Fatal thoracic aortic aneurysm and dissection in a large family with a novel MYLK gene mutation: delineation of the clinical phenotype

Adel ShalataEmail author View ORCID ID profile,
Mohammad Mahroom,
Dianna M. Milewicz,
Gong Limin,
Fadi Kassum,
Khader Badarna,
Nader Tarabeih,
Nimmer Assy,
Rona Fell,
Hector Cohen,
Munir Nashashibi,
Alejandro Livoff,
Muhammad Azab,
George Habib,
Dan Geiger,
Omer Weissbrod and
William Nseir

Orphanet Journal of Rare Diseases201813:41

https://doi.org/10.1186/s13023-018-0769-7

Received: 26 September 2017

Accepted: 23 January 2018

Published: 15 March 2018

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.