Open AccessA novel and recurrent KLHL40 pathogenic variants in a Chinese family of multiple affected neonates with nemaline myopathy 8
Author(s) -
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
Publication year - 2021
Publication title -
molecular genetics and genomic medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.765
H-Index - 29
ISSN - 2324-9269
DOI - 10.1002/mgg3.1683
Subject(s) - medicine , missense mutation , exome sequencing , nemaline myopathy , pediatrics , population , genetics , myopathy , congenital myopathy , muscle biopsy , mutation , biology , gene , biopsy , environmental health
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.