Clinical Application of Whole Exome Sequencing to Identify Rare but Remediable Neurologic Disorders

Abstract

Background: The aim of this study was to describe the application of whole exome sequencing (WES) in the accurate genetic diagnosis and personalized treatment of extremely rare neurogenetic disorders. Methods: From 2017 to 2019, children with neurodevelopmental symptoms were evaluated using WES in the pediatric neurology clinic and medical genetics center. The clinical presentation, laboratory findings including the genetic results from WES, and diagnosis-based treatment and outcomes of the four patients are discussed. Results: A total of 376 children with neurodevelopmental symptom were evaluated by WES, and four patients (1.1%) were diagnosed with treatable neurologic disorders. Patient 1 (Pt 1) showed global muscle hypotonia, dysmorphic facial features, and multiple anomalies beginning in the perinatal period. Pt 1 was diagnosed with congenital myasthenic syndrome 22 of PREPL deficiency. Pt 2 presented with hypotonia and developmental arrest and was diagnosed with autosomal recessive dopa-responsive dystonia due to TH deficiency. Pt 3, who suffered from intractable epilepsy and progressive cognitive decline, was diagnosed with epileptic encephalopathy 47 with a heterozygous FGF12 mutation. Pt 4 presented with motor delay and episodic ataxia and was diagnosed with episodic ataxia type II (heterozygous CACNA1A mutation). The patients’ major neurologic symptoms were remarkably relieved with pyridostigmine (Pt 1), levodopa (Pt 2), sodium channel blocker (Pt 3), and acetazolamide (Pt 4), and most patients regained developmental milestones in the follow-up period (0.4 to 3 years). Conclusions: The early application of WES helps in the identification of extremely rare genetic diseases, for which effective treatment modalities exist. Ultimately, WES resulted in optimal clinical outcomes of affected patients.

Diagnostic performance of automated, streamlined, daily updated exome analysis in patients with neurodevelopmental delay

“…A male patient (ID: 143) had maternal UPD 9 encompassing a region containing the VUS (Seo et al 2020 ). A male patient (ID: 71) with a homozygous variant in the PREPL gene responded to medical treatment after molecular diagnosis (Kim et al 2020 ).…”

“…Ketogenic diet was started in a patient 159 with GLUT1 deficiency syndrome 1. Patient 71 and 363 with myasthenic syndrome, congenital, 22 and segawa syndrome, recessive received pyridostigmine and levodopa beginning at age 2.6 years and 10 months, respectively (Kim et al 2020 ). Patient 278 and 402 with urea cycle disorder were managed with low protein diet.…”

Phenotypic and Genetic Complexity in Pediatric Movement Disorders

“…Variants were annotated, filtered and prioritized using software developed in-house, EVIDENCE (3bilion Inc, Seoul, South Korea). EVIDENCE incorporates daily automatically updated databases, variant classification schema based on the ACMG guidelines, and a symptom similarity scoring system as previously described ( Kim et al, 2020 ; Seo et al, 2020 ; Seo et al, 2022 ). All identified variants in this study were confirmed by Sanger sequencing and family study.…”

“…Since the advent of massively parallel, genomic-sequencing techniques in the early 2000s, the increased availability, reduced cost, and improved efficiency of next generation sequencing (NGS) have enhanced gene discovery for neurogenetic disorders and facilitated clinicians’ ability make accurate diagnoses ( Rexach et al, 2019 ; Kim et al, 2020 ). In particular, either whole exome sequencing (WES) or whole genome sequencing (WGS) can reveal more than 5,000 phenotypically and genetically diverse conditions with a single test.…”

“…Movement disorders are phenomenological, and each one has heterogeneous genetic causes; NGS is definitely more useful for genetic diagnosis than compared with a single gene test ( Neveling et al, 2013 ). Recent genetic diagnosis of pediatric movement disorders by WES has helped clinicians understand their underlying pathophysiology, expand the spectrum of the genotype–phenotype correlation, and provide personalized treatment ( Montaut et al, 2018 ; Graziola et al, 2019 ; Rexach et al, 2019 ; Kim et al, 2020 ; Papandreou et al, 2020 ). Moreover, movement disorders itself can be used as the key features for genetic diagnosis of pediatric neurological disorders using NGS.…”