Incomplete segregation of MYH11 variants with thoracic aortic aneurysms and dissections and patent ductus arteriosus

Abstract

Thoracic aortic aneurysms and dissections (TAAD) is a serious condition with high morbidity and mortality. It is estimated that 20% of non-syndromic TAAD cases are inherited in an autosomal-dominant pattern with variable expression and reduced penetrance. Mutations in myosin heavy chain 11 (MYH11), one of several identified TAAD genes, were shown to simultaneously cause TAAD and patent ductus arteriosus (PDA). We identified two large Dutch families with TAAD/PDA and detected two different novel heterozygote MYH11 variants in the probands. These variants, a heterozygote missense variant and a heterozygote in-frame deletion, were predicted to have damaging effects on protein structure and function. However, these novel alterations did not segregate with the TAAD/PDA in 3 out of 11 cases in family TAAD01 and in 2 out of 6 cases of family TAAD02. No mutation was detected in other known TAAD genes. Thus, it is expected that within these families other genetic factors contribute to the disease either by themselves or by interacting with the MYH11 variants. Such an oligogenic model for TAAD would explain the variable onset and progression of the disorder and its reduced penetrance in general. We conclude that in familial TAAD/PDA with an MYH11 variant in the index case caution should be exercised upon counseling family members. Specialized surveillance should still be offered to the non-carriers to prevent catastrophic aortic dissections or ruptures. Furthermore, our study underscores that segregation analysis remains very important in clinical genetics. Prediction programs and mutation evaluation algorithms need to be interpreted with caution.

Systematic Review of Studies That Have Evaluated Screening Tests in Relatives of Patients Affected by Nonsyndromic Thoracic Aortic Disease

“…Our results also suggest that genetic testing and cardiac imaging with at least TTE should be offered to all FDRs and SDRs of patients with suspected NS‐TADs. Mutation carriers should undergo further imaging (MRI or CT scan), focusing on thoracic aorta and/or other arterial trees based on the causative gene mutation 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74. For example, ACTA2‐mutation carriers should be monitored for coronary artery disease and occlusive cerebrovascular disease, in addition to the currently recommended routine imaging tests 32.…”

Structure of the Elastin-Contractile Units in the Thoracic Aorta and How Genes That Cause Thoracic Aortic Aneurysms and Dissections Disrupt This Structure

“…It is important to note that there are rare variants in MYH11 that do not segregate with disease in families with TAAD. 60 …”

The genetic architecture of non-syndromic thoracic aortic aneurysm

“…As such, this chromosome locus is not only responsible for families displaying this complex phenotype but also for aortic stiffness, an early hallmark of the disease 26. However, it should be noted that MYH11 variants have been identified in families that did not completely segregate with the disease,27 suggesting that additional modifying genes are contributing to the phenotype within these families. Interestingly, a Myh11 zebrafish model (meltdown (mlt)) with constitutive activation of the Myh11 ATPase part results in disruption of the vascular smooth muscle cells surrounding the posterior intestine, leading to high mortality.…”