Whole-Genome Sequencing Enables Genetic Diagnosis in Neurodevelopmental Disorders

Neurodevelopmental disorders include autism spectrum disorder and intellectual disability and can be difficult to diagnose because clinical presentations vary widely. In Italy, approximately 1% of children aged 7–9 are affected, underscoring the need for precise etiologic workups. Molecular investigations can help identify underlying causes and inform care and follow-up. Researchers now describe a genomics-based approach that clarified diagnoses for multiple families in a regional cohort.

Italian Institute of Technology (IIT) researchers at the Center for Clinical and Computational Genomics (C3G) in Aosta, together with the regional health authority Azienda USL della Valle d'Aosta, used whole-genome sequencing (WGS) to characterize 110 families from the Aosta Valley, involving a total of 300 individuals.Published in the journal npj Genomic Medicine, the work is presented as the first of its kind in Italy and yielded genetic diagnoses in 29 families whose cases previously lacked etiologic clarity. The approach examines the complete genomes of affected children and their parents to pinpoint variants linked to these conditions.

Analyses generated approximately 26 million variants across the cohort, from which clinically and research‑relevant findings were extracted. The team applied artificial intelligence (AI) algorithms to highlight variants in genes directly implicated in neurodevelopmental disorders and to define inheritance patterns in specific cases. The study began in May 2022 within the 5000genomi@VdA project, reflecting an ongoing regional effort to apply advanced genomics in pediatric evaluation.

Participants were organized into three groups to capture the spectrum of presentations typically seen in these disorders. Among the young people enrolled, 40 had autism spectrum disorder (ASD) without additional disabilities, most of whom had characteristics consistent with high‑functioning autism. Twenty‑seven had a diagnosis of intellectual disability (ID), and the remaining participants were diagnosed with both ASD and ID.

Beyond definitive diagnoses, investigators identified several alterations in genes not previously associated with these disorders. In one patient with autism and motor difficulties, a mutation in the KALRN gene, which plays an important role in the development of neurons and their connections, was detected; the team believes this gene could be added to lists associated with neurodevelopmental disorders. Newly identified genes and variants could support reassessment of patients with negative prior tests and improve the accuracy of future diagnostic workflows.

"One of the most meaningful results of this study was that we were able to provide long-awaited answers to many families by identifying the genetic cause of their condition. In addition to improving our understanding of genetic risk, these diagnoses can help inform care decisions and follow-up planning," said Laure Obino, director of the Struttura Complessa (SC) di Neuropsichiatria Infantile (NPI) in the Azienda USL della Valle d'Aosta (Complex Structure of child neuropsychiatry at the regional health authority).

"We are extremely proud of this collaboration between IIT's C3G and the AUSL Valle d'Aosta, which has produced results of real clinical and scientific importance. It demonstrates the impact that advanced genomics can have in clinical practice, helping make health care more personalized, predictive and better aligned with patients' needs," said Stefano Gustincich, director of the Center for Clinical and Computational Genomics at IIT in Aosta.

Related Links
Italian Institute of Technology