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. Dobyns; Theresa 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

doi:10.1016/j.gim.2022.07.005

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

Pediatric Genetics & Metabolism

Research output: Contribution to journal › Article › peer-review

5 Scopus citations

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.

Original language	English (US)
Pages (from-to)	2065-2078
Number of pages	14
Journal	Genetics in Medicine
Volume	24
Issue number	10
DOIs	https://doi.org/10.1016/j.gim.2022.07.005
State	Published - Oct 2022

Bibliographical note

Funding Information:
We would like to thank the patients and families for contributing to this study and to the providers who help to care for these families. We also thank Benjamin L. Allen (University of Michigan) for providing several resources for this study. This research was supported in part by the Intramural Research Program of the National Human Genome Research Institute, United States, National Institutes of Health, United States (J.P.). Sequencing and analysis of individual 8 was provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics and was funded by the National Human Genome Research Institute, the National Eye Institute, United States , and the National Heart, Lung and Blood Institute grant UM1 HG008900 and in part by National Human Genome Research Institute grant R01 HG009141. W.B.D. is supported by R01 NS050375 and W.B.D. and E.H.S. are supported by R01 NS058721. Research reported in this publication was also supported by the National Institute Of Mental Health of the National Institutes of Health under award number U01MH119689. This work was also supported by a grant from SFARI, United States (704413; E.B.R) and from the Stanley Center for Psychiatric Research at the Broad Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Publisher Copyright:
© 2022 American College of Medical Genetics and Genomics

Keywords

Hedgehog signaling
MYH10
Neurodevelopmental disorder
Nonmuscle myosin
Primary cilia

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10.1016/j.gim.2022.07.005

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Holtz, A. M., VanCoillie, 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., ... 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, 24(10), 2065-2078. https://doi.org/10.1016/j.gim.2022.07.005

Heterozygous variants in MYH10 associated with neurodevelopmental disorders and congenital anomalies with evidence for primary cilia-dependent defects in Hedgehog signaling. / Holtz, Alexander M.; VanCoillie, Rachel; Vansickle, Elizabeth A. et al.
In: Genetics in Medicine, Vol. 24, No. 10, 10.2022, p. 2065-2078.

Research output: Contribution to journal › Article › peer-review

Holtz, AM, VanCoillie, 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, 'Heterozygous variants in MYH10 associated with neurodevelopmental disorders and congenital anomalies with evidence for primary cilia-dependent defects in Hedgehog signaling', Genetics in Medicine, vol. 24, no. 10, pp. 2065-2078. https://doi.org/10.1016/j.gim.2022.07.005

@article{8da745d301f4484daab698adc5ce639c,

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

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.",

keywords = "Hedgehog signaling, MYH10, Neurodevelopmental disorder, Nonmuscle myosin, Primary cilia",

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

note = "Funding Information: We would like to thank the patients and families for contributing to this study and to the providers who help to care for these families. We also thank Benjamin L. Allen (University of Michigan) for providing several resources for this study. This research was supported in part by the Intramural Research Program of the National Human Genome Research Institute, United States, National Institutes of Health, United States (J.P.). Sequencing and analysis of individual 8 was provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics and was funded by the National Human Genome Research Institute, the National Eye Institute, United States , and the National Heart, Lung and Blood Institute grant UM1 HG008900 and in part by National Human Genome Research Institute grant R01 HG009141. W.B.D. is supported by R01 NS050375 and W.B.D. and E.H.S. are supported by R01 NS058721. Research reported in this publication was also supported by the National Institute Of Mental Health of the National Institutes of Health under award number U01MH119689. This work was also supported by a grant from SFARI, United States (704413; E.B.R) and from the Stanley Center for Psychiatric Research at the Broad Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Publisher Copyright: {\textcopyright} 2022 American College of Medical Genetics and Genomics",

year = "2022",

month = oct,

doi = "10.1016/j.gim.2022.07.005",

language = "English (US)",

volume = "24",

pages = "2065--2078",

journal = "Genetics in Medicine",

issn = "1098-3600",

publisher = "Elsevier B.V.",

number = "10",

}

TY - JOUR

T1 - Heterozygous variants in MYH10 associated with neurodevelopmental disorders and congenital anomalies with evidence for primary cilia-dependent defects in Hedgehog signaling

AU - Holtz, Alexander M.

AU - VanCoillie, Rachel

AU - Vansickle, Elizabeth A.

AU - Carere, Deanna Alexis

AU - Withrow, Kara

AU - Torti, Erin

AU - Juusola, Jane

AU - Millan, Francisca

AU - Person, Richard

AU - Guillen Sacoto, Maria J.

AU - Si, Yue

AU - Wentzensen, Ingrid M.

AU - Pugh, Jada

AU - Vasileiou, Georgia

AU - Rieger, Melissa

AU - Reis, André

AU - Argilli, Emanuela

AU - Sherr, Elliott H.

AU - Aldinger, Kimberly A.

AU - Dobyns, William B.

AU - Brunet, Theresa

AU - Hoefele, Julia

AU - Wagner, Matias

AU - Haber, Benjamin

AU - Kotzaeridou, Urania

AU - Keren, Boris

AU - Heron, Delphine

AU - Mignot, Cyril

AU - Heide, Solveig

AU - Courtin, Thomas

AU - Buratti, Julien

AU - Murugasen, Serini

AU - Donald, Kirsten A.

AU - O'Heir, Emily

AU - Moody, Shade

AU - Kim, Katherine H.

AU - Burton, Barbara K.

AU - Yoon, Grace

AU - Campo, Miguel del

AU - Masser-Frye, Diane

AU - Kozenko, Mariya

AU - Parkinson, Christina

AU - Sell, Susan L.

AU - Gordon, Patricia L.

AU - Prokop, Jeremy W.

AU - Karaa, Amel

AU - Bupp, Caleb

AU - Raby, Benjamin A.

N1 - Funding Information: We would like to thank the patients and families for contributing to this study and to the providers who help to care for these families. We also thank Benjamin L. Allen (University of Michigan) for providing several resources for this study. This research was supported in part by the Intramural Research Program of the National Human Genome Research Institute, United States, National Institutes of Health, United States (J.P.). Sequencing and analysis of individual 8 was provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics and was funded by the National Human Genome Research Institute, the National Eye Institute, United States , and the National Heart, Lung and Blood Institute grant UM1 HG008900 and in part by National Human Genome Research Institute grant R01 HG009141. W.B.D. is supported by R01 NS050375 and W.B.D. and E.H.S. are supported by R01 NS058721. Research reported in this publication was also supported by the National Institute Of Mental Health of the National Institutes of Health under award number U01MH119689. This work was also supported by a grant from SFARI, United States (704413; E.B.R) and from the Stanley Center for Psychiatric Research at the Broad Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Publisher Copyright: © 2022 American College of Medical Genetics and Genomics

PY - 2022/10

Y1 - 2022/10

N2 - 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.

AB - 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.

KW - Hedgehog signaling

KW - MYH10

KW - Neurodevelopmental disorder

KW - Nonmuscle myosin

KW - Primary cilia

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

Abstract

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