The cost and diagnostic yield of exome sequencing for children with suspected genetic disorders: a benchmarking study

PurposeThis study aimed to generate benchmark estimates for the cost, diagnostic yield, and cost per positive diagnosis of diagnostic exome sequencing (ES) in heterogeneous pediatric patient populations and to illustrate how the design of an ES service can influence its cost and yield.MethodsA literature review and Monte Carlo simulations were used to generate benchmark estimates for singleton and trio ES. A cost model for the Clinical Assessment of the Utility of Sequencing and Evaluation as a Service (CAUSES) study, which is testing a proposed delivery model for diagnostic ES in British Columbia, is used to illustrate the potential effects of changing the service design.ResultsThe benchmark diagnostic yield was 34.3% (95% confidence interval (CI): 23.2-46.5) for trio ES and 26.5% (95% CI: 12.9-42.9) for singleton ES. The benchmark cost of delivery was C$6,437 (95$5,305-$7,704) in 2016 Canadian dollars (US$4,859; 4,391[euro ]) for trio ES and C$2,576 (95$1,993-$3,270) (US$1,944; 1,757[euro ]) for singleton ES. Scenario models for CAUSES suggest that alternative service designs could reduce costs but might lead to a higher cost per diagnosis due to lower yields.ConclusionBroad conclusions about the cost-effectiveness of ES should be drawn with caution when relying on studies that use cost or yield assumptions that lie at the extremes of the benchmark ranges.GENETICS in MEDICINE advance online publication, 4 January 2018; doi:10.1038/gim.2017.22

Setd1b-associated neurodevelopmental disorder

Background: Dysfunction of histone methyltransferases and chromatin modifiers has been implicated in complex neurodevelopmental syndromes and cancers. SETD1B encodes a lysine-specific methyltransferase that assists in transcriptional activation of genes by depositing H3K4 methyl marks. Previous reports of patients with rare variants in SETD1B describe a distinctive phenotype that includes seizures, global developmental delay and intellectual disability. Methods: Two of the patients described herein were identified via genome-wide and exome-wide testing, with microarray and research-based exome, through the CAUSES (Clinical Assessment of the Utility of Sequencing and Evaluation as a Service) Research Clinic at the University of British Columbia. The third Vancouver patient had clinical trio exome sequencing through Blueprint Genetics. The fourth patient underwent singleton exome sequencing in Nantes, with subsequent recruitment to this cohort through GeneMatcher. Results: Here we present clinical reports of four patients with rare coding variants in SETD1B that demonstrate a shared phenotype, including intellectual disability, language delay, conserved musculoskeletal findings and seizures that may be treatment-refractory. We include supporting evidence from next-generation sequencing among a cohort of paediatric patients with epilepsy. Conclusion: Rare coding variants in SETD1B can cause a diagnosable syndrome and could contribute as a risk factor for epilepsy, autism and other neurodevelopmental phenotypes. In the long term, some patients may also be at increased risk for cancers and other complex diseases. Thus, longitudinal studies are required to further elucidate the precise role of SETD1B in neurodevelopmental disorders and other systemic disease

The cost trajectory of the diagnostic care pathway for children with suspected genetic disorders

Purpose: This study describes the cost trajectory of the standard diagnostic care pathway for children with suspected genetic disorders in British Columbia, Canada. Methods: Average annual per-patient costs were estimated using medical records review and a caregiver survey for a cohort of 498 children referred to BC Children’s and Women’s Hospitals (C&W) with unexplained intellectual disability (the TIDE-BC study) and families enrolled in the CAUSES study, which offered diagnostic genome-wide sequencing (GWS; exome and genome sequencing) to 500 families of children with suspected genetic disorders. Results: Direct costs peaked in the first year of patients’ diagnostic odyssey, with an average of C$2257 per patient (95$2074, C$2441) for diagnostic testing and C$631 (95% CI C$543, C$727) for specialist consultations at C&W. In subsequent years, direct costs accrued at a constant rate, with an estimated annual per-patient cost of C$511 (95$473, C$551) for diagnostic testing and C$334 (95% CI C$295, C$369) for consultations at C&W. Travel costs and caregiver productivity loss associated with attending diagnosis-related physician appointments averaged C$1907/family/year. Conclusions: The continuing long-term accrual of costs by undiagnosed patients suggests that economic evaluations of diagnostic GWS services should use longer time horizons than have typically been used

Comprehensive whole genome sequence analyses yields novel genetic and structural insights for Intellectual Disability

Background: Intellectual Disability (ID) is among the most common global disorders, yet etiology is unknown in ~30% of patients despite clinical assessment. Whole genome sequencing (WGS) is able to interrogate the entire genome, providing potential to diagnose idiopathic patients. Methods: We conducted WGS on eight children with idiopathic ID and brain structural defects, and their normal parents; carrying out an extensive data analyses, using standard and discovery approaches. Results: We verified de novo pathogenic single nucleotide variants (SNV) in ARID1B c.1595delG and PHF6 c.820C > T, potentially causative de novo two base indels in SQSTM1 c.115_116delinsTA and UPF1 c.1576_1577delinsA, and de novo SNVs in CACNB3 c.1289G > A, and SPRY4 c.508 T > A, of uncertain significance. We report results from a large secondary control study of 2081 exomes probing the pathogenicity of the above genes. We analyzed structural variation by four different algorithms including de novo genome assembly. We confirmed a likely contributory 165 kb de novo heterozygous 1q43 microdeletion missed by clinical microarray. The de novo assembly resulted in unmasking hidden genome instability that was missed by standard re-alignment based algorithms. We also interrogated regulatory sequence variation for known and hypothesized ID genes and present useful strategies for WGS data analyses for non-coding variation. Conclusion: This study provides an extensive analysis of WGS in the context of ID, providing genetic and structural insights into ID and yielding diagnoses.Medicine, Faculty ofOther UBCNon UBCMedical Genetics, Department ofPediatrics, Department ofReviewedFacult

Loss-of-Function and Gain-of-Function Mutations in KCNQ5 Cause Intellectual Disability or Epileptic Encephalopathy

KCNQ5 is a highly conserved gene encoding an important channel for neuronal function; it is widely expressed in the brain and generates M-type current. Exome sequencing identified de novo heterozygous missense mutations in four probands with intellectual disability, abnormal neurological findings, and treatment-resistant epilepsy (in two of four). Comprehensive analysis of this potassium channel for the four variants expressed in frog oocytes revealed shifts in the voltage dependence of activation, including altered activation and deactivation kinetics. Specifically, both loss-of-function and gain-of-function KCNQ5 mutations, associated with increased excitability and decreased repolarization reserve, lead to pathophysiology