Phenotypic and Genetic Complexity in Pediatric Movement Disorders

Abstract

The complex and evolving nature of clinical phenotypes have made genetically diagnosing pediatric patients with movement disorders difficult. Here, we describe this diverse complexity in the clinical and genetic features of a pediatric cohort examined by whole-exome sequencing (WES) and demonstrate the clinical benefit of WES as a diagnostic tool in a pediatric cohort. We evaluated 75 patients with diverse single or combined movement phenomenologies using WES. WES identified 42 variants in 37 genes (56.0%). The detection rate was highest in patients with dystonia (11/13, 84.6%), followed by ataxia (21/38, 55.3%), myoclonus (3/6, 50.0%), unspecified dyskinesia (1/4, 25.0%), tremor (1/1, 100%), respectively. Most genetically diagnosed patients (90.5%) were affected by other neurologic or systemic manifestations; congenital hypotonia (66.7%), and epilepsy (42.9%) were the most common phenotypes. The genetic diagnosis changed the clinical management for five patients (6.7%), including treatments targeting molecular abnormalities, and other systemic surveillance such as cancer screening. Early application of WES yields a high diagnostic rate in pediatric movement disorders, which can overcome the limitations of the traditional phenotype-driven strategies due to the diverse phenotypic and genetic complexity. Additionally, this early genetic diagnosis expands the patient’s clinical spectrum and provides an opportunity for tailored treatment.

Identification of the genetic basis of pediatric neurogenetic disorders at a tertiary referral hospital in Indonesia: Contribution of whole exome sequencing

“…The mean age of onset of NGDs in our study was 2.45 ± 3.23 years, while in pediatric movement disorder patients in South Korea, it was 1.8 ± 3.0 years [ 7 ]. The mean age of genetic testing in our study was 6.57 ± 5.47 years, while in South Korea, it was 5.3 ± 5.2 years, revealing a delay of around 5 years between age of onset and genetic testing [ 7 ]. A study in Argentina even reported that the average time elapsed from the onset of symptoms to WES is 11 years [ 15 ].…”

“…The development of molecular diagnostic technology reports gene mutations responsible for neurological disorders from various parts of the world [ 3 ]. Obtaining a specific molecular diagnosis will provide additional information regarding the pathophysiology, prognosis, and therapy, including genetic therapy opportunities in the future [ 7 ]. Next-generation sequencing (NGS) is a new DNA sequencing technique that can sequence a large number of genes, including targeted panel sequencing, whole-exome sequencing (WES) and whole-genome sequencing (WGS).…”

Hyperkinetic Movement Disorder Caused by the Recurrent c.892C>T NACC1 Variant

“…Recently, a de novo heterozygous NACC1 (nucleus accumbens‐associated 1), HUGO Gene Nomenclature Committee (HGNC) Identifier HGNC:20967, c.892C>T (NM_052876.4; NP_443108.1: p.Arg298Trp) variant has been described in nine patients with infantile onset epilepsy, postnatal microcephaly, severe to profound intellectual disability, bilateral cataracts, and hyperkinetic movements including hand stereotypies, chorea, and dystonia. 9 , 10 , 11 Furthermore, one of these patients also exhibited combined oxidative phosphorylation (OXPHOS) deficiency. 9 NACC1 encodes nucleus accumbens‐associated protein 1 (NACC1), which is also known as BTB/POZ domain‐containing protein 14B (BTBD14B), and it is a multifunctional protein that has been shown to act as a versatile transcription factor, but it also plays a role in protein turnover.…”

“…Recently, a de novo heterozygous NACC1 (nucleus accumbens‐associated 1), HUGO Gene Nomenclature Committee (HGNC) Identifier HGNC:20967, c.892C>T (NM_052876.4; NP_443108.1: p.Arg298Trp) variant has been described in nine patients with infantile onset epilepsy, postnatal microcephaly, severe to profound intellectual disability, bilateral cataracts, and hyperkinetic movements including hand stereotypies, chorea, and dystonia 9–11 . Furthermore, one of these patients also exhibited combined oxidative phosphorylation (OXPHOS) deficiency 9 .…”