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

Min-Jee Kim; Mi-Sun Yum; Go Hun Seo; Yena Lee; Han Na Jang; Tae-Sung Ko; Beom Hee Lee

doi:10.3390/jcm9113724

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

J Clin Med. 2020 Nov 20;9(11):3724. doi: 10.3390/jcm9113724.

Authors

Min-Jee Kim¹, Mi-Sun Yum¹, Go Hun Seo², Yena Lee³, Han Na Jang¹, Tae-Sung Ko¹, Beom Hee Lee²

Affiliations

¹ Department of Pediatrics, Asan Medical Center Children's Hospital, Ulsan University College of Medicine 88, Olympic-ro 43-Gil, Songpa-Gu, Seoul 05505, Korea.
² 3billion Inc., Seoul 06193, Korea.
³ Department of Genetics, Asan Medical Center, Ulsan University College of Medicine, 88, Olympic-ro 43-Gil, Songpa-Gu, Seoul 05505, Korea.

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.

Keywords: autosomal recessive dopa-responsive dystonia; congenital myasthenic syndrome; epileptic encephalopathy 47; episodic ataxia type II; neurogenetic disorders; rare genetic diseases; whole exome sequencing.