ClinGen Dosage Sensitivity Curation Page


Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function phenotype
PubMed ID Description
25003005 Tuzovic et al (2013) identified a de novo heterozygous nonsense MYH10 variant (p.E908X) in a patient with severe intellectual disability, microcephaly and multiple congenital anomalies including congenital diaphragmatic hernia. Iglesias et at (2014) also described the same patient in their whole-genome sequencing report (PMID: 24901346). The myosin heavy chain 10 (MYH10) gene encodes for non-muscle myosin IIB (NM IIB). Tuzovic et al generated a mouse model with a hypomorphic, homozygous R709C missense mutation in the motor domain of NM IIB. In this study, the homozygous mutants show 73% reduction in the expression of the NMHC-IIB and died in the early postnatal period. Brain tissue obtained from homozygous mutant mice show distorted cerebral cortex due to hydrocephalus and small and underdeveloped cerebellum. Those that survived longer showed severe growth retardation and progressive hydrocephalus and ataxia. Heterozygous mutants survived to adulthood without any obvious abnormalities. Further studies on germline ablated NMHC IIB mice and R709C mutant mice showed that both developed progressive hydrocephalus starting from E11.5, although the R709C mice develop it at a slower rate.
25284784 Dong et al (2014) described a de novo frameshift MYH10 variant in a patient with intellectual disability and autism spectrum disorder.
25363768 Iossifov et al (2014) identified de novo one frameshift and two missense variants in MYH10 in patients with autism spectrum disorder.

Evidence for Triplosenstive Phenotype

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.