1 , COL5A2 , WDR75 , SLC40A1 , ASNSD1 , ANKAR , OSGEPL1 , ORMDL1 , LOC100129592 , PMS1 , MSTN , C2orf88 , HIBCH , INPP1 , MFSD6 , TMEM194B , NAB1 , GLS , STAT1 , and STAT4 ), mutations in three of which ( COL5A2 , SLC40A1 , and MSTN ) have also been associated with an autosomal dominant disorder (EDS classical type, hemochromatosis type 4, and muscle hypertrophy). Physical and laboratory examinations revealed that true haploinsufficiency of COL3A1 , COL5A2 , and MSTN, but not that of SLC40A1 , leads to a clinical phenotype. Our data not only emphasize the impact/role of COL3A1 in AD patients but also extend the molecular etiology of several disorders by providing hitherto unreported evidence for true haploinsufficiency of the underlying gene.