## 1 Introduction  
[PERSON]'s disease (HD) is an autosomal degenerative disorder in the brain that progresses with age [1,2], resulting from the mutation in the huntingtin (HTT) gene in chromosome 4p16.3, where an expansion of CAG trinucleotide repeats (more than 35 CAG) in exon1 of the HTT gene onsets the disease by expressing a toxic HTT protein having expanded polyglutamine (polyQ) amino acids [1,2,3]. The symptoms of HD can be characterized by a triad of progressive motor, cognitive, and psychiatric/behavioral disturbances [1,4], and are typically categorized into three stages, which are presymptomatic, prodromal, and manifest [5]. The presymptomatic stage is a prolonged stage during which individuals do not demonstrate any indications or symptoms regarding HD despite having expanded CAG trinucleotide mutations [5]. Perhaps, individuals with HD often maintain a typical lifestyle, similar to those without HD, until the onset of the prodromal stage, where individuals with expanded CAG begin to exhibit unspecified or potential motor impairments upon examination and minor but notable cognitive alterations [5]. In the manifest stage, individuals display the triad symptoms of HD, including progressive motor, cognitive, and psychiatric/behavioral alterations [5]. HD is diagnosed based on confirmed motor, cognitive, and behavioral signs and symptoms [6]. These signs and symptoms, specifically, the motor function of HD, are most widely assessed using the Unified Huntington's Disease Rating Scale (UHDRS), which is based on the diagnostic confidence level (DCL) [6]. The DCL value varies from 1 to 4, where a DCL value of 4 indicates 99% confidence that the motor impairments are due to HD [6]. However, a DCL score of 4 reflects the advanced stage of the disease, indicating that, by that time, the disease has already progressed to the advanced stage [6]. Hence, detecting any early abnormalities and diagnosing HD during the prolonged presymptomatic stage utilizing the DCL score is insufficient [6], as during this stage, individuals do not demonstrate any of the triad of HD symptoms, which would appear as notable clinical signs after decades [5]. Thus, owing to the prolonged duration of the presymptomatic stage [5], clinical staging standards could fail to identify any subtle changes during this stage, highlighting the need for a robust and efficient way to monitor the disease onset as well as the progression and stage of the disease. Recent research has focused on developing an efficient HD staging approach that could precisely diagnose HD from birth until the medical diagnosis [6]. In 2022, [PERSON] et al. proposed an alternative HD diagnosis system, the Huntington's Disease Integrated Staging System (HD-ISS), which harnesses biomarkers, besides HD pathophysiology for HD staging [6]. In brief, the HD-ISS systems consist of four stages, 0 to 3, where individuals with stage 0 carry the HTT mutation, but no detectable clinical symptoms [6]. Individuals in stage 1 possess early pathological alterations, whereas stage 2 represents a clinical phenotype, and functional deterioration is associated with stage 3 [6]. However, owing to the stringent landmark assessment criteria of the HD-ISS system, which categorizes HD stages by assessing a measure in at least 100 cohorts, no HD biomarkers have been identified until now [6]. This makes it indispensable to develop novel biomarkers that may satisfy the HD-ISS system. Moreover, developing a prognostic biomarker offers not only a way of diagnosing HD during the presymptomatic stage but also an approach to monitor the disease progression, allowing individuals to take necessary actions to prevent and/or slow down the manifestation of HD [7]. They can also be utilized to monitor the efficacy of a therapy, select additional therapy, and monitor recurrent diseases [8, 9, 10]. One effective method for identifying HD-related gene-expression signatures is high-throughput transcriptome profiling.