KCNJ3 is a novel candidate gene for autosomal dominant pure hereditary spastic paraplegia identified using whole genome sequencing.
Woong-Woo LeeCha Gon LeeChang-Seok KiPublished in: American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics (2024)
Hereditary spastic paraplegia (HSP) is a group of familial diseases characterized by progressive corticospinal tract degeneration. Clinically, patients present with lower-limb spasticity and weakness. To date, more than 80 genetic HSP types have been identified. Despite advances in molecular genetics, novel HSP gene discoveries are ongoing, with a low genetic diagnostic yield. In this study, we aimed to determine pathogenic variants in a family with HSP, which was not diagnosed through conventional genetic testing. We clinically characterized a large family and conducted whole genome sequencing (WGS) analysis of four affected and three unaffected individuals in the family to identify the genetic cause of HSP. This family had autosomal dominant pure (uncomplicated) late childhood-onset HSP. The patients' symptoms accelerated between the ages of 20 and 30. Brain magnetic resonance images typically showed white matter changes, a thin corpus callosum, and cerebellar atrophy. We identified a heterozygous missense variant, KCNJ3 c.1297T>G (p.Leu433Val), through WGS and family genetic analysis, confirmed by Sanger sequencing. We suggest that the identification of KCNJ3 c.1297T>G (p.Leu433Val) constitutes the discovery of a potential novel gene responsible for HSP in this family. This is the first study to report the possible role of a KCNJ3 variant in HSP pathogenesis. Our findings further expand the phenotypic and genotypic spectrum of HSP.
Keyphrases
- heat shock protein
- heat shock
- heat stress
- copy number
- genome wide
- magnetic resonance
- white matter
- ejection fraction
- end stage renal disease
- lower limb
- cerebral palsy
- early onset
- computed tomography
- high throughput
- dna methylation
- magnetic resonance imaging
- single cell
- machine learning
- high frequency
- blood brain barrier
- physical activity
- urinary tract infection
- patient reported
- resting state
- contrast enhanced
- bioinformatics analysis