16p13.11 microdeletion uncovers loss‐of‐function of a MYH11 missense variant in a patient with megacystis‐microcolon‐intestinal‐hypoperistalsis syndrome

Abstract

Megacystis‐microcolon‐intestinal hypoperistalsis syndrome (MMIHS), a rare condition that affects smooth muscle cells, is caused by biallelic null alleles in MYH11. We report on a girl with MMIHS in addition to growth hormone deficiency, central hypothyroidism and a tonically dilated pupil with accommodation deficit. Sanger sequencing and arrayCGH uncovered the novel heterozygous missense variant c.379C>T in MYH11 and a heterozygous 1.3 Mb deletion in 16q13.11 encompassing MYH11, respectively. Her mother carries the deletion, whereas her father is heterozygous for the c.379C>T p.(Pro127Ser) change. Proline 127 is crucial for the formation of the Adenosine triphosphate binding pocket of the MYH11 motor domain and molecular modeling indicated that p.Pro127Ser alters nucleotide binding properties. Thus, the unusual and complex clinical presentation of the patient results from compound heterozygosity for a 16p13.11 microdeletion including the entire MYH11 gene and a loss‐of‐function missense variant on the remaining MYH11 allele. In conclusion, we recommend genetic testing both for MYH11 sequence alterations and copy number imbalances in individuals with MMIHS and smooth muscle cell‐associated abnormalities in additional organs, that is, multisystemic smooth muscle dysfunction.

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

“…In addition to the association with TAAD/PDA, four individuals with MYH11 mutations have been reported with MMIHS, a recessive disease characterized by impaired intestinal motility likely caused by smooth muscle degeneration through a loss‐of‐function mechanism (MIM# 155310). MYH11 mutations from this cohort include one homozygous nonsense variant, two compound heterozygous frameshift variants, a compound heterozygous missense variant and 1.3 Mb deletion in 16p13.11 that includes MYH11 , and a compound heterozygous missense variant and indel (Gauthier et al, 2015; Kloth et al, 2019; Q. Wang et al, 2019; Yetman & Starr, 2018). Mutations in ACTG2, MYL9, LMOD1 , and MYLK , which encode other smooth muscle proteins, have also been implicated in MMIHS disease pathogenesis (Halim, Brosens, et al, 2017; Halim, Wilson, et al, 2017; Moreno et al, 2018; Thorson et al, 2014; Wangler et al, 2014).…”

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

“…The variant locates at the end of the protein and elongates the protein. Although recessive genotypes in MYH11 were reported in three separated case (one homozygotes and two compound‐heterozygotes) as a cause of megacystis‐microcolon‐intestinal hypoperistalsis syndrome (Supplementary Figure 1), heterozygous MYH11 pathogenic variants have not been previously reported in CIPO. Heterozygous pathogenic MYH11 variants were reported for Thoracic Aortic Aneurysm and/or aortic Dissection (TAAD) and Patent Ductus Arteriosus .…”

“…It is one of the contractile apparatus components and pathogenic variants in the protein impair its polymerization and result in the reduced cellular contractility . Additionally, homozygous mutations in MYLK , MYH11 , LMOD1 , MYL9 , and RAD21 and X‐linked mutation in FLNA have been found in a small number of cases. Moreover, compound‐heterozygous mutations in MYH11 have also been reported in two CIPO families .…”

“…Moreover, compoundheterozygous mutations in MYH11 have also been reported in two CIPO families. 8,9 The genetic etiology of the remaining CIPO cases, however, remains elusive.…”

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

“…Several genetic studies identified heterozygous pathogenic missense variations in the enteric smooth muscle Actin γ‐2 gene ( ACTG2 , MIM#102545), 4‐12 as the major genetic cause of MMIHS. Recently, homozygous or compound heterozygous variants have been identified, respectively in the smooth muscle myosin heavy chain gene ( MYH11 , MIM#160745), 13‐16 the Leiomodin1 gene ( LMOD1 , MIM#602715), 17 and in the myosin light chain kinase gene ( MYLK , MIM#600922) 18 . In addition, a homozygous deletion of exon 4 of MYL9 (MIM#609905) has been reported 19 .…”