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Carey-Fineman-Ziter syndrome is an autosomal recessive congenital myopathy associated with deleterious variants in MYMK, a gene encoding the essential myoblast fusion protein myomaker (MYMK). The syndrome is characterized by facial weakness, hypotonia, short stature, and muscle fiber hypertrophy, with clinical manifestations emerging in early childhood (Carey-Fineman-Ziter syndrome).
Clinical evidence from independent case reports includes a report of 3 siblings with compound heterozygous mutations and an additional sporadic case with a similar genetic background (PMID:30065953) as well as a Spanish patient exhibiting hypotonia and motor delay (PMID:32333597). Segregation studies within these families identified additional affected relatives, reinforcing the autosomal recessive mode of inheritance.
Genetic evidence is supported by identification of pathogenic variants such as c.271C>A (p.Pro91Thr) that appear recurrently across studies. This missense change, reported verbatim in the literature, has been observed in multiple unrelated families and is highly consistent with the clinical phenotype. These data confirm that alteration of MYMK function is central to disease pathogenesis (PMID:30065953).
Functional studies further reinforce these findings. Experimental work using cellular models and animal systems, including zebrafish, has demonstrated that MYMK mutations lead to reduced myoblast fusion, a defect that mirrors the muscle fiber hypertrophy observed in patients. These models not only recapitulate the clinical features but also provide mechanistic insight into how impaired myomaker activity results in a reduced number of muscle fibers with compensatory hypertrophy (PMID:28681861).
Together, the clinical, genetic, and functional evidence converges to support a strong gene-disease association between MYMK and Carey-Fineman-Ziter syndrome. This integrated approach bolsters diagnostic confidence and promotes the clinical utility of MYMK testing in patients exhibiting congenital myopathy features.
Key take‑home sentence: The robust convergence of multi‐patient clinical data and functional assays confirms that pathogenic variants in MYMK cause Carey‑Fineman‑Ziter syndrome, thereby offering a reliable biomarker for targeted diagnostic decision‑making.
Gene–Disease AssociationStrongMultiple independent families featuring compound heterozygous variants, including recurrent c.271C>A (p.Pro91Thr) observed in at least 4 probands across studies (PMID:30065953, PMID:32333597), along with supportive functional data. Genetic EvidenceStrongGenetic findings from distinct cohorts reveal pathogenic MYMK variants (e.g. c.271C>A (p.Pro91Thr)) that segregate with the disease phenotype, confirming autosomal recessive inheritance. Functional EvidenceStrongIn vitro and in vivo studies, including zebrafish models and cell fusion assays, consistently demonstrate that MYMK mutations impair myoblast fusion, aligning with disease pathology (PMID:28681861). |