Three novel mutations in Chinese patients with CSF1R-related leukoencephalopathy

Min Chu; Dong-Xin Wang; Yue Cui; Yu Kong; Li Liu; Ke-Xin Xie; Tian-Xinyu Xia; Jing Zhang; Ran Gao; Ai-Hong Zhou; Chao-Dong Wang; Li-Yong Wu

doi:10.21037/atm-21-217

Three novel mutations in Chinese patients with CSF1R-related leukoencephalopathy

Ann Transl Med. 2021 Jul;9(13):1072. doi: 10.21037/atm-21-217.

Authors

Min Chu¹, Dong-Xin Wang^{1

2}, Yue Cui¹, Yu Kong¹, Li Liu¹, Ke-Xin Xie¹, Tian-Xinyu Xia¹, Jing Zhang¹, Ran Gao¹, Ai-Hong Zhou¹, Chao-Dong Wang¹, Li-Yong Wu¹

Affiliations

¹ Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China.
² Department of Neurology, Shijiazhuang People's Hospital, Shijiazhuang, China.

Abstract

Background: CSF1R-related encephalopathy refers to adult-onset leukodystrophy with neuroaxonal spheroids and pigmented glia (ALSP) due to CSF1R mutations, which is a rare autosomal dominant white matter disease including two pathological entities, hereditary diffuse leukoencephalopathy with spheroids (HDLS) and pigmentary orthochromatic leukodystrophy (POLD). The aim of this study was to identify additional causative mutations in the CSF1R gene and clarify their pathogenic effects.

Methods: Whole-exome sequencing was conducted for nine Chinese patients diagnosed with possible ALSP based on clinical and neuroimaging findings from March 2014 to June 2020 at Xuanwu Hospital (Beijing, China). Variant pathogenicity was assessed according to the American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG/AMP) Standards and Guidelines.

Results: Mean ± standard deviation (range) age of disease onset in the nine patients was 39.22±9.63 [25-54] years. Four of the nine patients were male, and four out of nine had a remarkable family history. Seven CSF1R mutations were identified in the nine patients; four (p.G17C, p.R579Q, p.I794T and c.2909_2910insATCA) have been previously reported, while three (p.V613L, p.W821R and c.2442+2_2442+3dupT) were novel. Of the latter, two (p.V613L and p.W821R) were likely pathogenic and 1 (c.2442+2_2442+3dupT) was of uncertain significance according to ACMG/AMP criteria.

Conclusions: These findings expand the mutational spectrum of ALSP and provide a basis for future investigations on etiologic factors and potential management strategies for this disease.

Keywords: Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP); colony-stimulating factor 1 receptor (CSF1R); hereditary diffuse leukoencephalopathy with spheroid (HDLS); mutational hotspot; novel mutation; pigmented orthochromatic leukodystrophy (POLD).