Bi-allelic MYMX variants cause a syndromic congenital myopathy with recognizable facial palsy, growth restriction, and dysmorphism
Myogenic fusion, primarily regulated by the Myomaker and Myomixer proteins, is essential for skeletal muscle development, yet its mechanisms remain poorly understood. This study presents the clinical and molecular details of the third and fourth reported patients with biallelic variants in MYMX, the gene that encodes Myomixer. We identified a homozygous truncating variant [c.107 T > A (p.Leu36Ter)] and a homozygous stop-codon loss variant [c.255 A > G (p.Ter85TrpextTer41)] in MYMX, both associated with a complex neuromuscular syndrome characterized by generalized hypotonia, congenital myopathy, facial nerve palsy, growth restriction and facial dysmorphism. Additional variable features include hearing loss (confirmed in one patient, suspected in the other), scoliosis, joint contractures, cleft palate, hypoglossia, potentially contributing to Pierre Robin sequence, and abnormalities on neuroimaging studies including cerebellar atrophy and Chiari 1 deformity. Comparative analysis of patients with pathogenic variants in MYMK and MYMX, including our cases, reveals largely overlapping phenotypes, underscoring their synergistic role in myofiber formation and implicating their involvement in the etiology of neuromuscular conditions.
Authors
- Shazia Maqbool (ORCID: https://orcid.org/0000-0003-1454-3623)
- Gabriela E. Oprea (ORCID: https://orcid.org/0000-0001-5467-5247)
- Fatima Rahman (ORCID: https://orcid.org/0000-0003-1312-1007)
- Stéphanie Efthymiou (ORCID: https://orcid.org/0000-0003-4900-9877)
- Barbara Vona (ORCID: https://orcid.org/0000-0002-6719-3447)
- Cesar Alves (ORCID: https://orcid.org/0000-0001-5877-9086)
- Huma Arshad Cheema (ORCID: https://orcid.org/0000-0002-0463-687X)
- Domizia Pasquetti (ORCID: https://orcid.org/0000-0002-8220-3420)
- Thomas Smol (ORCID: https://orcid.org/0000-0002-0119-5896)
- Abolfazl Rad (ORCID: https://orcid.org/0000-0001-8627-8828)
- Luisa Marsili (ORCID: https://orcid.org/0000-0002-6691-541X)
- Henry Houlden (ORCID: https://orcid.org/0000-0002-2866-7777)
- Reza Maroofian (ORCID: https://orcid.org/0000-0001-6763-1542)
- Muhammad Nadeem Anjum
Institutions
- Università Cattolica del Sacro Cuore (IT)
- Boston Children's Hospital (US)
- Harvard University (US)
- Utrecht University (NL)
- Université de Lille (FR)
- University of Health Sciences Lahore (PK)
- University Medical Center Utrecht (NL)
- Centre Hospitalier Universitaire de Lille (FR)
- Universitätsmedizin Göttingen (DE)
- MRC Prion Unit (GB)
- CS Diagnostics (DE)
- National Hospital for Neurology and Neurosurgery (GB)
- University College London (GB)
- University of Göttingen (DE)
Publication Details
- Journal
- European Journal of Human Genetics
- Published
- 2024-12-12
- DOI
- https://doi.org/10.1038/s41431-024-01759-9
- Citations
- 2
- Primary Topic
- Neurogenetic and Muscular Disorders Research
- Type
- article
- Field-Weighted Citation Impact
- 0.88
Funders
- Michael J. Fox Foundation for Parkinson's Research
- Wellcome Trust
- Multiple System Atrophy Coalition
- National Institute for Health and Care Research
- University College London
- Rosetrees Trust
- Deutsche Forschungsgemeinschaft
- National Institutes of Health
- Medical Research Council