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
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Article info
Publication history
Published online: August 18, 2022
Accepted:
July 1,
2022
Received in revised form:
June 30,
2022
Received:
December 2,
2021
Identification
Copyright
© 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.
