Diagnostic yield of next-generation sequencing in 87 families with neurodevelopmental disorders

Abstract

Background Neurodevelopmental disorders (NDDs) are a group of heterogeneous conditions, which include mainly intellectual disability, developmental delay (DD) and autism spectrum disorder (ASD), among others. These diseases are highly heterogeneous and both genetic and environmental factors play an important role in many of them. The introduction of next generation sequencing (NGS) has lead to the detection of genetic variants in several genetic diseases. The main aim of this report is to discuss the impact and advantages of the implementation of NGS in the diagnosis of NDDs. Herein, we report diagnostic yields of applying whole exome sequencing in 87 families affected by NDDs and additional data of whole genome sequencing (WGS) from 12 of these families. Results The use of NGS technologies allowed identifying the causative gene alteration in approximately 36% (31/87) of the families. Among them, de novo mutation represented the most common cause of genetic alteration found in 48% (15/31) of the patients with diagnostic mutations. The majority of variants were located in known neurodevelopmental disorders genes. Nevertheless, some of the diagnoses were made after the use of GeneMatcher tools which allow the identification of additional patients carrying mutations in THOC2, SETD1B and CHD9 genes. Finally the use of WGS only allowed the identification of disease causing variants in 8% (1/12) of the patients in which previous WES failed to identify a genetic aetiology. Conclusion NGS is more powerful in identifying causative pathogenic variant than conventional algorithms based on chromosomal microarray as first-tier test. Our results reinforce the implementation of NGS as a first-test in genetic diagnosis of NDDs.

Genome sequencing with gene panel-based analysis for rare inherited conditions in a publicly funded healthcare system: implications for future testing

“…Those families who achieved a confirmed genetic diagnosis from the SGP Study after not having achieved one from historic standard testing benefitted from better understanding of prognosis and reproductive risks, giving opportunities for improved reproductive choice in future pregnancy, better ongoing care and, in a small number, the opportunity for a trial of a targeted therapy. Both the overall diagnostic yield and the variation among yield estimates from the 393 families in the SGP Study are broadly in line with those reported for the 100,000 Genomes Project pilot study in NHS England [16], and other studies of genome sequencing in rare inherited conditions [17][18][19]. For those phenotypes with lowest yields (Tumour Syndromes, Renal Syndromes and Cardiovascular lower yields are likely attributable to the standard of care pre-testing comprising comprehensive targeted panels with excellent coverage; alternatively, it may be that these phenotypes are caused by complex genetic abnormalities not captured by the technology and/or identified by the analysis pipeline, such as large structural rearrangement or non-coding variation, polygenic inheritance of genes of modest attributable risk not considered within the clinical analysis pipeline, and/or phenocopies.…”

Implementation of Exome Sequencing in Clinical Practice for Neurological Disorders

“…Physical examination revealed obvious clinical signs of CdLs, such as long philtrum, long eyelashes, high-arched palate, anteverted nares, and hypospadias. Despite this variant being present in one individual in gnomAD v2 ( (accessed on 15 June 2021)) and in two individuals in gnomAD v3 ( (accessed on 15 June 2021)), and all the in silico predictors tools suggesting it was not deleterious, the absence of additional genetic alterations associated to NDDs and de novo origin reinforced the idea of a probably pathogenic variant [ 11 ]. Hence, when using a general population as a control cohort, the presence of individuals with subclinical disease is always a possibility and thus variants with a low allelic frequency should not be discarded.…”

Molecular diagnostic yield of genome sequencing versus targeted gene panel testing in racially and ethnically diverse pediatric patients

“…Previous studies with smaller numbers of children have reported the molecular diagnostic yield of genetic testing in pediatric neurodevelopmental diseases to be around 30% -40%, which is higher than what we observed, and may reflect differences in inclusion criteria, which were relatively broad in NYCKidSeq. [33][34][35] We compared the diagnostic yield and concordance of GS and TGP in 642 probands who had both types of tests and found that less than 40% (45 of 113) of diagnoses were achieved by both test modalities. GS-only diagnoses included structural variants and non-exonic sequence variants; however, the majority of GS-only diagnoses were exonic SNVs, most of which were in genes not present on the TGPs.…”