A single center experience with publicly funded clinical exome sequencing for neurodevelopmental disorders or multiple congenital anomalies (original) (raw)
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Clinical genetics, 2017
Although whole-exome sequencing (WES) is the gold standard for the diagnosis of neurodevelopmental disorders (NDDs), it remains expensive for some genetic centers. Commercialized panels comprising all OMIM-referenced genes called "medical exome" (ME) constitute an alternative strategy to WES, but its efficiency is poorly known. In this study, we report the experience of 2 clinical genetic centers using ME for diagnosis of NDDs. We recruited 216 consecutive index patients with NDDs in 2 French genetic centers, corresponded to the daily practice of the units and included non-syndromic intellectual disability (NSID, n = 33), syndromic ID (NSID = 122), pediatric neurodegenerative disorders (n = 7) and autism spectrum disorder (ASD, n = 54). We sequenced samples from probands and their parents (when available) with the Illumina TruSight One sequencing kit. We found pathogenic or likely pathogenic variants in 56 index patients, for a global diagnostic yield of 25.9%. The diagnos...
Genetics in Medicine, 2019
and the NDD Exome Scoping Review Work Group Purpose: For neurodevelopmental disorders (NDDs), etiological evaluation can be a diagnostic odyssey involving numerous genetic tests, underscoring the need to develop a streamlined algorithm maximizing molecular diagnostic yield for this clinical indication. Our objective was to compare the yield of exome sequencing (ES) with that of chromosomal microarray (CMA), the current first-tier test for NDDs. Methods: We performed a PubMed scoping review and metaanalysis investigating the diagnostic yield of ES for NDDs as the basis of a consensus development conference. We defined NDD as global developmental delay, intellectual disability, and/or autism spectrum disorder. The consensus development conference included input from genetics professionals, pediatric neurologists, and developmental behavioral pediatricians. Results: After applying strict inclusion/exclusion criteria, we identified 30 articles with data on molecular diagnostic yield in individuals with isolated NDD, or NDD plus associated conditions (such as Rett-like features). Yield of ES was 36% overall, 31% for isolated NDD, and 53% for the NDD plus associated conditions. ES yield for NDDs is markedly greater than previous studies of CMA (15-20%). Conclusion: Our review demonstrates that ES consistently outperforms CMA for evaluation of unexplained NDDs. We propose a diagnostic algorithm placing ES at the beginning of the evaluation of unexplained NDDs.
Whole Exome Sequencing in Neurodevelopmental Disorders: A Single Center Study
Basic and Clinical Neuroscience Journal, 2024
Introduction: Neurodevelopmental disorders (NDDs) comprise clinically and genetically heterogeneous diseases. It is challenging to diagnose the underlying origin of NDDs. We aim to evaluate whole exome sequencing (WES) results in our NDD patients and the responsible genetic variants. Methods: This study evaluated the WES analysis of 25 NDD patients retrospectively. Also, the diagnostic yield of WES in our cases and clinical findings were examined. Results: After WES analysis, we diagnosed 13 patients (52%) with pathogenic and likely pathogenic variants, but 12(48%) had variants of uncertain significance (VUS). However, after phenotype consistency and following segregation analysis, we reevaluated 2 VUS as the disease-causing variants, and our yield rate increased to 60%. We also reported the secondary findings. Conclusion: Our study’s diagnostic yield of WES in NDD was 60%. The latest American College of Medical Genetics and Genomics (ACMG) guideline recommends WES as the first-tier test in NDD. WES is time- and cost-effective when performed on a well-selected patient. Also, determining the underlying cause of NDD will provide patients with a more precise diagnosis and clinical follow-up.
Genetics in Medicine
Disclaimer: The ACMG has recruited expert panels, chosen for their scientific and clinical expertise, to develop evidence-based guidelines (EBG) for clinical practice. An EBG focuses on a specific scientific question and then describes recommendations intended to optimize patient care that are informed by a systematic review of evidence and an assessment of the benefits and harms of alternative care options. ACMG EBGs are provided primarily as an educational resource for medical geneticists and other clinicians to help them provide quality medical services. They should not be considered inclusive of all relevant information on the topic reviewed. Reliance on this EBG is completely voluntary and does not necessarily ensure a successful medical outcome. In determining the propriety of any specific procedure or test, the clinician should consider the best available evidence, and apply his or her own professional judgment, taking into account the needs, preferences and specific clinical circumstances presented by the individual patient. Clinicians are encouraged to document the reasons for the use of a particular procedure or test, whether or not it is in conformance with this EBG. Clinicians are also advised to take notice of the date this EBG was published, and to consider other medical and scientific information that becomes available after that date. PURPOSE: To develop an evidence-based clinical practice guideline for the use of exome and genome sequencing (ES/GS) in the care of pediatric patients with one or more congenital anomalies (CA) with onset prior to age 1 year or developmental delay (DD) or intellectual disability (ID) with onset prior to age 18 years. METHODS: The Pediatric Exome/Genome Sequencing Evidence-Based Guideline Work Group (n = 10) used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) evidence to decision (EtD) framework based on the recent American College of Medical Genetics and Genomics (ACMG) systematic review, and an Ontario Health Technology Assessment to develop and present evidence summaries and health-care recommendations. The document underwent extensive internal and external peer review, and public comment, before approval by the ACMG Board of Directors. RESULTS: The literature supports the clinical utility and desirable effects of ES/GS on active and long-term clinical management of patients with CA/DD/ID, and on family-focused and reproductive outcomes with relatively few harms. Compared with standard genetic testing, ES/GS has a higher diagnostic yield and may be more cost-effective when ordered early in the diagnostic evaluation. CONCLUSION: We strongly recommend that ES/GS be considered as a firstor second-tier test for patients with CA/DD/ID.
Diagnostic yield of pediatric and prenatal exome sequencing in a diverse population
npj Genomic Medicine
The diagnostic yield of exome sequencing (ES) has primarily been evaluated in individuals of European ancestry, with less focus on underrepresented minority (URM) and underserved (US) patients. We evaluated the diagnostic yield of ES in a cohort of predominantly US and URM pediatric and prenatal patients suspected to have a genetic disorder. Eligible pediatric patients had multiple congenital anomalies and/or neurocognitive disabilities and prenatal patients had one or more structural anomalies, disorders of fetal growth, or fetal effusions. URM and US patients were prioritized for enrollment and underwent ES at a single academic center. We identified definitive positive or probable positive results in 201/845 (23.8%) patients, with a significantly higher diagnostic rate in pediatric (26.7%) compared to prenatal patients (19.0%) (P = 0.01). For both pediatric and prenatal patients, the diagnostic yield and frequency of inconclusive findings did not differ significantly between URM a...
2019
Background: Neurological diseases are phenotypically and genotypically heterogeneous. Clinical exome sequencing (CES) has been shown to provide a high diagnostic yield for these disorders in the European population but remains to be demonstrated for the Indian population. Methods: A cohort of 19 idiopathic patients with neurological phenotypes, primarily intellectual disability and developmental delay, were recruited. CES covering 4620 genes was performed on all patients. Candidate variants were validated by Sanger sequencing. Results: CES in 19 patients provided identified 21 variants across 16 genes which have been associated with different neurological disorders. Fifteen variants were reported previously and 6 variants were novel to our study. Eleven patients were diagnosed with autosomal dominant de novo variants, 7 with autosomal recessive and 1 with X-linked recessive variants. CES provided definitive diagnosis to 10 patients, hence the diagnostic yield was 53%. Conclusion: Ou...
Orphanet Journal of Rare Diseases
Intellectual disability (ID) has a prevalence of 1–3% and aproximately 30–50% of ID cases have a genetic cause. Development of next-generation sequencing has shown a high diagnostic potential. The aim of this work was to evaluate the diagnostic yield of clinical exome sequencing in 188 ID patients and the economic impact of its introduction in clinical practice. An analysis of diagnostic yield according to the different clinical variables was performed in order to establish an efficient diagnostic protocol for ID patients. Diagnostic yield of clinical exome sequencing was significant (34%) supporting its utility in diagnosis of ID patients. Wide genetic heterogeneity and predominance of autosomal dominant de novo variants in ID patients were observed. Time to diagnosis was shortened and diagnostic study costs decreased by 62% after implementation of clinical exome sequencing. No association was found between any of the variables analyzed and a higher diagnostic yield; added to the f...
JAMA psychiatry, 2017
Autosomal recessive inherited neurodevelopmental disorders are highly heterogeneous, and many, possibly most, of the disease genes are still unknown. To promote the identification of disease genes through confirmation of previously described genes and presentation of novel candidates and provide an overview of the diagnostic yield of exome sequencing in consanguineous families. Autozygosity mapping in families and exome sequencing of index patients were performed in 152 consanguineous families (the parents descended from a same ancestor) with at least 1 offspring with intellectual disability (ID). The study was conducted from July 1, 2008, to June 30, 2015, and data analysis was conducted from July 1, 2015, to August 31, 2016. Of the 152 consanguineous families enrolled, 1 child (in 45 families [29.6%]) or multiple children (107 families [70.4%]) had ID; additional features were present in 140 of the families (92.1%). The mean (SD) age of the children was 10.3 (9.0) years, and 171 o...