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Summary: Genome-wide sequencing (GWS) is a standard of care for diagnosis of suspected genetic disorders, but the proportion of patients found to have pathogenic or likely pathogenic variants ranges from less than 30% to more than 60% in reported studies. It has been suggested that the diagnostic rate can be improved by interpreting genomic variants in the context of each affected individual’s full clinical picture and by regular follow-up and reinterpretation of GWS laboratory results.Trio exome sequencing was performed in 415 families and trio genome sequencing in 85 families in the CAUSES study. The variants observed were interpreted by a multidisciplinary team including laboratory geneticists, bioinformaticians, clinical geneticists, genetic counselors, pediatric subspecialists, and the referring physician, and independently by a clinical laboratory using standard American College of Medical Genetics and Genomics (ACMG) criteria. Individuals were followed for an average of 5.1 years after testing, with clinical reassessment and reinterpretation of the GWS results as necessary. The multidisciplinary team established a diagnosis of genetic disease in 43.0% of the families at the time of initial GWS interpretation, and longitudinal follow-up and reinterpretation of GWS results produced new diagnoses in 17.2% of families whose initial GWS interpretation was uninformative or uncertain. Reinterpretation also resulted in rescinding a diagnosis in four families (1.9%). Of the families studied, 33.6% had ACMG pathogenic or likely pathogenic variants related to the clinical indication. Close collaboration among clinical geneticists, genetic counselors, laboratory geneticists, bioinformaticians, and individuals’ primary physicians, with ongoing follow-up, reanalysis, and reinterpretation over time, can improve the clinical value of GWS.

Increased application of next generation sequencing has led to the discovery of a multitude of new neurodevelopmental syndromes, contributing to an increased diagnostic rate for exome sequencing from 25% originally to 40% currently. Owing to the recent recognition of these syndromes, as well as the types of large‐scale studies (with limited phenotype information) often making these discoveries, these disorders may be poorly characterized clinically. As a result there is very limited information and disorder‐specific support available to patients and families. We used a qualitative approach to explore how families experience a diagnosis of a new syndrome. We conducted semi‐structured telephone interviews with parents and adult siblings of children who received a diagnosis of a new syndrome after whole exome sequencing (WES) performed through a translational research study. The interviews were recorded, transcribed verbatim, and transcripts were analyzed using grounded theory methods. Analysis of the 12 interviews revealed that a lack of information about the child's condition continues to play a large role in these families' experiences even after diagnosis. Almost all (92%) participants expressed ongoing uncertainty about their child's health and future. Most (83%) participants were interested in identifying other families with the same syndrome, which was related to both social support and seeking of information. Interestingly, 33% of participants worried about the child's risk for cancer due to their syndrome. Our results highlight some of the needs of families of children with new syndromes, and emphasize important issues care providers should address in pre‐ and post‐test genetic counseling for WES and whole genome sequencing. [ABSTRACT FROM AUTHOR]