Whole-exome sequencing identified novel KIF5A mutations in Chinese patients with amyotrophic lateral sclerosis and Charcot-Marie-Tooth type 2

The kinesin heavy chain isoform 5A (KIF5A) gene on chromosome 12q13.3 encodes a neuron-specific kinesin heavy chain (KHC), which consists of an N-terminal motor domain, a stalk domain and a C-terminal cargo-binding domain. KIF5A is an ATPase-active molecular motor protein and is involved in the microtubule-dependent axonal transport of cytoplasmic cargo. KIF5A gene has been identified as a causative gene of hereditary spastic paraplegia (HSP), Charcot-Marie-Tooth (CMT) type 2 (CMT2) and amyotrophic lateral sclerosis (ALS).1 2 As HSP, CMT and ALS affect central and peripheral nervous systems differently, what play a key role for the patients with KIF5A mutation to manifest different phenotype is little known. In previous reports, the use of different genetic testing methods and ranges may yield inconsistent findings. Hence, we conducted a study using whole-exome sequencing (WES) with the aim of screening the KIF5A gene and other CMT or ALS-causative genes in Chinese CMT2 and ALS patients. A total of 154 unrelated CMT2 probands, 581 sporadic ALS (sALS) patients and 1015 controls without history of neurological diseases were enrolled from the Department of Neurology of Peking University Third Hospital from 2007 to 2018. All ALS cases were diagnosed as possible, probable or definite ALS according to the revised El Escorial criteria. The diagnosis of CMT2 was based on clinical manifestations and neurophysiology. All subjects signed informed consent forms. Fragment-length and repeat-primed PCR was performed to detect duplications or deletions of PMP22 gene in CMT2 patients, as well as ATXN2 and C9orf72 (hexanucleotide …