AbstractMyogenic 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.

摘要主要由Myomaker和Myomixer蛋白调节的肌源性融合对于骨骼肌发育至关重要，但其机制仍知之甚少。这项研究介绍了第三和第四例报告的MYMX双等位基因变异患者的临床和分子细节，MYMX是编码肌混合器的基因。

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.

我们在MYMX中鉴定了一个纯合的截短变体[c.107 T>a（p.Leu36Ter）]和一个纯合的终止密码子丢失变体[c.255 a>G（p.Ter85Trpexter41）]，两者都与以全身性肌张力低下，先天性肌病，面神经麻痹，生长受限和面部畸形为特征的复杂神经肌肉综合征有关。

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.

其他可变特征包括听力损失（一名患者确诊，另一名患者疑似），脊柱侧弯，关节挛缩，left裂，舌功能减退，可能导致Pierre Robin序列，以及神经影像学研究异常，包括小脑萎缩和Chiari 1畸形。

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..

对MYMK和MYMX致病变异患者（包括我们的病例）的比较分析显示，表型在很大程度上重叠，强调了它们在肌纤维形成中的协同作用，并暗示了它们参与了神经肌肉疾病的病因。。

IntroductionDuring the physiological process of skeletal muscle development and regeneration, the fusion of mononucleated myoblasts to form multinucleated myofibers plays a pivotal role; nevertheless, in contrast to earlier stages of myogenesis, the mechanism and regulation of myogenic fusion are poorly understood.

引言在骨骼肌发育和再生的生理过程中，单核成肌细胞融合形成多核肌纤维起着关键作用；然而，与肌生成的早期阶段相反，对肌原性融合的机制和调控知之甚少。

Studies have proven that two muscle-specific regulators, namely Myomaker [1] (coded by MYMK) and Myomixer [2] (coded by MYMX) act together as a molecular switch of myoblast fusion during muscle formation [3].Despite numerous evidence supporting the biological role of Myomaker and Myomixer, their correlation with human diseases is largely unknown; recently, biallelic variants in MYMK were shown to cause a rare congenital neuromuscular disorder, known as Carey-Fineman-Ziter syndrome (CFZS1; OMIM #254940).

研究证明，两种肌肉特异性调节剂，即Myomaker〔1〕（由MYMK编码）和Myomixer〔2〕（由MYMX编码）在肌肉形成过程中共同作为成肌细胞融合的分子开关〔3〕。尽管有大量证据支持Myomaker和Myomixer的生物学作用，但它们与人类疾病的相关性在很大程度上是未知的；最近，MYMK中的双等位基因变异被证明会引起罕见的先天性神经肌肉疾病，称为Carey-Fineman-Ziter综合征（CFZS1；OMIM#254940）。

CFZS1, clinically described in nearly 20 patients [4], is characterized by hypotonia, developmental delay, Pierre Robin and Moebius sequences. In subsequent studies, MYMK homozygous or compound heterozygous variants were identified in 9 patients from 5 unrelated families [5] and in a 69-year-old man, presenting with juvenile-onset proximal myopathy [6].Consequently, a homozygous nonsense variant in MYMX was identified in two sibs with facial weakness and myopathy [7].

。在随后的研究中，在来自5个无关家庭的9名患者和一名69岁男性中发现了MYMK纯合子或复合杂合子变体，表现为青少年发作的近端肌病。因此，在两个患有面部无力和肌病的同胞中发现了MYMX的纯合性无意义变异（7）。

Experimental evidence, including defective fusion of patient-derived myoblasts and the premature death of mouse models bearing the MYMX variant, suggests that biallelic MYMX pathogenic variants cause a monogenic human disease (CFZS2, OMIM #619941), highly overlapping with Carey-Fineman-Ziter syndrome [8,9,10].In this study, we detail the clinical and molecular characteristics of two unrelated patients, both carrying novel homozygous variants in MYMX and presenting with complex neuromuscular sympt.

实验证据，包括患者来源的成肌细胞融合缺陷和携带MYMX变体的小鼠模型过早死亡，表明双等位基因MYMX致病变体引起单基因人类疾病（CFZS2，OMIM#619941），与Carey-Fineman-Ziter综合征高度重叠[8,9,10]。在这项研究中，我们详细介绍了两名无关患者的临床和分子特征，这两名患者均在MYMX中携带新的纯合变异体，并伴有复杂的神经肌肉症状。

Data availability

数据可用性

All data relevant to the study are included in the article.

与该研究相关的所有数据均包含在本文中。

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Download referencesAcknowledgementsWe are grateful for the important support from patients and families, our UK and international collaborators, brainbank and biobanks.FundingThis work is supported by funding from The Wellcome Trust, The MRC, The MSA Trust, The National Institute for Health Research (NIHR) University College London Hospitals Biomedical Research Centre), The Michael J Fox Foundation (MJFF), The Fidelity Trust, Rosetrees Trust, Alzheimer’s Research UK (ARUK), MSA Coalition, NIH NeuroBioBank, MRC Brainbank Network and the German Research Foundation (DFG VO 2138/7-1 grant 469177153).Author informationAuthor notesThese authors contributed equally: Fatima Rahman, Luisa Marsili.Authors and AffiliationsDepartment of Developmental-Behavioral Pediatrics, The Children’s Hospital and University of Child Health Sciences, Lahore, PakistanFatima Rahman & Shazia MaqboolUniversity of Lille, ULR7364 RADEME, CHU Lille, Service de Génétique Clinique, Lille, FranceLuisa Marsili & Thomas SmolDepartment of Genetics, University Medical Center Utrecht, Utrecht University, Utrecht, NetherlandsLuisa MarsiliSection of Genomic Medicine, Department of Life Sciences and Public Health, Catholic University of Sacred Heart, Rome, ItalyDomizia PasquettiArcensus Diagnostics, Rostock, GermanyAboulfazl Rad & Gabriela OpreaDepartment of Pediatric Gastroenterology Hepatology and Genetic Diseases, Children’s Hospital and University of Child Health Sciences, Lahore, PakistanMuhammad Nadeem Anjum & Huma Arshad CheemaInstitute for Auditory Neuroscience and InnerEarLab, University Medical Center Göttingen, Göttingen, GermanyBarbara VonaInstitute of Human Genetics, University Medical Center Göttingen, Göttingen, GermanyBarbara VonaDivision of Neuroradiology, Department of Radiology,.

下载参考文献致谢我们感谢患者和家属，我们的英国和国际合作者，脑库和生物库的重要支持。资助这项工作得到了惠康信托基金，MRC，MSA信托基金，国家健康研究所（NIHR）大学学院伦敦医院生物医学研究中心，迈克尔·福克斯基金会（MJFF），富达信托基金，玫瑰树信托基金，英国阿尔茨海默氏病研究（ARUK），MSA联盟，NIH神经生物库，MRC脑库网络和德国研究基金会（DFG VO 2138/7-1 grant 469177153）的资助。作者信息作者注意到这些作者做出了同样的贡献：Fatima Rahman，Luisa Marsili。作者和附属机构儿童医院和儿童健康科学大学发展行为儿科系，巴基斯坦拉合尔Fatima Rahman＆Shazia MaqboolUniversity of Lille，ULR7364 RADEME，CHU Lille，Service de Génétique Clinique，Lille，FranceLuisa Marsili＆Thomas SmolDepartment of Genetics，University Medical Center Utrecht，Utrecht University，Utrecht，NetherlandsLuisa MarsiliSection of Genomic Medicine，Department of Life Sciences and Public Health，天主教圣心大学，罗马，ItalyDomizia Pasquettiarcusion Diagnostics，罗斯托克，GermanyAboulfazl-Rad＆Gabriela OpreaDepartment of Pediatric Gastroenterology Hepatology and Genetic Diseases，Children’s Hospital and University of Child Health Sciences，巴基斯坦拉合尔，巴基斯坦拉合尔，穆哈迈德·纳迪姆·安朱姆和乌玛·阿尔沙德·奇梅斯特恩听觉神经科学研究所和内尔拉布，哥廷根大学医学中心，哥廷根，德国哥廷根大学医学中心人类遗传学研究所，GermanyBarbara VonaDivision神经放射学，放射科，。

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PubMed Google ScholarContributionsFR, SM, MNA, HAC, GO and AR collected patient 1 and managed the clinical surveillance; LM and TS collected patient 2 and managed the clinical surveillance; DP and RM revised the genetic data and prepared the manuscripts files; BV revised the audiograms; CAA performed the neuroimaging review; HH, SF and GO revised the manuscript files.Corresponding authorCorrespondence to.

PubMed Google ScholarContributionsFR，SM，MNA，HAC，GO和AR收集了患者1并管理了临床监测；；DP和RM修改了遗传数据并准备了手稿文件；BV修订了听力图；CAA进行了神经影像学检查；HH，SF和GO修改了手稿文件。对应作者对应。

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Competing interests

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Aboulfazl Rad and Gabriela Oprea are employed by the Company Arcensus Diagnostics.

Aboulfazl Rad和Gabriela Oprea受雇于Arcensus Diagnostics公司。

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这项研究涉及人类参与者，并得到了UCL的批准。

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Reprints and permissionsAbout this articleCite this articleRahman, F., Marsili, L., Pasquetti, D. et al. Bi-allelic MYMX variants cause a syndromic congenital myopathy with recognizable facial palsy, growth restriction, and dysmorphism.

转载和许可本文引用本文Rahman，F.，Marsili，L.，Pasquetti，D。等人。双等位基因MYMX变体引起综合征性先天性肌病，伴有可识别的面瘫，生长受限和畸形。

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