Meta-analysis and multidisciplinary consensus statement: exome sequencing is a first-tier clinical diagnostic test for individuals with neurodevelopmental disorders

Abstract

PurposeFor 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.MethodsWe performed a PubMed scoping review and meta-analysis 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.ResultsAfter 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%).ConclusionOur 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.

Secuenciación de nueva generación (NGS) de ADN: presente y futuro en la práctica clínica

“…La interpretación de los resultados puede ser más compleja y puede ser más probable encontrar variantes de significado incierto o variantes que no se correlacionen con la clínica del paciente, en cuyo caso el estudio de familiares -como el exoma trío, es decir, secuenciación de exoma del probando y sus dos progenitores-podría resultar útil (15). Su uso clínico se ha propuesto, por ejemplo, como primera prueba diagnóstica en trastornos del neurodesarrollo (28).…”

Limitations of exome sequencing in detecting rare and undiagnosed diseases

“…While ES is considered to have strong diagnostic utility, it provides a genetic diagnosis in only about 31% of cases (range 24–68%, note the higher rates are seen in consanguineous cohorts; Clark et al, ; Farwell et al, ; Lee et al, ; Retterer et al, ; Yang et al, ; Yang et al, ). ES is suggested by some as a first line test (Srivastava et al, ); however, it is often thought of as the last resort by many other clinicians. Since many variations including CNV and noncoding variants (NCV) may not be detected, the patient may not receive a diagnosis even if one is genetically identifiable.…”

The Feasibility and Outcomes of Genetic Testing for Autism and Neurodevelopmental Disorders on an Inpatient Child and Adolescent Psychiatry Service

“…Diagnostic genetic testing for patients with NDDs, using chromosomal microarrays (CMAs) to detect CNVs and polymerase chain reaction to detect FX syndrome, is now recommended by many professional medical organizations including the American College of Medical Genetics and Genomics (ACMG) and the American Academy of Child and Adolescent Psychiatry [Miller et al, 2010;Muhle et al, 2017]. Diagnostic yield using CMA is reported as 15-20% [Srivastava et al, 2019]. Exome sequencing (ES) to detect SNVs is often used as a second-line diagnostic test, but new guidelines suggest it as a first-tier test with diagnostic yields of 31-53% [Srivastava et al, 2019].…”