A +3 variant at a donor splice site leads to a skipping of the MYH11 exon 32, a recurrent RNA defect causing Heritable Thoracic Aortic Aneurysm and Dissection and/or Patent Ductus Arteriosus

Abstract

This is an open access article under the terms of the Creat ive Commo ns Attri butio n-NonCo mmerc ial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Early Onset Parkinson Syndrome, Type A Aortic Aneurysm and Noncompaction Associated With the Novel Variant c.2225C>T in MYH11: A Case Report

“…Cardiovascular / cerebrovascular manifestation The patient reported no gastrointestinal symptoms suggestive of VM, CIPO, or MMIHS, nor any recurrent fractures, visual disturbances, hypoacusis, stroke, urinary problems, or renal disease, as previously reported in MYH11 mutation carriers (Table 1) [9][10][11][12][13][14][15][16][17][18][19][20]. Whether Parkinson syndrome was due to cerebrovascular involvement or another cause remains controversial.…”

“…The patient is of interest for a novel heterozygous variant of MYH11, which manifested phenotypically as aortic aneurysm, Parkinson syndrome, and noncompaction. Whether the detected heterozygous MYH11 variant was actually responsible for the clinical manifestations remains speculative, but several previous studies reported that heterozygous MYH11 variants can be pathogenic (Table 1) [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. Except for aortic aneurysm [7,8], the other clinical manifestations of the index patient were not reported in association with MYH11 variants.…”

“…None of these possible complications were noted in the index patient. However, one argument for causality is that, in addition to aortic dissection, other cardiac anomalies such as patent ductus arteriosus [11] or bicuspid aortic valves (index case) have also been reported in MYH11 mutation carriers (Table 1) [13].…”

“…Chromosomal rearrangements involving the MYH11 gene are associated with acute myeloid leukaemia and sarcoma [2]. Mutations in MYH11 are associated with multisystem disease, predominantly presenting as visceral myopathy (VM) [3], megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) [4,5], chronic intestinal pseudo-obstruction (CIPO) [6], and familial thoracic aortic aneurysm and dissection [7,8] but also with various other features [9][10][11][12][13][14][15][16][17][18][19][20]. Aortic aneurysm, noncompaction, also known as left ventricular hypertrabeculation (LVHT), and Parkinson syndrome have not been reported in association with MYH11 variants.…”

Complex genotype–phenotype correlation of MYH11: new insights from monozygotic twins with highly variable expressivity and outcomes

“…variants in MYH11 result in incorrect assembly of the myosin filament and microfilament, thereby affecting the synthetic and contractile functions of SMCs [ 10 , 11 ]. Pathogenic variants in MYH11 may result in hereditary TAAD/PDA, visceral myopathy 2, or megacystis–microcolon–intestinal hypoperistalsis syndrome [ 12 ]. The proliferation and migration of SMCs leads to the formation of intimal cushions in the ductus arteriosus after birth, and constriction of SMCs results in ductal contraction and permanent ductus closure [ 13 , 14 ].…”