MYO18B was first reported in patients with autosomal recessive Klippel-Feil anomaly-myopathy-facial dysmorphism syndrome in 2015 (PMID 25748484). Evidence supporting this gene-disease relationship includes case-level data and experimental data.
Numerous pathogenic nonsense and frameshift variants in relation to Klippel-Feil syndrome have been submitted to ClinVar. Nine variants (nonsense, frameshift, splice-site) that have been reported in twelve probands in seven publications (PMIDs: 25748484, 27858739, 30932893. 31195167, 32184166, 32637634, 33179433) and in ClinVar (Variation ID: 3382539) are included in this curation. At least one variant, MYO18B:c.6905C>A (p.Ser2302Ter), reported in homozygosity in six affected individuals in the Saudi Arabian population (PMIDs: 25748484, 33179433), is suspected to be a founder variant. An additional report of four individuals harboring biallelic MYO18B variants and affected with congenital myopathy, cardiomyopathy, short stature, Klippel-Feil anomaly, and dysmorphisms has been described (Donkervoort et al., 2023 abstract presented at 2023 World Muscle Society Congress). Although heterozygous MYO18B missense variants were reported in patients affected by Klippel-Feil syndrome (PMID: 32278351), the overall mechanism for disease is postulated to be homozygous loss of function (PMID: 32184166).
Experimental-level genetic evidence supporting this gene-disease relationship includes animal model (PMIDs: 27879346, 28104788), non-human cell model (PMID: 30581023) and mRNA expression studies (PMIDs: 12547197). Also of note, both clinical and functional evidence to date suggest variants in MYO18B are associated with congenital myopathy, not nemaline myopathy, although nemaline rods may occur as a secondary consequence of disease. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached.
The MYO18B-autosomal recessive Klippel-Feil anomaly-myopathy-facial dysmorphism syndrome gene-disease pair was originally evaluated by the Congenital Myopathies GCEP on June 28, 2021. It was reevaluated on April 28, 2025. As a result of this re-evaluation, the classification increased from Moderate to Definitive with the addition of two variants, experimental evidence from zebrafish and cell models, and application of current version of the gene curation guidelines. This classification was approved by the ClinGen Congenital Myopathies Gene Curation Expert Panel on the meeting date April 28, 2025 (SOP Version 11).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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