Endocrine Abstracts

Introduction: Rare genetic overgrowth disorders are a group of conditions characterised by height and/or head circumference >2 S.D. above the mean for age and sex, learning disability, congenital anomalies, and in some cases childhood tumours. POD is a national cohort study that includes a next generation sequencing (NGS) panel of overgrowth genes. We present a new model for clinical confirmation of pathogenic variants identified by this research panel. Clinicians requesting diagnostic testing for patients meeting the eligibility criteria are charged only if (1) a pathogenic variant is identified and (2) the variant is confirmed by the West Midlands Regional Genetics Laboratory. If no pathogenic variants are identified, no charge is incurred. POD is a pilot project for assessing the cost effectiveness of this strategy.

Methods: An OpenClinica electronic data capture system was used to collect Human Phenotype Ontology (HPO) coded clinical data. The custom NGS panel was designed using Agilent SureDesign software and Agilent SureSelect QXT Target Enrichment was used for library preparation prior to sequencing on the Illumina MiSeq. Bioinformatic analysis was performed using Agilent SureCall software. Pathogenic variants were confirmed by Sanger sequencing in the service laboratory before results were fed back to clinicians.

Results: Twenty-eight individuals with undiagnosed overgrowth disorders were tested on the panel of 20 genes and pathogenic variants identified and confirmed in two participants. One participant was diagnosed with Malan syndrome due to a de novo missense variant in NFIX and a second patient was diagnosed with Tatton-Brown-Rahman syndrome due to a de novo nonsense mutation in DNMT3A.

Conclusions: Panel testing of overgrowth genes in the research setting translates into improvements in clinical care by identifying previously unknown diagnoses. We believe the novel ‘no win, no fee’ model will be attractive to clinicians, increase equity of access to genetic testing and reduce time spent on the ‘diagnostic odyssey’. We anticipate that diagnosis rates for rare genetic overgrowth disorders will improve with national recruitment to POD through paediatric endocrinology clinics and the implementation of an updated panel of 44 overgrowth genes.