Journal of Genetic Disorders & Genetic Reports ISSN: 2327-5790

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Case Report, J Genet Disor Genet Rep Vol: 4 Issue: 1

Single Amino Acid Deletion in MYH11 Segregating in a Family with TAAD

Pawel T Pomianowski1,2*, Daniel Dykas2, Murim Choi4, Jingshing Wu2, Gregory A Kuzmik3, Dawn Ardito3, Sandip Mukherjee3 and John A Elefteriades3
1Department of Veterans Affairs, West Haven, CT, USA
2Department of Genetics, Yale School of Medicine, New Haven CT, USA
3Department of Surgery, Yale School of Medicine, New Haven CT, USA
4Department of Genetics, Howard Hughes Medical Institute, USA
Corresponding author : Pawel Pomianowski, MD
950 Campbell Ave, West Haven CT, USA, 06516
Tel: 860-670-8604; Fax: 860-549-8922
E-mail: [email protected]
Received: November 09, 2014 Accepted: December 03, 2014 Published: January 01, 2015
Citation: Dykas D, Choi M, Wu J, Kuzmik GA, Ardito D, et al. (2015) Single Amino Acid Deletion in MYH11 Segregating in a Family with TAAD. J Genet Disor Genet Rep 4:1. doi:10.4172/2327-5790.1000119


 Single Amino Acid Deletion in MYH11 Segregating in a Family with TAAD

Background Seven genes have been identified as causative in the development of thoracic aortic aneurysms (TAA) and dissections (TAAD). In this study, we identify a single amino acid deletion in MYH11 gene which segregates with disease in a large TAAD family. Methods We identified five members in one family who had a history of TAA or TAAD. Blood samples from fifteen members of this family were collected for whole exome sequencing (WES) analysis and mutation analysis. Thirteen members of this family underwent echocardiography and cardiac pulse wave velocity (PWV) measurement. Results WES analysis revealed a mutation of myosin heavy chain 11 (MYH11) – a three base-pair deletion of leucine at position 1264 - that segregated with the disease phenotype in this family. PWV was not correlated with mutation or disease status. Conclusion Deletion of leucine at position 1264 in MYH11 appears to play an important role in the development of familial TAA and TAAD.

Keywords: Whole Exome Sequencing, Aorta, TAA, FTAA, MYH11Non-standard Abbreviations: WES: Whole Exome Sequencing; TAA: Thoracic Aortic Aneurysms; TTE: Trans Thoracic Echocardiogram; MYH11: Myosin Heavy Chain 11


Whole Exome Sequencing, Aorta, TAA, FTAA, MYH11Non-standard


WES: Whole Exome Sequencing; TAA: Thoracic Aortic Aneurysms; TTE: Trans Thoracic Echocardiogram; MYH11: Myosin Heavy Chain 11


Thoracic aortic aneurysms (TAA) and aortic dissections (TAAD) are responsible for 15,000 deaths in the United States annually [1]. TAA and TAAD may be divided into two broad categories: syndromic (associated with extra-aortic abnormalities) and non-syndromic (associated with manifestations restricted to the aorta) [2]. Nonsyndromic Aortic Aneurysms are further sub-divided into Familial Thoracic AorticAneurysms/Dissections (FTAA/FTAAD) – where more than one person in the family is affected and sporadic TAA where only a single person in the family is known to have an aneurysm. FTAAs typically present earlier in life, have a higher annual growth rate then sporadic aneurysms, and do not demonstrate association with traditional risk factors for aortic disease such as coronary artery disease [3,4].
Familial Thoracic Aortic Aneurysms and Dissections (FTAA and FTAAD) are genetically heterogeneous. Mutations in five genes (MYH11, TGFβR1, TGFβR2, MYLK, and ACTA2) have thus far been identified and all have autosomal dominant inheritance [2-5]. Together these account for only 23% of familial non-syndromic cases. [2-6].
We have identified a family with FTAAD in whom a 3 base pair (3bp) deletion (c.3790_3792delCTG), amino acid [L1264del] in MYH11gene demonstrated segregation among family members. This is the first report to our knowledge of an area which encodes a single amino acid in MYH11 that imparts a significant risk for FTAAD development. Prior reports described deletions of a much larger region (which included our deletion) as leading to FTAAD [7]. Our observation implicating leucine at position 1264 is also in line with published reports which describe a missense mutation at this position that resulted in FTAA development [8].
To verify that no other genes contribute to our patient’s phenotype in addition to mutations in MYH11, exome sequencing of our patient’s DNA was performed. We used next generation exome sequencing as a method to evaluate all genes present in our patient’s DNA as this method allowed for an unbiased analysis of all known genes responsible for TAAD.

Materials and Methods

The proband of this study was identified through clinical practice of the author J.A.E. after the subject presented to our institution with acute TAAD. A significant family history of dissected aortic aneurysms was revealed. Members of the proband’s extended family were subsequently contacted, clinically assessed for aortic dilation or dissection and a trans thoracic echocardiogram (TTE) with pulse wave velocity using echocardiography were performed. For family members who expired from sudden cardiac death, death certificates and autopsy reports were reviewed to asses for aortic pathology. Peripheral blood samples were collected from each living subject and analyzed via WES. This study was approved by the Yale University Human Investigations Committee.
CT scan
A 64-MSCT scanner (SOMATOM Sensation 64; Siemens Medical Solutions, Erlangen, Germany) was utilized. Supine scanning of the entire thorax and abdomen in a single breath-hold (if able to breathhold) with 0.5 second gantry rotation time was performed.
Exome Analysis
WES analysis was used to test for all known TAA genes. Genomic DNA was captured on a NimbleGen 2.1M Human Exome Array (Roche/NimbleGen) as previously described [9].
COILS Program
COILS is a program that compares a sequence to a database of known parallel two-stranded coiled-coils and derives a similarity score. By comparing this score to the distribution of scores in globular and coiled-coil proteins, the program then calculates the probability that the sequence will adopt a coiled-coil conformation. Probability of coiled coil formation in the identified MYH11 mutation was estimated according to COILS [10]. (
Transthoracic Echocardiogram (TTE)
The proband was evaluated for aortic dilation by two-dimensional echocardiogram (S5 probe; Philips Medical Systems) at several time points. Aortic diameters of family members were likewise assessed via echocardiography either at our institution or at outside facilities. Aortic measurements were performed at maximum systolic dimensions from inner edge to inner edge of the vessel wall. The patients’ weight and height at the time of examination was recorded.
Pulse Wave Velocity (PWV) Measurements
Measure of the PWV (defined as the distance (x) that the pulse wave resulting from cardiac contraction travels over time t) was accomplished with an ultrasound doppler technique with measurements taken at the carotid and femoral arteries [11]. Reference values for PWV that have been defined based on age and blood pressure category were used for comparison. In general, PWV >12 m/s using the direct carotid to femoral measurement was considered abnormally elevated [12]. In our study, ultrasound Doppler PWV measurements were carried out by a single ultra-sonographer [13,14].


Case presentation
The proband is a 64 year-old male with past medical history significant for hypertension, gout, anxiety, and prostate cancer (statuspost retro pubic prostatectomy) who presented with sudden excruciating interscapular back pain. At the time of the examination, the patient was awake, alert and responsive, with a normal neurological examination. His cardiovascular examination demonstrated normal S1/S2 heart sounds and a regular rhythm. Dorsalis pedis pulses were 2+ bilaterally. Family history was significant for multiple family members expiring from dissected aortic aneurysms. A CT was obtained which demonstrated thoracoabdominal aortic dissection from the arch level to the iliac bifurcation (Figure 1A). Patient’s dissection was managed conservatively with anti-impulse therapy, and repeat CT scans confirmed a stable dissection [15]. No PDA was identified in the patient. Given patient’s positive family history, DNA was obtained and analyzed via WES for genes known to be causative of TAA.
Figure 1: Thoraco-abdominal Computed Tomography demonstrating descending thoracic aortic dissection in the proband (A) and his twin brother (B) at the level of the aortic arch and extending to the level of iliac bifurcation.
Data from WES demonstrated a three base-pair (bp) deletion (c. 3790_3792delCTG) in the MYH11 gene at amino acid position 1264 [L1264del]. This finding was confirmed using Sanger sequencing. This deletion was not detected in 2,500 exomes of Yale internal database, NHLBI database, and 1000 genomes database. Fourteen additional family members were also tested for this same deletion and the mutation was noted to segregate with disease in the family (Figure 2).
Figure 2: Scrambled pedigree of the family demonstrating segregation of (c.3790_3792delCTG), amino acid [L1264del] in MYH11gene.
A total of 13 family members underwent a complete TTE and PWV evaluation. In comparing the PWV of the MYH11 mutation positive group to the mutation negative group, we found no significant difference between their mean PWVs. Although the mean PWV was higher in the mutation positive group when compared to age-matched reference values, only one mutation positive patient had an elevated PWV. The PWV of two mutation positive patients who had previously undergone aortic repair for thoracic aortic aneurysm/dissection were not included in this analysis as the presence of an aortic graft with different mechanical properties compared to the native aorta could result in spurious PWV measurements.


TAAs are the second most common aortic aneurysms after abdominal aortic aneurysms [6]. Patients and siblings of affected patients carry up to a 50% chance of a similar outcome. Compared with abdominal aortic aneurysms, TAAs affect twice as many men as women, and are more commonly associated with hypertension and bicuspid aortic valve [16].
Mutations in the MYH11 gene which encode MYH11 protein (chromosome 16p13.11) account for 2% of non-syndromic TAADs and have been often associated with patent ductus arteriosus (PDA) [17]. Heterozygous MYH11 gene mutations result in thoracic aortic aneurysms and are thought to act via a dominant negative mechanism. Mutations in MYH11 gene identified in FTAAD families are predominantly splice-site mutations resulting in in-frame deletions and missense mutations [8-15].
We used whole exome sequencing (WES) to evaluate our proband after he presented to an outpatient clinic with an early onset of TAAD, no risk factors, and a very strong family history of sudden death. We have chosen to use WES in our proband as this method is regarded by many as the most powerful technology in clinical use for detecting genetic mutations [18]. This platform also has the advantage of identifying all types of mutations including insertions and deletions (indels), variants which are normally missed using sequencing technology [18]. All known genes involved in aortic aneurysms and/or dissections were examined with good coverage.
Using WES technology we have identified an important deletion in MYH11 gene (c.3790_3792delCTG) in our proband (II-7). Our deletion in MYH11 gene was confirmed with Sanger sequencing and segregation of the deletion was observed among other affected family members (Figure 2). All available and willing family members (total of 13 patients) were Sanger sequenced for (c.3790_3792delCTG) in the MYH11 gene at amino acid position 1264 [L1264del]. Death certificates and autopsy reports were reviewed of the deceased family members and demonstrated TAADs as the cause of death in all cases. During our evaluation of the proband, his twin brother (II-8), who also carried identical deletion, presented with chest pain and was surprisingly found to have a descending thoracic aortic dissection in the same area (Figure 1A and B).
Our identified deleted region involved just one amino acid (leucine) at position 1264 in the coiled region of the MYH11 protein. This deletion localized to larger regions in the coiled domain described in prior reports of TAAD development [7]. COILS modeling predict our deletion to disrupt the coiled-coil region of MYH11 [10] (Figure 3). To date, however, no crystal structure of MYH11 exists, and no studies have been performed which demonstrate the assembly domain of the coiled-coil region [17].
Figure 3: Coiled-coil output in MYH11 with L1264del. Decreased probability of coiled coil formation in the MYH11 protein with (c. 3790_3792delCTG), amino acid [L1264del] (MYH11 MUT) as compared to wild type MYH11 protein (MYH11 WT) at 14 and 21 window frames as per COILS program.
In our case, data implicates leucine at position 1264 as playing an important role in the MYH11 protein. In the family we evaluated, multiple lines of evidence point to L1264del as being important for maintaining aortic integrity. First, the deletion segregated with the disease phenotype, TAAD. Second, large deletions, which encompassed our deleted region, have been previously shown to cause TAAD. Third, previously described missense mutation of the specific amino acid found deleted in our family has been demonstrated to cause aortic aneurysms [17]. Although majority of patients in our family pedigree have experienced aortic dissections in their 60s, patients III-2 and IV-7 died suddenly earlier in their life. Patient III-2 was in later stages of pregnancy and thus the aortic strain associated with a weakened aortic wall might explain her TAAD. Patient IV-7, however, was in her 30s and died suddenly of aortic thoracic dissection. What is surprising is that patient II-10 who is mutation positive has not had a TAAD and is in her early 70s. Her daughter who is in her 50s (III-12) is also asymptomatic but her granddaughter (IV-7) died suddenly of TAAD. Evidence that at least one family member with MYH11 L1264del is asymptomatic in her early 70s is supportive of incomplete penetrance which have been previously described for MYH11 gene mutations [17]. It is also possible; however, that MYH11 L1264del mutation confers a risk and requires other as of yet unidentified modifier gene(s) or environmental factors for TAAD development [19].
Since aortic dissections often give no warning signs before rupture, prior efforts have been made to evaluate for loss of aortic compliance and impending failure using PWV and Magnetic Resonance Imaging (MRI) [20]. In our case, we have chosen to use PWV as it is the gold standard for measuring aortic stiffness and has established normalized values for population across various age groups [21]. We tested both affected and unaffected subjects within our family using pulse wave velocity, but no appreciable changes in aortic stiffness were detected (Table 1). PWV using TTE, therefore, has not proven to be an effective test in predicting TAA as a result of MYH11 L1264del. Given recent reports of success using MRI to evaluate aortic compliance in patients with MYH11 mutations, however, it is reasonable in the future to reevaluate our family using MRI technology [22].
Table 1: Comparison of the PWV among MYH11 mutation positive family members and MYH11 mutation negative family members. (* In normotensive subjects).


Our case demonstrates an important deletion in MYH11 gene which segregated with TAAD in an extended family. Deletion of leucine at position 1264 in MYH11 may thus represent a testable mutation which denotes important genetic burden for familial aortic disease.

Conflict of Interest

No conflict of interest exists for any of the authors listed on this manuscript.


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