Journal article
Cross-sectional, Neuromuscular Phenotyping Study of Arhinia Patients With SMCHD1 Variants
Neurology, Vol.98(13), pp.e1384-e1396
02/04/2022
DOI: 10.1212/WNL.0000000000200032
PMCID: PMC8967428
PMID: 35121673
Abstract
Facioscapulohumeral muscular dystrophy type 2 (FSHD2) and arhinia are two distinct disorders caused by pathogenic variants in the same gene,
. The mechanism underlying this phenotypic divergence remains unclear. In this study, we characterize the neuromuscular phenotype of individuals with arhinia caused by
variants and analyze their complex genetic and epigenetic criteria to assess their risk for FSHD2.
Eleven individuals with congenital nasal anomalies, including arhinia, nasal hypoplasia, or anosmia, underwent a neuromuscular exam, genetic testing, muscle ultrasound, and muscle MRI. Risk for FSHD2 was determined by combined genetic and epigenetic analysis of 4q35 haplotype, D4Z4 repeat length and methylation profile. We also compared expression levels of pathogenic DUX4 mRNA in primary myoblasts or dermal fibroblasts (upon myogenic differentiation or epigenetic transdifferentiation, respectively) in these individuals to those with confirmed FSHD2.
Among the eleven individuals with rare, pathogenic, heterozygous missense variants in exons 3-11 of
only a subset (n=3/11; 1 male, 2 females; age 25-51 years) met the strict genetic and epigenetic criteria for FSHD2 (D4Z4 repeat unit length <21 in
with a 4qA haplotype, and D4Z4 methylation <30%). None of the 3 individuals had typical clinical manifestations or muscle imaging findings consistent with FSHD2. However, the arhinia patients meeting the permissive genetic and epigenetic criteria for FSHD2 displayed some DUX4 expression in dermal fibroblasts under the epigenetic de-repression by drug treatment and in the primary myoblasts undergoing myogenic differentiation.
In this cross-sectional study, we identified arhinia patients who meet the full genetic and epigenetic criteria for FSHD2 and display the molecular hallmark of FSHD, that is
de-repression and expression
but who do not manifest with the typical clinicopathologic phenotype of FSHD2. The distinct dichotomy between FSHD2 and arhinia phenotypes despite an otherwise poised
locus implies the presence of novel disease-modifying factors that seem to operate as a "switch", resulting in one phenotype and not the other. Identification and further understanding of these disease-modifying factors will likely provide valuable insight with therapeutic implications for both diseases.
Details
- Title: Subtitle
- Cross-sectional, Neuromuscular Phenotyping Study of Arhinia Patients With SMCHD1 Variants
- Creators
- Payam Mohassel - Neuromuscular and Neurogenetic Disorders of Childhood Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MDNing Chang - Department of Pharmacology, University of Nevada, Reno School of Medicine, Reno, Nevada, USAKaoru Inoue - Pediatric Neuroendocrinology Group, Clinical Research Branch, National Institute of Environmental Health Sciences, National Institutes of Health, RTP, NCAngela Delaney - National Institute of Child Health and Development, National Institutes of Health, Bethesda, MDYing Hu - Neuromuscular and Neurogenetic Disorders of Childhood Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MDSandra Donkervoort - Neuromuscular and Neurogenetic Disorders of Childhood Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MDDimah Saade - Neuromuscular and Neurogenetic Disorders of Childhood Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MDB Jeanne Billioux - International Neuroinfectious Diseases Unit, Division of Neuroimmunology and Neurovirology, National institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MDBrooke Meader - National Institute of Child Health and Development, National Institutes of Health, Bethesda, MDRita Volochayev - Environmental Autoimmunity Group, Clinical Research Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Bethesda, MDChamindra G Konersman - Department of Neurosciences, University of California, San Diego, San Diego, CAAngela M Kaindl - Charitè-Universitätsmedizin Berlin, Department of Pediatric Neurology, Center for Chronically Sick Children and Institute of Cell Biology and Neurobiology, Berlin, GermanyChie-Hee Cho - Institute for diagnostic and interventional Radiology, University Clinic, Jena, GermanyBianca Russell - Division of Pediatric Genetics, Department of Pediatrics, University of California, Los Angeles, Los Angeles, CAAdrian Rodriguez - Nashville Skin and Cancer, Nashville, TNK Wade Foster - Florida Dermatology and Skin Cancer Centers, Winter Haven, FLA Reghan Foley - Neuromuscular and Neurogenetic Disorders of Childhood Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MDSteven A Moore - Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, Iowa, USAPeter L Jones - Department of Pharmacology, University of Nevada, Reno School of Medicine, Reno, Nevada, USACarsten G Bonnemann - Neuromuscular and Neurogenetic Disorders of Childhood Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MDTakako Jones - Department of Pharmacology, University of Nevada, Reno School of Medicine, Reno, Nevada, USANatalie D Shaw - Pediatric Neuroendocrinology Group, Clinical Research Branch, National Institute of Environmental Health Sciences, National Institutes of Health, RTP, NC natalie.shaw@nih.gov
- Resource Type
- Journal article
- Publication Details
- Neurology, Vol.98(13), pp.e1384-e1396
- DOI
- 10.1212/WNL.0000000000200032
- PMID
- 35121673
- PMCID
- PMC8967428
- NLM abbreviation
- Neurology
- eISSN
- 1526-632X
- Language
- English
- Date published
- 02/04/2022
- Academic Unit
- Stead Family Department of Pediatrics; Pathology; Iowa Neuroscience Institute; Neurology (Pediatrics)
- Record Identifier
- 9984215125602771
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