The KLHL40C.1516A>C is a Chinese-specific founder mutation in causing nemaline myopathy 8

Abstract

Background: Autosomal recessive or compound heterozygous mutation in KLHL40 is one of the causes of severe nemaline myopathy (nemaline myopathy 8, phenotype MIM number 615348). This severe form of nemaline myopathy is characterized by congenital fetal akinesia/hypokinesia, fractures, respiratory failure, and swallowing difficulties. Patients usually pass away in infancy. We identified five patients from four families of non-consanguineous Chinese were affected by nemaline myopathy 8. All were found to carry at least one pathogenic KLHL40:c.1516A>C p.(Thr506Pro) variant, and hence we hypothesized that the c.1516A>C variant is a founder mutation in Chinese. Methods: The prenatal history and postnatal outcome of these four families were retrieved from the medical records. Three patients included in this study have been published recently (Lee et al. 2019).Using the Infinium OmniZhongHua-8 v1.4 BeadChip, we examined the region of homozygosity on three patients carrying the homozygous c.1516A>C mutation. Results: Prenatal history of five pregnancies can be retrieved. Common prenatal features included reduced fetal movement (n=3), clubfoot (n=2) and polyhydramnios (n=2). Two pregnancies were terminated in view of the abnormal ultrasound findings, including one family that had two pregnancies affected where the first was live-born while the second pregnancy was terminated. There were four live-born and their clinical features were compatible with typical nemaline myopathy 8. The length of survival ranged from 49 days to 17 months with respiratory failure or infection being the principal causes of death. Haplotype and region of homozygosity analyses showed a shared haplotype block of >1cM spanning over the c.1516A>C. This suggests that the c.1516A>C variant is a Chinese-specific founder mutation. Conclusion: The KLHL40:c.1516A>C variant is a Chinese-specific founder mutation. Together with other reported cases in the literature, it is the most common molecular cause of nemaline myopathy 8 in the Chinese.