High Performance of a Dominant/X-Linked Gene Panel in Patients with Neurodevelopmental Disorders.

Researchers tested a genetic panel on nearly 400 people with developmental delays and autism. They found genetic causes in about 29% of cases, discovering problems in 83 different genes. People with intellectual disabilities were more likely to have genetic causes found than those with autism alone. Surprisingly, genetic causes were found more often in girls than boys, even though more boys were tested.

This study evaluated a targeted gene panel testing 460 dominant and X-linked genes in 398 patients with neurodevelopmental disorders (NDDs), including intellectual disability/global developmental delay and autism spectrum disorder. The panel achieved a 28.6% diagnostic yield, identifying pathogenic variants in 83 different genes. Key findings included higher diagnostic rates in patients with ID/GDD compared to autism-only cases, and surprisingly higher rates in females despite more males being tested. The study demonstrated significant genetic heterogeneity in NDDs and suggested that detailed phenotypic profiling may help predict the likelihood of finding pathogenic variants.

Results support use of targeted gene panels as effective first-tier genetic testing for NDDs, particularly for patients with ID/GDD. Higher female diagnostic yield warrants further investigation. Deep phenotypic profiling may enhance variant prediction. Findings suggest panel could serve as preliminary step before whole exome sequencing.

Single-center study with unclear methodology details. Sample size and demographic characteristics not fully specified. Comparison claims about higher diagnostic yield versus other panels lack detailed comparative data. Study type and specific filtering procedures not comprehensively described.

Neurodevelopmental disorders (NDDs) affect 2-5% of the population and approximately 50% of cases are due to genetic factors. Sincepathogenic variants account for the majority of cases, a gene panel including 460 dominant and X-linked genes was designed and applied to 398 patients affected by intellectual disability (ID)/global developmental delay (GDD) and/or autism (ASD). Pathogenic variants were identified in 83 different genes showing the high genetic heterogeneity of NDDs. A molecular diagnosis was established in 28.6% of patients after high-depth sequencing and stringent variant filtering.

Compared to other available gene panel solutions for NDD molecular diagnosis, our panel has a higher diagnostic yield for both ID/GDD and ASD. As reported previously, a significantly higher diagnostic yield was observed: () in patients affected by ID/GDD compared to those affected only by ASD, and () in females despite the higher proportion of males among our patients. No differences in diagnostic rates were found between patients affected by different levels of ID severity. Interestingly, patients harboring pathogenic variants presented different phenotypic features, suggesting that deep phenotypic profiling may help in predicting the presence of a pathogenic variant.

Despite the high performance of our panel, whole exome-sequencing (WES) approaches may represent a more robust solution. For this reason, we propose the list of genes included in our customized gene panel and the variant filtering procedure presented here as a first-tier approach for the molecular diagnosis of NDDs in WES studies.