Cost-effectiveness of genome-wide sequencing for unexplained developmental disabilities and multiple congenital anomalies

Li, Chunmei; Vandersluis, Stacey; Holubowich, Corinne; Ungar, Wendy J.; Goh, Elaine Suk‐Ying; Boycott, Kym M.; Sikich, Nancy; Dhalla, Irfan A.; Ng, Vivian

doi:10.1038/s41436-020-01012-w

Cited by 37 publications

(49 citation statements)

References 29 publications

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“…All candidate variants were confirmed visually using an Integrative Genomics Viewer followed by Sanger sequencing with ABI3500XL Genetic Analyzer (Applied Biosystems, Foster City, CA, USA). In addition, copy number variations (CNVs) are a source of human genetic alteration and have been reported previously as a genetic cause of unexplained DD/ID, GR, facial dysmorphism, and/or CI [ 51 , 52 , 53 ]. VisCap, inference and visualization tool of germline CNVs from targeted clinical sequencing data, were used for additional depth-of-coverage analysis of exome sequencing data [ 54 ].…”

Section: Methodsmentioning

confidence: 99%

A Recurrent De Novo Terminal Duplication of 14q32 in Korean Siblings Associated with Developmental Delay and Intellectual Disability, Growth Retardation, Facial Dysmorphism, and Cerebral Infarction: A Case Report and Literature Review

Han

Park

2021

Genes

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The terminal 14q32 duplication has been reported often in association with other cytogenetic abnormalities, and individuals with this specific duplication showed varying degrees of developmental delay/intellectual disability (DD/ID) and growth retardation (GR), and distinct facial dysmorphisms. Herein, based on the limited cases of terminal duplication of 14q32 known to date, we present new affected siblings presenting with DD/ID, GR, and facial dysmorphism, as well as cerebral infarction caused by recurrent de novo der(14)t(14;14)(p11.2;q32.1) leading to terminal duplication of 14q32. We used coverage analysis generated via duo exome sequencing, performed chromosomal microarray (CMA) as a confirmatory test, and compared our findings with those reported previously. Coverage analysis generated via duo exome sequencing revealed a 17.2 Mb heterozygous duplication at chromosome 14q32.11-q32.33 with a Z ratio ranging between 0.5 and 1 in the proband and her elder brother. As a complementary method, CMA established a terminal duplication described as the arr[hg19]14q32.11q32.33(90,043,558_107,258,824)x3 in the proband and her elder brother; however, the parents and other siblings showed normal karyotyping and no abnormal gain or loss of CMA results. Five candidate genes, BCL11B, CCNK, YY1, DYNC1H1, and PACS2, were associated with the clinical phenotypes in our cases. Although the parents had normal chromosomes, two affected cases carrying terminal duplication of 14q32 can be explained by gonadal mosaicism. Further studies are needed to establish the association between cerebrovascular events and terminal duplication of chromosome 14q32, including investigation into the cytogenetics of patients with precise clinical descriptions.

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Section: Methodsmentioning

confidence: 99%

A Recurrent De Novo Terminal Duplication of 14q32 in Korean Siblings Associated with Developmental Delay and Intellectual Disability, Growth Retardation, Facial Dysmorphism, and Cerebral Infarction: A Case Report and Literature Review

Han

Park

2021

Genes

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“…This area of research deserves further exploration. Notably, from a health economic perspective, several published studies demonstrate that earlier incorporation of genome-wide approaches such as exome or genome sequencing is cost-effective by preventing long expensive diagnostic odysseys 21 , 22 , 45 , 46 . A recent study in the Netherlands found that medical costs decreased substantially following ES—regardless of whether there was a diagnosis—a finding they termed an “end of trajectory” effect 47 .…”

Section: Discussionmentioning

confidence: 99%

The diagnostic trajectory of infants and children with clinical features of genetic disease

Schroeder

Gonzaludo

Everson³

et al. 2021

npj Genom. Med.

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We characterized US pediatric patients with clinical indicators of genetic diseases, focusing on the burden of disease, utilization of genetic testing, and cost of care. Curated lists of diagnosis, procedure, and billing codes were used to identify patients with clinical indicators of genetic disease in healthcare claims from Optum’s de-identified Clinformatics® Database (13,076,038 unique patients). Distinct cohorts were defined to represent permissive and conservative estimates of the number of patients. Clinical phenotypes suggestive of genetic diseases were observed in up to 9.4% of pediatric patients and up to 44.7% of critically-ill infants. Compared with controls, patients with indicators of genetic diseases had higher utilization of services (e.g., mean NICU length of stay of 31.6d in a cohort defined by multiple congenital anomalies or neurological presentations compared with 10.1d for patients in the control population (P < 0.001)) and higher overall costs. Very few patients received any genetic testing (4.2–8.4% depending on cohort criteria). These results highlight the substantial proportion of the population with clinical features associated with genetic disorders and underutilization of genetic testing in these populations.

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“…As a result, studies often rely on less robust evidence of value that is hypothetical or contains uncertainty. [3][4][5][6][7] The use of real-world evidence from patient medical records, registries, surveys, and observational studies presents a practical and robust alternative. 8,9 Care4Rare-SOLVE (SOLVE) is a Genome Canada funded initiative that aims to (1) use new sequencing technologies to establish the molecular etiology of currently unsolved rare diseases and (2) generate evidence of the clinical utility and cost consequences of clinical exome sequencing (ES) to inform adoption and reimbursement decisions across provincial ministries of health in Canada.…”

Section: Introductionmentioning

confidence: 99%

The complexity of diagnosing rare disease: An organizing framework for outcomes research and health economics based on real-world evidence

Hayeems

Michaels-Igbokwe

Venkataramanan

et al. 2022

Genetics in Medicine

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To facilitate robust economic analyses of clinical exome and genome sequencing, this study was taken up with the objective of establishing a framework for organizing diagnostic testing trajectories for patients with rare disease. Methods: We collected diagnostic investigations-related data before exome sequencing from the medical records of 228 cases. Medical geneticist experts participated in a consensus building process to develop the SOLVE Framework for organizing the complex range of observed tests. Experts categorized tests as indicator or nonindicator tests on the basis of their specificity for diagnosing rare diseases. Face validity was assessed using case vignettes. Results: Most cases had symptom onset at birth (42.5%) or during childhood (43.4%) and had intellectual disability (73.3%). On average, the time spent seeking a diagnosis before sequencing was 1989 days (SD = 2137) and included 16 tests (SD = 14). Agreement across experts on test categories ranged from 83% to 96%. The SOLVE Framework comprised observed tests, including 186 indicator and 39 nonindicator tests across cytogenetic/molecular, biochemical, imaging, electrical, and pathology test categories. Conclusion: Real-world diagnostic testing data can be ascertained and organized to reflect the complexity of the journey of the patients with rare diseases. SOLVE Framework will improve the accuracy and certainty associated with value-based assessments of genomic sequencing.

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Cost-effectiveness of genome-wide sequencing for unexplained developmental disabilities and multiple congenital anomalies

Cited by 37 publications

References 29 publications

A Recurrent De Novo Terminal Duplication of 14q32 in Korean Siblings Associated with Developmental Delay and Intellectual Disability, Growth Retardation, Facial Dysmorphism, and Cerebral Infarction: A Case Report and Literature Review

A Recurrent De Novo Terminal Duplication of 14q32 in Korean Siblings Associated with Developmental Delay and Intellectual Disability, Growth Retardation, Facial Dysmorphism, and Cerebral Infarction: A Case Report and Literature Review

The diagnostic trajectory of infants and children with clinical features of genetic disease

The complexity of diagnosing rare disease: An organizing framework for outcomes research and health economics based on real-world evidence

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