Heterozygous variants in MYH10 associated with neurodevelopmental disorders and congenital anomalies with evidence for primary cilia-dependent defects in Hedgehog signaling

Alexander M. Holtz*, Rachel VanCoillie, Elizabeth A. Vansickle, Deanna Alexis Carere, Kara Withrow, Erin Torti, Jane Juusola, Francisca Millan, Richard Person, Maria J. Guillen Sacoto, Yue Si, Ingrid M. Wentzensen, Jada Pugh, Georgia Vasileiou, Melissa Rieger, André Reis, Emanuela Argilli, Elliott H. Sherr, Kimberly A. Aldinger, William B. DobynsTheresa Brunet, Julia Hoefele, Matias Wagner, Benjamin Haber, Urania Kotzaeridou, Boris Keren, Delphine Heron, Cyril Mignot, Solveig Heide, Thomas Courtin, Julien Buratti, Serini Murugasen, Kirsten A. Donald, Emily O'Heir, Shade Moody, Katherine H. Kim, Barbara K. Burton, Grace Yoon, Miguel del Campo, Diane Masser-Frye, Mariya Kozenko, Christina Parkinson, Susan L. Sell, Patricia L. Gordon, Jeremy W. Prokop, Amel Karaa, Caleb Bupp*, Benjamin A. Raby*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


Purpose: Nonmuscle myosin II complexes are master regulators of actin dynamics that play essential roles during embryogenesis with vertebrates possessing 3 nonmuscle myosin II heavy chain genes, MYH9, MYH10, and MYH14. As opposed to MYH9 and MYH14, no recognizable disorder has been associated with MYH10. We sought to define the clinical characteristics and molecular mechanism of a novel autosomal dominant disorder related to MYH10. Methods: An international collaboration identified the patient cohort. CAS9-mediated knockout cell models were used to explore the mechanism of disease pathogenesis. Results: We identified a cohort of 16 individuals with heterozygous MYH10 variants presenting with a broad spectrum of neurodevelopmental disorders and variable congenital anomalies that affect most organ systems and were recapitulated in animal models of altered MYH10 activity. Variants were typically de novo missense changes with clustering observed in the motor domain. MYH10 knockout cells showed defects in primary ciliogenesis and reduced ciliary length with impaired Hedgehog signaling. MYH10 variant overexpression produced a dominant-negative effect on ciliary length. Conclusion: These data presented a novel genetic cause of isolated and syndromic neurodevelopmental disorders related to heterozygous variants in the MYH10 gene with implications for disrupted primary cilia length control and altered Hedgehog signaling in disease pathogenesis.

Original languageEnglish (US)
Pages (from-to)2065-2078
Number of pages14
JournalGenetics in Medicine
Issue number10
StatePublished - Oct 2022


  • Hedgehog signaling
  • MYH10
  • Neurodevelopmental disorder
  • Nonmuscle myosin
  • Primary cilia

ASJC Scopus subject areas

  • Genetics(clinical)


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