Layout 1 MYH3 mutation and scoliosis Eur J Transl Myol 35 (3) 13832, 2025 doi: 10.4081/ejtm.2025.13832 Dear Editor, We were interested to read the article by Maccarone et al. about a 15-year-old girl with scoliosis, growth retardation, facial dysmorphism and delayed puberty.1 Genetic testing revealed the heterozygous variant NM_002470.4(MYH3): c.326G>A (p.Arg109His) in MYH3. The patient benefited from a Lyon ARTbrace after refusing surgical correction of scoliosis.1 The study is noteworthy, but several points should be discussed. The first point is that the pathogenicity of the variant NM_002470.4(MYH3):c.326G>A is uncertain. The vari- ant has not been reported in PubMed or Google Scholar. There is also no report on the pathogenicity of the variant in dbSNP.2 Also according to ClinVar, the variant was only reported in the index study, but not observed in significant frequency in large population cohorts (gnomAD).3 After in silico analyses, the variant was classified as probably pathogenic, due to this lack of evidence for the pathogen- icity of the variant, biochemical and functional studies are required to prove its pathogenicity. Secondly, MYH3 mutations usually manifest as arthrogry- posis 2A, also known as Freeman-Sheldon syndrome or whistling face syndrome (mask-like face, small mouth with whistling appearance, low-set ears, broad nasal bridge, long philtrum, H-shaped dimple on the chin, windmill wing hand position and severe talipes equinovarus deformity),4 arthro- gryposis 2B3, also known as Sheldon-Hall syndrome (mul- tiple congenital contractures, triangular face, downturned palpebral fissures, small mouth, high-arched palate, muscle weakness),5 spondylo-carpo-tarsal synostosis syndrome type 1A or 1B,6 or single or multiple pterygia. There is also a study of 10 families with carriers of MYH3 variants who presented with some atypical phenotypic features such as small mouth with dowslanting corners, camptodactyly, broad chest, increased distance between the nipples, en- larged knee joints with contractures and pterygia, flat feet, prominent philtrum, ptosis. clinodactyly of the 5th finger, multiple cervical and thoracic vertebral fusions, rudimen- tary disc spaces, rib crowding, posterior vertebral fusions, and lunotriquetral fusion.7 Were any of these features also present in the index pa- tient? The third point is that it was not reported whether first- degree relatives other than the mother and grandmother were also clinically affected and whether family members other than the mother and grandmother were also carriers of the MYH3 variant. Knowing the exact segregation of the variant within the family is crucial not only for deter- mining pathogenicity, disease progression and outcome, but also for genetic counseling. If the phenotype segre- gates with the genotype within a family, this indicates that the genotype is responsible. If only one patient is found in a family, the correlation between genotype and pheno- type is less strong. The fourth point is that it is incomprehensible why the index patient did not undergo genetic testing earlier than the age of 15. Short stature and facial dysmorphism must have occurred earlier than at age 15, which should have indicated a genetic defect. Has she also undergone a CGH array to rule out microdeletions or microduplications? Since the patient showed atypical features of a MYH3 mu- tation (delayed puberty, short stature), an additional chro- mosomal defect should definitely be ruled out. The fifth point: It was not reported whether the scoliosis had a secondary effect on cardiac or pulmonary function. Since pulmonary or cardiac impairment due to scoliosis or thoracic deformity strongly influences the outcome, it is important to examine these patients prospectively for cardiac or pulmonary involvement.8 Was there any ev- idence of diastolic dysfunction or impaired respiratory function? Were echocardiography and pulmonary function tests normal? The sixth point is that the interpretation of EEG spectral analysis is highly speculative.1 Whether the Fourier transformation of raw EEG signals can really detect al- tered motor innervation of axial muscles and altered pro- cessing of sensory input in scoliosis patients remains speculative. In summary, this interesting study has limitations that put the results and their interpretation into perspective. Addressing these limitations could strengthen the con- Key Words: MYH3, scoliosis, genetic testing, Freeman-Sheldon syndrome, Sheldon Hall syndrome. Eur J Transl Myol 35 (3) 13832, 2025 doi: 10.4081/ejtm.2025.13832 Before scoliosis can be attributed to the variant c.326G>A in MYH3, its pathogenicity must be proven Josef Finsterer Neurology Department, Neurology & Neurophysiology Center, Vienna, Austria. This article is distributed under the terms of the Creative Commons Attribution Noncommercial License (CC BY-NC 4.0) which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited. - 244 - MYH3 mutation and scoliosis Eur J Transl Myol 35 (3) 13832, 2025 doi: 10.4081/ejtm.2025.13832 clusions and corroborate the study’s message. Before scoliosis can be attributed to the c.326G>A variant in MYH3, its pathogenicity must be proven. Patients with a MYH3 mutation not only require treatment for scolio- sis and thoracic deformity, but also cardiac and pul- monary examinations to ensure that cardiac and respiratory involvement is not overlooked. Availability of data and material All data are available from the corresponding author. Consent to participation Not applicable. Consent for publication Not applicable. Funding None received. Conflict of interest The author declares that the research was conducted in the absence of any commercial or financial relation- ships that could be construed as a potential conflict of interest. Ethical approval Not applicable. Corresponding author Josef Finsterer, Neurology Department, Neurology & Neu- rophysiology Center, Postfach 20, 1180 Vienna, Austria. Tel.: +43-1-5861075; Fax: +43-1-5861075. ORCID ID: 0000-0003-2839-7305 E-mail: fifigs1@yahoo.de References 1. Maccarone MC, Paramento M, Passarotto E, et al. A neurophysiological and genetic assessment of a case of rapidly progressive scoliosis. Eur J Transl Myol 2024;35:13249. 2. dbSNP. Short genetic variations. National Library of Medicine. Accessed 13.4.2025. Available from: https:// www. ncbi.nlm.nih.gov/snp/rs773615398 3. ClinVAr. NM_002470.4(MYH3):c.326G>A (p.Arg 109His). Last accessed 18th March 2025. Available from: https://www.ncbi.nlm.nih.gov/clinvar/variation/ 1321646/ 4. Salati SA, Hussain M. Freeman-sheldon syndrome. APSP J Case Rep 2013;4:7. 5. Toydemir RM, Bamshad MJ. Sheldon-Hall syndrome. Orphanet J Rare Dis 2009;4:11. 6. Mangaraj S, Choudhury AK, Singh M, et al. Spondy- locarpotarsal synostosis syndrome. A rare case of short stature and congenital scoliosis. Clin Cases Miner Bone Metab 2017;14:258-61. 7. Zhao S, Zhang Y, Hallgrimsdottir S, et al. Expanding the mutation and phenotype spectrum of MYH3-asso- ciated skeletal disorders. NPJ Genom Med 2022;7:11. 8. Siwiec A, Domagalska-Szopa M, Kwiecień-Czerwie- niec I, et al. Impact of idiopathic scoliosis on the car- diopulmonary capacity of adolescents. J Clin Med 2024;13:4414. Disclaimer All claims expressed in this article are solely those of the authors and do not necessarily represent those of their af- filiated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. Submitted: 18 March 2025. Accepted: 14 April 2025. Early access: 27 June 2025. - 245 - https://www.ncbi.nlm.nih.gov/clinvar/variation