Background: Rare reports on patients with congenital myopathy with excess of muscle spindles (CMEMS), hypertrophic cardiomyopathy, and variable features resembling Noonan syndrome have been published, but the genetic basis of this condition has been unknown.
Methods and Results: We analyzed PTPN11 and RAS genes in five unrelated patients with this phenotype and found HRAS mutations in four of them. Two disease-associated mutations, G12V and G12S, have previously been observed in patients with Costello syndrome (CS), while two other mutations, E63K and Q22K, are novel. All four mutations are predicted to enhance downstream H-Ras signaling, suggesting that CMEMS is a developmental consequence of sustained H-Ras activation in skeletal muscle.
Conclusion: This type of myopathy may represent a previously unrecognized manifestation of CS. However, some patients carrying HRAS mutations may exhibit prominent congenital muscular dysfunction, while features of CS are less obvious, suggesting that germline HRAS mutations may underlie some cases of otherwise unclassified neonatal neuromuscular disorders.
- Costello syndrome
- Noonan syndrome
- congenital myopathy
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