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

Holtz AM, Vancoil R, Vansickle EA, Carere DA, Withrow K, Torti E, Juusola J, Millan F, Person R, Guillen Sacoto MJ, Si Y, Wentzensen IM, Pugh J, Vasileiou G, Rieger M, Reis A, Argilli E, Sherr EH, Aldinger KA, Dobyns WB, Brunet T, Hoefele J, Wagner M, Haber B, Kotzaeridou U, Keren B, Heron D, Mignot C, Heide S, Courtin T, Buratti J, Murugasen S, Donald KA, O'Heir E, Moody S, Kim KH, Burton BK, Yoon G, Campo Md, Masser-Frye D, Kozenko M, Parkinson C, Sell SL, Gordon PL, Prokop JW, Karaa A, Bupp C, Raby BA (2022)

Publication Type: Journal article

Publication year: 2022

Journal

DOI: 10.1016/j.gim.2022.07.005

Abstract

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.

Authors with CRIS profile

Involved external institutions

Boston Children's Hospital United States (USA) (US) Helen DeVos Children's Hospital United States (USA) (US) GeneDX United States (USA) (US) National Human Genome Research Institute (NHGRI) United States (USA) (US) University of California San Francisco (UCSF) United States (USA) (US) Center for Integrative Brain Research United States (USA) (US) University of Minnesota (UMN) United States (USA) (US) Technische Universität München (TUM) Germany (DE) Universitätsklinikum Heidelberg Germany (DE) Sorbonne Université France (FR) University of Cape Town (UCT) South Africa (ZA) Eli and Edythe L. Broad Institute of MIT and Harvard United States (USA) (US) University of Texas Health Science Center at Houston (UTHealth) United States (USA) (US) Ann & Robert H. Lurie Children's Hospital of Chicago United States (USA) (US) The Hospital for Sick Children (SickKids) Canada (CA) UC San Diego School of Medicine United States (USA) (US) Rady Children's Hospital San Diego United States (USA) (US) Hamilton Health Sciences (HHS) Canada (CA) Penn State Health Children's Hospital United States (USA) (US) Michigan State University United States (USA) (US) Veterans Affairs Healthcare System Boston and Harvard Medical School United States (USA) (US)

How to cite

APA:

Holtz, A.M., Vancoil, R., Vansickle, E.A., Carere, D.A., Withrow, K., Torti, E.,... Raby, B.A. (2022). Heterozygous variants in MYH10 associated with neurodevelopmental disorders and congenital anomalies with evidence for primary cilia-dependent defects in Hedgehog signaling. Genetics in Medicine. https://dx.doi.org/10.1016/j.gim.2022.07.005

MLA:

Holtz, Alexander M., et al. "Heterozygous variants in MYH10 associated with neurodevelopmental disorders and congenital anomalies with evidence for primary cilia-dependent defects in Hedgehog signaling." Genetics in Medicine (2022).

BibTeX: Download