title: Caution in interpretation of disease causality for heterozygous loss-of-function variants in the MYH8 gene associated with autosomal dominant disorder.
abstract: To date, the NM_002472.2(MYH8):c.2021G>A (p.Arg674Gln) missense variant in the MYH8 gene is the only known genetic change in individuals with autosomal dominant trismus-pseudocamptodactyly syndrome with unknown molecular mechanism. Next-generation sequencing (NGS), including targeted gene panels and whole-exome sequencing, is routinely performed in many clinical diagnostic laboratories as standard-of-care testing aimed at identifying disease-causing genomic variants. Whole-exome sequencing has revealed loss-of-function variants in the MYH8 gene. To properly classify the MYH8 loss-of-function variants, we either retrieved them from public databases or retrospectively collected them from individuals genetically tested by custom NGS panels or by whole-exome sequencing and confirmed using Sanger sequencing. We further evaluated the respective clinical presentations of these individuals with the MYH8 loss-of-function variants. Heterozygous loss-of-function variants in the MYH8 gene were detected in 16 individuals without trismus-pseudocamptodactyly syndrome. Four of these 16 individuals had a pathogenic or likely pathogenic variant detected in another gene that could explain their clinical presentation. Moreover, there are ∼100 MYH8 heterozygous protein-truncating and splice site variants in the ExAC database in different populations. Our results, combined with the population data, indicate that loss-of-function variants in the MYH8 gene do not cause autosomal dominant trismus-pseudocamptodactyly syndrome, and the clinical significance of these variants remains unknown at present. This result highlights the importance of considering the molecular mechanism of disease, variants published in the medical literature, and population genomic data for the correct interpretation of loss-of-function variants in genes associated with autosomal dominant diseases.
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA; EGL Genetic Diagnostics, 2460 Mountain Industrial Blvd, Tucker, GA 30084, USA. Electronic address: zunyan.dai@emory.edu.
authors.forename: Zunyan
authors.initials: Z
authors.lastname: Dai
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA; EGL Genetic Diagnostics, 2460 Mountain Industrial Blvd, Tucker, GA 30084, USA.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Whitt
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA; EGL Genetic Diagnostics, 2460 Mountain Industrial Blvd, Tucker, GA 30084, USA.
authors.forename: Lindsey C
authors.initials: LC
authors.lastname: Mighion
authors.affiliation: Center for the Study of Rare Hereditary Diseases, Niguarda Ca' Granda Metropolitan Hospital, Milan, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Pontoglio
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA; EGL Genetic Diagnostics, 2460 Mountain Industrial Blvd, Tucker, GA 30084, USA.
authors.forename: Lora J H
authors.initials: LJH
authors.lastname: Bean
authors.affiliation: Institute of Clinical Biochemistry, Faculty of Medicine, Catholic University of the Sacred Heart, Rome, Italy; Center for the Study of Rare Hereditary Diseases, Niguarda Ca' Granda Metropolitan Hospital, Milan, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Colombo
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Madhuri
authors.initials: M
authors.lastname: Hegde
mesh_terms: D000015:Abnormalities, Multiple / Q000175:diagnosis / Q000235:genetics*; D001176:Arthrogryposis / Q000175:diagnosis / Q000235:genetics*; D059472:Exome; D005820:Genetic Testing / Q000592:standards; D006579:Heterozygote; D006801:Humans; D020125:Mutation, Missense; D018995:Myosin Heavy Chains / Q000235:genetics*; D012326:RNA Splicing; D014313:Trismus / Q000175:diagnosis / Q000235:genetics*
chemical_list: C488292:MYH8 protein, human; D018995:Myosin Heavy Chains
keywords: Autosomal dominant disorders; Loss-of-function variants; MYH8; Next-generation sequencing (NGS); Variant interpretation