The Usefulness of a Targeted Next Generation Sequencing Gene Panel in Providing Molecular Diagnosis to Patients With a Broad Spectrum of Neurodevelopmental Disorders

Abstract

Background: Neurodevelopmental disorders comprise a clinically and genetically heterogeneous group of conditions that affect 2%–5% of children and represents a public health challenge due to complexity of the etiology. Only few patients with unexplained syndromic and non-syndromic NDDs receive a diagnosis through first-tier genetic tests as array-CGH and the search for FMR1 CGG expansion. The aim of this study was to evaluate the clinical performance of a targeted next-generation sequencing (NGS) gene panel as a second-tier test in a group of undiagnosed patients with NDDs.Method: A 221-gene next-generation sequencing custom panel was designed and used to analyze a cohort of 338 patients with a broad spectrum of NDDs (202 males and 136 females) including Intellectual Disability (ID), Autism Spectrum Disorders (ASD), Epilepsy, language and motor disorders.Results: A molecular diagnosis was established in 71 patients (21%) and a de novo origin was present in 38 (64.4%) of the available trios. The diagnostic yield was significantly higher in females than in males (29.4% vs. 15.3%; p = 0.0019) in particular in ASD (36.8% vs. 7.6%; p = 0.0026) and Epilepsy (38.9% vs. 14.4% p = 0.001). The most involved genes were SLC2A1, SCN1A, ANKRD11, ATP1A2, CACNA1A, FOXP1, and GNAS altered in more than two patients and accounting for the 19.7% of the diagnosis.Conclusion: Our findings showed that this NGS panel represents a powerful and affordable clinical tool, significantly increasing the diagnostic yield in patients with different form of NDDs in a cost- and time-effective manner without the need of large investments in data storage and bioinformatic analysis.

Autism spectrum disorders: an impaired glycolysis induces an ATP deficiency and a reduced cell respiration

“…At one end, we noticed a misexpression, usually an under-expression, of at least 2 of 4 glucose transporters in every patient. This finding is consistent with studies describing a link between neurodevelopmental disorders, including ASD, and gene anomalies, namely variants or deletions (Mellone et al 2022; Mir et al 2022; López-Rivera et al 2020; Lee, Smith, and Paciorkowski 2015; Redin et al 2014; Srour et al 2017). However, at the other end, no previous study reported an association between ASD and molecular anomalies for SLC16A9 and SLC16A14, two pyruvate transporters.…”

Genetic outcomes in children with developmental language disorder: a systematic review

“…Next generation sequencing (NGS) can detect underlying pathogenic gene variants. It has been demonstrated that NGS, analyzing a large number of genes simultaneously, proves to be highly efficient and cost-effective ( 72 , 73 ). By implementation of novel analysis tools, CNVs can also be detected by NGS.…”

Co-Occurrence of a Pathogenic HSD3B2 Variant and a Duplication on 10q22.3-q23.2 Detected in Newborn Twins with Salt-Wasting Congenital Adrenal Hyperplasia

“…In general, the joint detection of CNVs and SNVs (single nucleotide variants) should be performed in newborns with complex phenotypes, as it might disclose the co-presence of multiple genetic factors. Currently, such patients are diagnosed through a step by step approach, including aCGH [ 27 ], targeted gene panels [ 28 ], exome sequencing, and in some accurately selected cases Whole Genome Sequencing (WGS), which is still expensive and requires specialized bioinformatic skills. In the future, with the improvement of bioinformatic tools, training of specialized personnel, and cost reductions, the introduction of routine diagnostics of WGS, detecting any type of genetic alteration, will greatly improve the management of these patients.…”