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

Published:August 18, 2022DOI:



      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.


      An international collaboration identified the patient cohort. CAS9-mediated knockout cell models were used to explore the mechanism of disease pathogenesis.


      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.


      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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        • Newell-Litwa K.A.
        • Horwitz R.
        • Lamers M.L.
        Non-muscle myosin II in disease: mechanisms and therapeutic opportunities.
        Dis Model Mech. 2015; 8: 1495-1515
        • Tullio A.N.
        • Accili D.
        • Ferrans V.J.
        • et al.
        Nonmuscle myosin II-B is required for normal development of the mouse heart.
        Proc Natl Acad Sci U S A. 1997; 94: 12407-12412
        • Tullio A.N.
        • Bridgman P.C.
        • Tresser N.J.
        • et al.
        Structural abnormalities develop in the brain after ablation of the gene encoding nonmuscle myosin II-B heavy chain.
        J Comp Neurol. 2001; 433: 62-74
        • Ozkan E.D.
        • Aceti M.
        • Creson T.K.
        • et al.
        Input-specific regulation of hippocampal circuit maturation by non-muscle myosin IIB.
        J Neurochem. 2015; 134: 429-444
        • Gavin C.F.
        • Rubio M.D.
        • Young E.
        • Miller C.
        • Rumbaugh G.
        Myosin II motor activity in the lateral amygdala is required for fear memory consolidation.
        Learn Mem. 2011; 19: 9-14
        • Kim H.T.
        • Yin W.
        • Jin Y.J.
        • et al.
        Myh10 deficiency leads to defective extracellular matrix remodeling and pulmonary disease.
        Nat Commun. 2018; 9: 4600
        • Haque F.
        • Kaku Y.
        • Fujimura S.
        • Ohmori T.
        • Adelstein R.S.
        • Nishinakamura R.
        Non-muscle myosin II deletion in the developing kidney causes ureter-bladder misconnection and apical extrusion of the nephric duct lineage epithelia.
        Dev Biol. 2017; 427: 121-130
        • Ma X.
        • Kawamoto S.
        • Hara Y.
        • Adelstein R.S.
        A point mutation in the motor domain of nonmuscle myosin II-B impairs migration of distinct groups of neurons.
        Mol Biol Cell. 2004; 15: 2568-2579
        • Kim K.Y.
        • Kovács M.
        • Kawamoto S.
        • Sellers J.R.
        • Adelstein R.S.
        Disease-associated mutations and alternative splicing alter the enzymatic and motile activity of nonmuscle myosins II-B and II-C.
        J Biol Chem. 2005; 280: 22769-22775
      1. Ma X, Adelstein RS. A point mutation in Myh10 causes major defects in heart development and body wall closure. Circ Cardiovasc Genet. 2014;7(3):257-265. Published correction appears in Circ Cardiovasc Genet. 2014;7(4):570.

        • Petrovski S.
        • Aggarwal V.
        • Giordano J.L.
        • et al.
        Whole-exome sequencing in the evaluation of fetal structural anomalies: a prospective cohort study.
        Lancet. 2019; 393: 758-767
        • Tuzovic L.
        • Yu L.
        • Zeng W.
        • et al.
        A human de novo mutation in MYH10 phenocopies the loss of function mutation in mice.
        Rare Dis. 2013; 1e26144
        • Hamdan F.F.
        • Srour M.
        • Capo-Chichi J.M.
        • et al.
        De novo mutations in moderate or severe intellectual disability.
        PLoS Genet. 2014; 10e1004772
        • Iossifov I.
        • O’Roak B.J.
        • Sanders S.J.
        • et al.
        The contribution of de novo coding mutations to autism spectrum disorder.
        Nature. 2014; 515: 216-221
        • Kosmicki J.A.
        • Samocha K.E.
        • Howrigan D.P.
        • et al.
        Refining the role of de novo protein-truncating variants in neurodevelopmental disorders by using population reference samples.
        Nat Genet. 2017; 49: 504-510
        • Satterstrom F.K.
        • Kosmicki J.A.
        • Wang J.
        • et al.
        Large-scale exome sequencing study implicates both developmental and functional changes in the neurobiology of autism.
        Cell. 2020; 180: 568-584.e23
        • Li J.
        • Cai T.
        • Jiang Y.
        • et al.
        Genes with de novo mutations are shared by four neuropsychiatric disorders discovered from NPdenovo database.
        Mol Psychiatry. 2016; 21 (Published correction appears in Mol Psychiatry. 2016;21(2):298): 290-297
      2. Aspromonte MC, Bellini M, Gasparini A, et al. Characterization of intellectual disability and autism comorbidity through gene panel sequencing. Hum Mutat. 2019;40(9):1346-1363. Published correction appears in Hum Mutat. 2020;41(6):1183.

        • Carraro M.
        • Monzon A.M.
        • Chiricosta L.
        • et al.
        Assessment of patient clinical descriptions and pathogenic variants from gene panel sequences in the CAGI-5 intellectual disability challenge.
        Hum Mutat. 2019; 40: 1330-1345
        • Jin S.C.
        • Homsy J.
        • Zaidi S.
        • et al.
        Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands.
        Nat Genet. 2017; 49: 1593-1601
        • O’Roak B.J.
        • Vives L.
        • Girirajan S.
        • et al.
        Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations.
        Nature. 2012; 485: 246-250
        • Qiao L.
        • Wynn J.
        • Yu L.
        • et al.
        Likely damaging de novo variants in congenital diaphragmatic hernia patients are associated with worse clinical outcomes.
        Genet Med. 2020; 22: 2020-2028
        • Holtz A.M.
        • Peterson K.A.
        • Nishi Y.
        • et al.
        Essential role for ligand-dependent feedback antagonism of vertebrate hedgehog signaling by PTCH1, PTCH2 and HHIP1 during neural patterning.
        Development. 2013; 140: 3423-3434
        • Sobreira N.
        • Schiettecatte F.
        • Valle D.
        • Hamosh A.
        GeneMatcher: a matching tool for connecting investigators with an interest in the same gene.
        Hum Mutat. 2015; 36: 928-930
      3. Karczewski KJ, Francioli LC, Tiao G, et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 2020;581(7809):434-443. Published correction appears in Nature. 2021;590(7846):E53. Published correction appears in Nature. 2021;597(7874):E3-E4.

        • Kopanos C.
        • Tsiolkas V.
        • Kouris A.
        • et al.
        VarSome: the human genomic variant search engine.
        Bioinformatics. 2019; 35: 1978-1980
        • Münnich S.
        • Pathan-Chhatbar S.
        • Manstein D.J.
        Crystal structure of the rigor-like human non-muscle myosin-2 motor domain.
        FEBS Lett. 2014; 588: 4754-4760
      4. Frazer J, Notin P, Dias M, et al. Disease variant prediction with deep generative models of evolutionary data. Nature. 2021;599(7883):91-95. Published correction appears in Nature. 2022;601(7892):E7.

      5. Wu Y, Li R, Sun S, Weile J, Roth FP. Improved pathogenicity prediction for rare human missense variants. Am J Hum Genet. 2021;108(10):1891-1906. Published correction appears in Am J Hum Genet. 2021;108(12):2389.

        • Kopinke D.
        • Norris A.M.
        • Mukhopadhyay S.
        Developmental and regenerative paradigms of cilia regulated hedgehog signaling.
        Semin Cell Dev Biol. 2021; 110: 89-103
        • Rao Y.
        • Hao R.
        • Wang B.
        • Yao T.P.
        A Mec17-myosin II effector axis coordinates microtubule acetylation and actin dynamics to control primary cilium biogenesis.
        PLoS One. 2014; 9e114087
        • Hong H.
        • Kim J.
        • Kim J.
        Myosin heavy chain 10 (MYH10) is required for centriole migration during the biogenesis of primary cilia.
        Biochem Biophys Res Commun. 2015; 461: 180-185
        • Kim J.
        • Lee J.E.
        • Heynen-Genel S.
        • et al.
        Functional genomic screen for modulators of ciliogenesis and cilium length.
        Nature. 2010; 464: 1048-1051
        • Elliott K.H.
        • Brugmann S.A.
        Sending mixed signals: cilia-dependent signaling during development and disease.
        Dev Biol. 2019; 447: 28-41
        • Breslow D.K.
        • Hoogendoorn S.
        • Kopp A.R.
        • et al.
        A CRISPR-based screen for Hedgehog signaling provides insights into ciliary function and ciliopathies.
        Nat Genet. 2018; 50: 460-471
        • Drummond M.L.
        • Li M.
        • Tarapore E.
        • et al.
        Actin polymerization controls cilia-mediated signaling.
        J Cell Biol. 2018; 217: 3255-3266
        • Richards S.
        • Aziz N.
        • Bale S.
        • et al.
        Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
        Genet Med. 2015; 17: 405-424
        • Pecci A.
        • Canobbio I.
        • Balduini A.
        • et al.
        Pathogenetic mechanisms of hematological abnormalities of patients with MYH9 mutations.
        Hum Mol Genet. 2005; 14: 3169-3178
        • Park I.
        • Han C.
        • Jin S.
        • et al.
        Myosin regulatory light chains are required to maintain the stability of myosin II and cellular integrity.
        Biochem J. 2011; 434: 171-180
        • Ma X.
        • Kawamoto S.
        • Uribe J.
        • Adelstein R.S.
        Function of the neuron-specific alternatively spliced isoforms of nonmuscle myosin II-B during mouse brain development.
        Mol Biol Cell. 2006; 17: 2138-2149