Authors :
Presenting Author: Byoung Chan Lee, BSc – The Children’s Hospital at Westmead Clinical School, The University of Sydney, Sydney, NSW, Australia
Shekeeb S Mohammad, FRACP, PhD – The Children’s Hospital at Westmead Clinical School, Department of Neurology, Kids Neuroscience Centre, The University of Sydney, Sydney, NSW, Australia
Michael Buckley, BSc – Randwick Genomics, NSW Health Pathology, Prince of Wales Hospital, Randwick, New South Wales, Australia.
Katrina Fisk, BSc – Western Sydney Genetics Program, The Children’s Hospital at Westmead, Sydney, Australia
Bruce Bennetts, BSc – Western Sydney Genetics Program, The Children’s Hospital at Westmead, Sydney, Australia
Russell C Dale, MRCPCH, PhD – The Children’s Hospital at Westmead Clinical School, Department of Neurology,Kids Neuroscience Centre,The University of Sydney, Sydney, NSW, Australia
Sachin Gupta, FRACP – TY Nelson Department of Neurology and Neurosurgery, The Children’s Hospital at Westmead, Sydney, NSW, Australia
Deepak Gill, MRCPCH – The Children’s Hospital at Westmead Clinical School, Department of Neurology, Kids Neuroscience Centre, The University of Sydney, Sydney, NSW, Australia
Tony Roscioli, FRACP, PhD – Randwick Genomics, NSW Health Pathology, Prince of Wales Hospital, Randwick, New South Wales, Australia.
Kavitha Kothur, FRACP, PhD – The Children’s Hospital at Westmead Clinical School, Department of Neurology, Kids Neuroscience Centre, The University of Sydney, Sydney, NSW, Australia
Rationale: Next-gene sequencing technology has been increasingly used to improve the diagnosis and treatment of paediatric neurological disorders, but current resources are limited in terms of the optimal testing modalities. We aim to evaluate various genetic testing practices (exome, commercial Invitae genetic panels, and in-house epilepsy and movement disorder genetic panel with rigorous pretest clinical phenotyping) from a large tertiary hospital and identify clinical associations with pathogenic genetic variants.
Methods: Data was gathered from patients (age< 18y) from a neurology department for whom genetic testing was requested for investigation of underlying neurological disorders (2020–2023). The details regarding clinical phenotype were collected from the pathology request form, and the diagnostic genetic labs provided the genetic variant results. Logistic regression was used to identify clinical features that were predictive of positive results.
Results: Over the study period, 421 patients underwent genetic testing via whole exome sequencing (
n=126), commercial panel (
n=171), in-house epilepsy (
n=79) and movement disorder (
n=45) gene panels. Patients who underwent in-house gene panels were carefully phenotyped via triage multidisciplinary meetings before enrolling for genetic testing. There was an average annual increase in requests for exome (6%) and commercial panel (32%), whereas epilepsy panel requests decreased (5.5%). Exome had the highest pathogenic yield (39%, 76 genes), followed by epilepsy (28%, 19 genes), movement disorder (24%, 11 genes) and commercial (15%, 20 genes) panels. Variants of uncertain significance in the final report were highest in commercial (58%) and epilepsy (33%) panels. Figure 1 shows that amongst the total exome cohort, the predominant clinical features were developmental delay / intellectual disability (81%), epilepsy (33%) and movement disorder (29%). Pathogenic variants were more likely in patients with microcephaly (67%), hypotonia (51%) and dysmorphic features (48%), though none of these reached statistical significance on multivariable analysis (
p >0.05).
Conclusions: This study demonstrates that exome sequencing outperforms gene panels in confirming genetic diagnoses in paediatric neurological disorders. It promotes enhancing local clinical resources to ensure the most effective testing methods. The higher yield in in-house panel testing reflects the importance of rigorous pretest clinical phenotyping before enrolment.
Funding:
This work was supported by scholarship from NHMRC EL1 investigator grant
2017279.