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Holtz, A.M.* ; Vancoil, R.* ; Vansickle, E.A.* ; Carere, D.A.* ; Withrow, K.* ; Torti, E.* ; Juusola, J.* ; Millan, F.* ; Person, R.* ; Guillen Sacoto, M.J.* ; Si, Y.* ; Wentzensen, I.M.* ; Pugh, J.* ; Vasileiou, G.* ; Rieger, M.* ; Reis, A.* ; Argilli, E.* ; Sherr, E.H.* ; Aldinger, K.A.* ; Dobyns, W.B.* ; 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, K.A.* ; O'Heir, E.* ; Moody, S.* ; Kim, K.H.* ; Burton, B.K.* ; Yoon, G.* ; Campo, M.d.* ; Masser-Frye, D.* ; Kozenko, M.* ; Parkinson, C.* ; Sell, S.L.* ; Gordon, P.L.* ; Prokop, J.W.* ; Karaa, A.* ; Bupp, C.* ; Raby, B.A.*

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

Genet. Med. 24, 2065-2078 (2022)

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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.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Hedgehog Signaling ; Myh10 ; Neurodevelopmental Disorder ; Nonmuscle Myosin ; Primary Cilia

ISSN (print) / ISBN 1530-0366

e-ISSN 1098-3600

Journal Genetics in Medicine

Quellenangaben Volume: 24, Issue: 10, Pages: 2065-2078

Publisher Lippincott Williams & Wilkins

Publishing Place Baltimore, Md.

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Neurogenomics (ING)

Grants Simons Foundation Autism Research Initiative
Broad Institute
National Eye Institute
National Human Genome Research Institute
National Heart, Lung, and Blood Institute
National Institute of Mental Health
National Institutes of Health
Harvard Center for Mendelian Genomics