Fatal thoracic aortic aneurysm and dissection in a large family with a novel MYLK gene mutation: delineation of the clin
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RESEARCH
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Fatal thoracic aortic aneurysm and dissection in a large family with a novel MYLK gene mutation: delineation of the clinical phenotype Adel Shalata1,2,3* , Mohammad Mahroom1,2,3, Dianna M. Milewicz4, Gong Limin4, Fadi Kassum3, Khader Badarna3, Nader Tarabeih3, Nimmer Assy5, Rona Fell6, Hector Cohen7, Munir Nashashibi8,9, Alejandro Livoff7, Muhammad Azab2, George Habib9,10, Dan Geiger11, Omer Weissbrod11 and William Nseir12
Abstract Background: Thoracic and abdominal aortic aneurysms and dissection often develop in hypertensive elderly patients. At higher risk are smokers and those who have a family history of aortic aneurysms. In most affected families, the aortic aneurysms and dissection is inherited in an autosomal dominant manner with decreased penetrance and variable expressivity. Mutations at two chromosomal loci, TAA1 at 11q23 and the TAA2 at 5q13–14, and eight genes, MYLK, MYH11, TGFBR2, TGFBR1, ACTA2, SMAD3, TGFB2, and MAT2A, have been identified as being responsible for the disease in 23% of affected families. Results: Herein, we inform on the clinical, genetic and pathological characteristics of nine living and deceased members of a large consanguineous Arab family with thoracic aortic aneurysm and dissection who carry a missense mutation c.4471G > T (Ala1491Ser), in exon 27 of MYLK gene. We show a reduced kinase activity of the Ala1491Ser protein compared to wildtype protein. This mutation is expressed as aortic aneurysm and dissection in one of two distinct phenotypes. A severe fatal and early onset symptom in homozygous or mild late onset in heterozygous genotypes. Conclusions: We found that MYLK gene Ala1491Ser mutation affect the kinase activity and clinically, it presents with vascular aneurysms and dissection. We describe a distinct genotype phenotype correlation where; heterozygous patients have mild late onset and incomplete penetrance disease compared with the early onset severe and generally fatal outcome in homozygous patients. Keywords: MYLK gene mutation, Aortic aneurysm and dissection, Genotype-phenotype
Background Thoracic aortic aneurysms and aortic dissections (TAAD) often develop in hypertensive individuals, predominantly in men aged 65 years and older who may have a family history of aortic disease. In most affected families, a predisposition for TAAD is inherited in an autosomal dominant manner with decreased penetrance and variable expressivity. The * Correspondence: [email protected] 1 Simon Winter Institute for Human Genetics, B’nai Zion Medical Center, P.O.B 4940, 31048 Haifa, Israel 2 Genetic Unit, Ziv Medical Center, Safed, Israel Full list of author information is available at the end of the article
prevalence of thoracic aortic aneurysms is underestimated because these aneurysms are typically asymptomatic. Nevertheless, the occurrence of aortic aneurysms has gradually increased over the past few decades [1–4]. The estimated annual incidence of rupture of thoracic aortic aneurysms (TAA) is 3/100000 persons and 9/100000 persons for abdominal ao
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