A novel and recurrent KLHL40 pathogenic variants in a Chinese family of multiple affected neonates with nemaline myopathy 8. Issue 6 (12th May 2021)

• Record Type: Journal Article
• Authors: Yi, Sheng; Zhang, Yue; Qin, Zailong; Yi, Shang; Zheng, Haiyang; Luo, Jingsi; Li, Qifei; Wang, Jin; Yang, Qi; Li, Mengting; Chen, Fei; Zhang, Qiang; Zhang, Qinle; Shen, Yiping
• Is Part Of: Molecular genetics & genomic medicine. Volume 9:Issue 6(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-05-12
• Subjects: appendicular hypertonia -- KLHL40 -- nemaline myopathy 8 -- pathogenic variants -- Southern Chinese; Medical genetics -- Periodicals; Genomics -- Periodicals; 616.042
• DOI: 10.1002/mgg3.1683
• Languages: English
• ISSNs: 2324-9269

Abstract

Abstract: Background: Nemaline myopathy 8 is a severe autosomal recessive muscle disorder characterized by fetal akinesia or hypokinesia, contractures, fractures, respiratory failure and swallowing difficulties apparent at birth. Methods: An affected dizygotic twin pair from a non‐consanguineous Chinese family presented with severe asphyxia, lethargy and no response to stimuli. The dysmorphic features included prominent nasal bridge, telecanthus, excessive hip abduction, limb edema, absent palmar and sole creases, acromelia, bilateral clubfoot, appendicular hypertonia and cryptorchidism. Both infants died in the first week of life. Whole‐exome sequencing was used to identify the causative gene. Results: Whole‐exome sequencing identified a recurrent missense variant c.1516A>C and a novel splice‐acceptor variant c.1153‐1G>C in KLHL40 gene in both siblings. We estimated the disease incidence in Southern Chinese population to be 2.47/100, 000 based on the cumulative allele frequency of pathogenic and likely pathogenic variants in our internal database. Conclusion: Our study expanded the mutation spectrum of KLHL40 and the condition could have been underdiagnosed before. We identified a recurrent missense variant c.1516A>C and provided evidence further supporting the founder effect of this variant in Southern Chinese population. Given the severity of the condition and the relative high incidence, this not‐so‐rare disorder should be included in expanded carrier screening panel for Chinese population. Abstract : Two male babies with nemaline myopathy‐8 also showed appendicular hypertonia exome sequencing identified a recurrent missense variant and a novel splice‐acceptor variant in KLHL40 Four additional novel pathogenic variants of KLHL40 were identified and it is speculated that nemaline myopathy‐8 is not‐so‐rare in Chinese population.