Identification of a dominant <i>MYH11</i> causal variant in chronic intestinal pseudo‐obstruction: Results of whole‐exome sequencing

Dong, Weilai; Baldwin, Clinton T.; Choi, Jungmin; Milunsky, Jeff M.; Zhang, Junhui; Bilgüvar, Kaya; Lifton, Richard P.; Milunsky, Aubrey

doi:10.1111/cge.13617

Cited by 26 publications

(24 citation statements)

References 20 publications

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“…In addition, phenotype information is not provided for individuals in ExAC and gnomAD, and it is possible that these individuals may be asymptomatic or have mild symptoms, which is expected for this variably expressed condition. Functional evidence further strengthens the pathogenicity of the deletion variant, as it has been shown to result in unregulated motor activity of the encoded myosin and was recently implicated in Chronic Intestinal Pseudo‐Obstruction (CIPO), a GI disorder affecting smooth muscle contractility that includes overlapping dysmotility phenotypes that we describe in our two families, although specific clinical manifestations in the recently reported individuals were not provided (Alhopuro et al, 2008; Dong et al, 2019; Jo, Kim, Yoo, & Lee, 2018).…”

Section: Discussionsupporting

confidence: 72%

“…The discovery of two, similar MYH11 variants in two unrelated families and the recent identification of the deletion variant in seven affected individuals in a third family with CIPO (Dong et al, 2019), is strongly suggestive of pathogenicity given the smooth muscle deficiency that presents within the affected individuals. We hypothesize that the mechanism of pathogenesis and inheritance dictates the type of smooth muscle disease that arises from MYH11 pathogenic variants, a hypothesis that has already been proposed (Gauthier et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

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Protein‐elongating mutations inMYH11are implicated in a dominantly inherited smooth muscle dysmotility syndrome with severe esophageal, gastric, and intestinal disease

et al. 2020

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Gastrointestinal motility disorders include a spectrum of mild to severe clinical phenotypes that are caused by smooth muscle dysfunction. We investigated the genetic etiology of severe esophageal, gastric, and colonic dysmotility in two unrelated families with autosomal dominant disease presentation. Using exome sequencing, we identified a 2 base pair insertion at the end of the myosin heavy chain 11 (MYH11) gene in all affected members of Family 1 [NM_001040113:c. 5819_5820insCA(p.Gln1941Asnfs*91)] and a 1 base pair deletion at the same genetic locus in Proband 2 [NM_001040113:c.5819del(p.Pro1940Hisfs*91)]. Both variants are predicted to result in a similarly elongated protein product. Heterozygous dominant negative MYH11 pathogenic variants have been associated with thoracic aortic aneurysm and dissection while biallelic null alleles have been associated with megacystis microcolon intestinal hypoperistalsis syndrome. This report highlights heterozygous protein-elongating MYH11 variants affecting the SM2 isoforms of MYH11 as a cause for severe gastrointestinal dysmotility, and we hypothesize that the mechanistic pathogenesis of this disease, dominant hypercontractile loss-of-function, is distinct from those implicated in other diseases involving MYH11 dysfunction. K E Y W O R D S dysmotility, gastroparesis, hiatal hernia, MYH11, pseudo-obstruction

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Section: Discussionsupporting

confidence: 72%

Section: Discussionmentioning

confidence: 99%

Protein‐elongating mutations inMYH11are implicated in a dominantly inherited smooth muscle dysmotility syndrome with severe esophageal, gastric, and intestinal disease

et al. 2020

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“…8 A dominant causal variant in MYH11 associated with smooth muscle dysfunction has been reported recently in families with chronic intestinal pseudoobstruction. 9 The MYH11 variant in our patient is a novel mutation not previously described. This mutation could be a pathogenic one in our patient due to the existence of two concomitant smooth muscles disorders: ductal aneurysm and intestinal atresia.…”

Section: Discussionmentioning

confidence: 62%

Congenital ductus arteriosus aneurysm in association with MYH11 mutation: a case report

Ardhanari

Swaminathan

2020

Cardiol Young

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Congenital ductus arteriosus aneurysms develop in the third trimester of fetal life, possibly due to abnormal intimal cushion formation or elastin expression in the ductal wall. It is often diagnosed in infants before 2 months of age. Most have a benign course and resolve spontaneously. However, life-threatening complications have been reported. We report a case of large ductal aneurysm diagnosed incidentally in a neonate, in whom there was a novel mutation in the smooth muscle myosin protein gene—MYH11.

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“…Conversely, biallelic MYH11 variants previously described in MMIHS are frameshift or null mutations, disrupting the expression of the protein 13‐16 . More recently, two heterozygous frameshift variants have been reported, suggesting possible dominant inheritance of MYH11 in gastrointestinal motility disorders 33,34 . The loss‐of‐function then results in a deficient muscle contraction, causing the MMIHS phenotype.…”

Section: Discussionmentioning

confidence: 99%

Fetal megacystis‐microcolon: Genetic mutational spectrum and identification of PDCL3 as a novel candidate gene

et al. 2020

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Megacystis‐microcolon‐intestinal‐hypoperistalsis syndrome (MMIHS) is a severe congenital visceral myopathy characterized by an abdominal distension due to a large non‐obstructed urinary bladder, a microcolon and intestinal hypo‐ or aperistalsis. Most of the patients described to date carry a sporadic heterozygous variant in ACTG2. More recently, recessive forms have been reported and mutations in MYH11, LMOD1, MYLK and MYL9 have been described at the molecular level. In the present report, we describe five patients carrying a recurrent heterozygous variant in ACTG2. Exome sequencing performed in four families allowed us to identify the genetic cause in three. In two families, we identified variants in MMIHS causal genes, respectively a nonsense homozygous variant in MYH11 and a previously described homozygous deletion in MYL9. Finally, we identified compound heterozygous variants in a novel candidate gene, PDCL3, c.[143_144del];[380G>A], p.[(Tyr48Ter)];[(Cys127Tyr)]. After cDNA analysis, a complete absence of PDLC3 expression was observed in affected individuals, indicating that both mutated transcripts were unstable and prone to mediated mRNA decay. PDCL3 encodes a protein involved in the folding of actin, a key step in thin filament formation. Presumably, loss‐of‐function of this protein affects the contractility of smooth muscle tissues, making PDCL3 an excellent candidate gene for autosomal recessive forms of MMIHS.

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Identification of a dominant MYH11 causal variant in chronic intestinal pseudo‐obstruction: Results of whole‐exome sequencing

Cited by 26 publications

References 20 publications

Protein‐elongating mutations inMYH11are implicated in a dominantly inherited smooth muscle dysmotility syndrome with severe esophageal, gastric, and intestinal disease

Protein‐elongating mutations inMYH11are implicated in a dominantly inherited smooth muscle dysmotility syndrome with severe esophageal, gastric, and intestinal disease

Congenital ductus arteriosus aneurysm in association with MYH11 mutation: a case report

Fetal megacystis‐microcolon: Genetic mutational spectrum and identification of PDCL3 as a novel candidate gene

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