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The diagnosis of children with genetic conditions places a significant economic burden on health care services. The lack of well-defined comparative cohorts has been a limitation of health economic studies comparing first-line genomic sequencing (GS) against traditional approaches. Aim(s): To evaluate utility and cost effectiveness of early GS in pediatric patients with complex monogenic conditions compared to a matched historical cohort. Method(s): Data, including diagnosis rate and investigation costs, were collected in a prospective cohort of 92 pediatric patients who underwent singleton GS over an 18-month period (2016-2017). Inclusion required patients to have two of the following: a condition with high morbidity or mortality, a multi-system disease involving three or more organ systems, or severe limitation of daily function. For comparison, data were collected in a historical patient cohort fulfilling the inclusion criteria who underwent traditional investigations in the two years (2012-2013) prior to the availability of clinical genomic sequencing. Result(s): Genomic sequencing yielded a diagnosis in 42% while traditional investigations yielded a diagnosis in 23% (p = 0.003). 75% of diagnosed patients experienced a change in management, compared to 33% of diagnosed patients who underwent traditional investigations. In the GS cohort, four times fewer invasive investigations were observed. Compared to traditional investigations, singleton genomic sequencing at a cost of $3100 AUD resulted in a mean saving per person of $2780 AUD (95%CI $1585-$3974). Conclusion(s): Early genomic sequencing is highly costeffective while doubling the diagnostic yield of traditional approaches and improving the care of patients with complex genetic conditions.

Purpose: Cost-effectiveness evaluations of first-line genomic sequencing (GS) in the diagnosis of children with genetic conditions are limited by the lack of well-defined comparative cohorts. We sought to evaluate the cost-effectiveness of early GS in pediatric patients with complex monogenic conditions compared with a matched historical cohort. Method(s): Data, including investigation costs, were collected in a prospective cohort of 92 pediatric patients undergoing singleton GS over an 18-month period (2016-2017) with two of the following: a condition with high mortality, multisystem disease involving three or more organs, or severe limitation of daily function. Comparative data were collected in a matched historical cohort who underwent traditional investigations in the years 2012-2013. Result(s): GS yielded a diagnosis in 42% while traditional investigations yielded a diagnosis in 23% (p = 0.003). A change in management was experienced by 74% of patients diagnosed following GS, compared with 32% diagnosed following traditional investigations. Singleton GS at a cost of AU$3100 resulted in a mean saving per person of AU$3602 (95% confidence interval [CI] AU$2520-4685). Cost savings occurred across all investigation subtypes and were only minimally offset by clinical management costs. Conclusion(s): GS in complex pediatric patients saves significant costs and doubles the diagnostic yield of traditional approaches.Copyright © 2020, American College of Medical Genetics and Genomics.

Congenital hearing impairment (HI) is the most common sensory impairment and can be isolated or part of a syndrome. Diagnosis through newborn hearing screening and management through early intervention, hearing aids and cochlear implantation is well established in the Australian setting; however understanding the genetic basis of congenital HI has been missing. This population-derived cohort comprised infants with moderate-profound bilateral HI born in the 2016-2017 calendar years, detected through newborn hearing screening. Participants were recruited through an integrated paediatric, otolaryngology and genetics HI clinic and offered whole exome sequencing (WES) on a HiSeq4000 or NextSeq500 (Illumina) platform with a targeted average sequencing depth of 100x and chromosome microarray on the Illumina Infinium core exome-24v1.2 platform. Of those approached, 68% (106/156) consented to participate. The rate of genetic diagnosis was 56% (59/106), significantly higher than standard of care (GJB2/6 sequencing only), 21% (22/106). There were clinical implications for the 106 participants: 36% required no further screening, 9% had tailored screening initiated, 2% were offered treatment and 4% had informed care for a complex neurodevelopmental syndrome. WES in this cohort demonstrates the range of diagnoses associated with congenital HI and confirms the genetic heterogeneity of congenital HI. The high diagnostic yield and clinical implications emphasises the need for genomic sequencing to become standard of care.Copyright © 2019, The Author(s), under exclusive licence to European Society of Human Genetics.

In Table 3, on pages 591-592 of the original article, in the fourth row of the table, an alteration in GJB2 is shown as "c.429G>A p.(Glu147Lys)", but it should read "c.439G>A p.(Glu147Lys)".Copyright © 2020, The Author(s), under exclusive licence to European Society of Human Genetics.