P752: Sequencing of a KLK15 gene variant in a large cohort of hypermobile Ehlers-Danlos syndrome patients

Results: Copy number, mosaic and intronic variants in addition to single nucleotide variants were detected.The concordance of detected CNVs between GS and CMA testing was 100%.The diagnostic yield of 106 ASD patients was 60% (P/LP variants).An additional 19% of the findings were potentially actionable VUS (approaching LP based on available evidence).The diagnostic yield is 36% for ASD patients with no comorbidity, and 56% for those with at least one comorbidity.For patients with abnormal behavior with neurodevelopmental disorder symptoms, including attention deficit hyperactivity disorders, the diagnostic yield was 75%.Most variant findings included autistic behavior as a part of the associated symptoms.Genetic Counseling Implications: For affected families, their main motivations for testing were assisting clinical management (62%), understanding the prognosis (39%), and family planning or cascade screening (30%).The statistics provided insights for physicians and genetic counselors for their counseling.Regular reviewing of VUS approaching LP classification: GS enables more reliable detection of variants not routinely obtained exome sequencing, resulting in significant improvement in detecting VUS with evidence of pathogenicity.This increases the need for regularly reviewing VUS for reclassification which may further increase GS diagnostic yield over time.Conclusion: In this retrospective review of Hong Kong ASD patients with diagnostic GS, significantly more patients were diagnosed with a genetic etiology across multiple symptom categories, compared to conventional testing approaches.We also found a significant difference in the diagnostic yields between ASD with and without comorbidities.The findings can improve our genetic counseling services for children affected by ASD and neurodevelopmental disorders.The high diagnostic yield is equally significant for the families, especially since many of the parents hope to utilize GS results to guide the clinical management of their children and family planning.