Two novel MYLK nonsense mutations causing thoracic aortic aneurysms/dissections in patients without apparent family history

To the Editor: Only 20% of all familial thoracic aortic aneurysms/dissections (FTAAD) cases are explained, of which <1% are caused by mutations in the MYLK gene. So far, 3 heterozygous MYLK mutations have been reported (Figure 1). We identified 2 novel disease-causing MYLK mutations (c.4372C>T, p.Arg1458* & c.4459C>T, p.Arg1487*) (Figure 1) using TAAD gene panel sequencing, explaining the cardiovascular phenotype in 0.6% of the cases (n = 358). Both heterozygous point mutations result in a pre-mature termination codon, probably leading to nonsense-mediated mRNA decay and, hence, haploinsufficiency. This suggests that a loss-of-function mechanism underlies MYLK-related TAAD, fitting prior observations. Screening of first-degree relatives of the proband of family A revealed the mutation only in the father. In family B, the mutation was found in the paternal half-brother of the proband, suggesting either transmission through the father or germline mosaicism. All available siblings of the father (n = 4) tested negative. The probands did not harbor mutations in other known TAAD genes. The study protocol was approved by the ethics committee. In family A (Figure 1), the proband (IV:1) presented with a type B aortic dissection from the left subclavian to the left common iliac artery (diameter descending aorta 30 mm) with a saccular aortic arch aneurysm between the left carotid artery and truncus brachiocephalicus at age 49. After 1 month of conservative treatment she underwent a Petticoat procedure at the aortic level (thoracic endovascular aortic repair [TEVAR] + bare aorta stent) and received an iliac stent for a compressed true lumen with abdominal and right leg ischemia. In a second stage, chimney TEVAR for the saccular arch aneurysm was performed. Her medical history mentioned significant hypertension, which was treated by metoprolol 10 years prior to dissection. Besides cardiovascular findings, unilateral iris flocculi, hyperopia, retrognathia and osteoarthrosis (onset age 44) were observed. A computed tomography (CT)-scan of the aorta at age 50 showed an aortic root diameter of 33 mm. The medical history of her father (III:1) involved a cerebrovascular accident (age 74), arterial hypertension (age 66) and arthrosis. Magnetic resonance (MR)-angiography showed an aortic size of 39 mm with a proximal descending aortic diameter of 25 mm. In family B, the proband (III:1) presented with an acute type B dissection at age 47, starting from the arteria lusoria to the aortic bifurcation (descending aortic diameter 42-44 mm). She was diagnosed with hypertension at the time of dissection and conservative treatment was maintained. A recent CT-scan revealed dilatation of the proximal descending aorta (46 mm). Non-cardiovascular features included myopia (1.75 dioptres), striae, delayed wound healing with mild atrophic scars, pes planus and hypercholesterolemia. She underwent hemithyroidectomy for a non-malignant nodule (38 mm). The paternal half-brother (III:2) underwent mitral valvuloplasty surgery for severe mitral insufficiency with significant P2-prolapse (age 41) and bypass surgery of the left anterior descending coronary artery. Aortic evaluation at age 48 by echocardiography and MR-angiography revealed no aortic aneurysm. He is known with hypertension which is treated by angiotensin-converting-enzym (ACE)-inhibition. Initial presentation of aortic disease was a type B dissection at relatively young ages in patients with a clear history of hypertension. Importantly, we also observed 2 mutation carriers, who are currently without aortic aneurysms (A-III:1, B-III:2). Additional risk factors (eg, hypertension) thus might be required to provoke dissections. Interestingly, 1 of the 2 previously published MYLK patients with type B dissection presented with hypertension too. As previously described, vascular disease beyond the aorta was observed in our mutation carriers. Furthermore, various systemic clinical features present, suggesting that the phenotypic spectrum of MYLK mutations might encompass non-syndromic and syndromic TAAD. Our data support that these mutations associate to aortic disease with little to no aortic enlargement prior to dissection. Importantly, we believe that the cardiovascular management strategy in MYLK mutation carriers should focus on strict treatment of cardiovascular risk factors like hypertension, as no other predictive markers for aortic dissection are available. Funding information Fund for Scientific Research Flanders (FWO), Grant/Award number: G.0221. 12; Foundation Leducq, Grant/Award number: 12CVD03; European Research Council, Grant/Award number: ERC-StG-2012-30972; Agency for Innovation by Science and Technology: IWT.141429. Received: 13 December 2016 Revised: 15 February 2017 Accepted: 16 February 2017