MYL9 – megacystis-microcolon-intestinal hypoperistalsis syndrome

Recent case‐report evidence has linked biallelic loss‑of‑function variants in MYL9 (HGNC:15754) to megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) (MONDO_0025986). In one study, a homozygous deletion encompassing the last exon of MYL9 was identified in two affected siblings from a consanguineous family (PMID:29453416), supporting an autosomal recessive inheritance pattern. A separate report described a proband with compound heterozygous loss‑of‑function variants, including the splice site variant c.184+2_184+10del, with parental testing confirming the variants were in trans (PMID:33031641). These independent observations provide compelling genetic evidence for the involvement of MYL9 in MMIHS.

The genetic evidence is further reinforced by the observation that affected individuals exhibit key features of MMIHS, such as megacystis and intestinal pseudo‑obstruction. Segregation analysis in the reported families—where at least one additional affected sibling was observed—adds further credence to the association. Together, these case reports establish a strong gene‑disease link for MYL9 in the context of MMIHS.

Although direct functional studies on MYL9 in the MMIHS context are limited, the known role of MYL9 in regulating smooth muscle contraction offers strong biological plausibility. MYL9 encodes a regulatory myosin light chain whose phosphorylation is crucial for proper smooth muscle function. Disruption of this process is consistent with the urinary and gastrointestinal dysmotility observed in MMIHS (PMID:32621347).

Moreover, the convergence of genetic findings from multiple independent case reports, together with supportive in vitro and mechanistic insights, underlines the pathogenic impact of MYL9 disruption on smooth muscle integrity. The observed loss‑of‑function variants correlate well with the clinical manifestations of MMIHS, reinforcing both diagnostic and therapeutic considerations in affected individuals.

It should be noted that while the functional data are not as extensive as the genetic evidence, they nonetheless provide a key mechanistic bridge explaining how MYL9 deficiency could lead to the severe contractile defects inherent to MMIHS. This integrative evidence supports a strong clinical assertion for MYL9 as a candidate gene worthy of inclusion in genetic testing panels for MMIHS and related smooth muscle myopathies.

Key Take‑home: MYL9 represents a strong candidate gene for autosomal recessive MMIHS, with both genetic and functional data providing critical support for its role in disease pathogenesis.

References

• European Journal of Human Genetics • 2018 • Homozygous deletion in MYL9 expands the molecular basis of megacystis-microcolon-intestinal hypoperistalsis syndrome PMID:29453416
• Molecular Genetics & Genomic Medicine • 2020 • Compound heterozygous loss of function variants in MYL9 in a child with megacystis-microcolon-intestinal hypoperistalsis syndrome PMID:33031641
• Clinical Genetics • 2020 • Fetal megacystis-microcolon: Genetic mutational spectrum and identification of PDCL3 as a novel candidate gene PMID:32621347

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