Exome sequencing in paediatric neurogenetic diseases

Abstract

Diagnosing paediatric neurological diseases is clinically challenging owing to phenotypic heterogeneity. Conventional molecular technology is not effective in making genetic diagnoses owing to genotypic heterogeneity. With advances in exome sequencing (ES), precise molecular diagnosis can be reached promptly.

The objective of this study is to evaluate the clinical utility based on the diagnostic yield of ES in patients with drug-resistant epilepsy (DRE), neuromuscular disorders (NMD), movement disorders (MOVD) and mitochondrial diseases (MitoD). This is a representative cohort of paediatric neurogenetic diseases, as these are the dominant paediatric neurological disorders.

First, ES was performed in 67 patients with DRE, with a diagnostic yield of 22.4% (15/67). Genetic diagnoses can provide guidelines on anti-epileptic drug (AED) selection and a prognosis on the risk of sudden unexpected death in epilepsy (SUDEP). A novel epilepsy gene was discovered through international collaboration, which demonstrates the advantage of ES over other conventional molecular tests.

Second, ES was used in the diagnosis of 60 patients with NMD, with a diagnostic yield of 26.7% (16/60). A review of the mutation spectrum of collagen VI-related myopathies was carried out, as this was found to be relatively common in the local cohort. ES benefits patients as it helps to diagnose non-NMD patients with NMD presentation through the illustration of the TGFB1 variant found. Moreover, a genetic diagnosis can provide a prognosis, guide management and provide potential therapeutic strategy to NMD patients.

Third, ES was used to investigate the genetic cause of 31 patients with MOVD, giving a diagnostic yield of 32.3% (10/31). The mutation spectrum of CTNNB1-associated disorders was reviewed. The importance of genetic study in the local population is shown by the example using TGM6, a reported gene associated with spinocerebellar ataxia type 35. Reported pathogenic rare variants were found in the local patients with various phenotypes and asymptomatic parents, with a significant inflation of 592 in East Asian population and 111 in the overall population, casting doubts on the pathogenicity of TGM6 variants. Extra care is therefore required when analysing variants with ethnicity bias.

Last, ES was performed to identify the causative variant in 66 patients with clinical features of MitoD. The diagnostic yield achieved was 34.8% (23/66). Among the patients with a positive diagnosis, 18 patients were found to have non-MitoD. This finding demonstrates that ES is an effective tool in diagnosing MitoD, owing to the overlapping phenotype of MitoD and non-MitoD and the misleading MDC score. Furthermore, in collaboration with the National Taiwan University Hospital, we characterized the largest case series of primary coenzyme Q10 deficiency 7. We expanded the clinical presentation of this disease from classical neonatal-onset encephalo-cardiomyopathy to infantile-onset encephalopathy with or without cardiomyopathy. We also elucidated a Southern East Asian founder mutation in COQ4, c.370G>A p.(Gly124Ser), which enriches the disease occurrence in the Chinese population.

In summary, this study shows that ES is an effective diagnostic tool in paediatric neurological diseases. The diagnostic yield is promising, and the results shed light on the mutation spectrum of neurogenetic diseases in the local Chinese cohort.