Genomic diagnosis for children with intellectual disability and/or developmental delay

Area of Science:

• Genetics
• Genomics
• Developmental Biology

Background:

• Developmental disabilities stem from diverse genetic origins requiring precise identification for accurate diagnosis.
• Genomic data from 371 individuals with developmental disabilities were analyzed, including 309 proband-parent trios.

Purpose of the Study:

• To identify genetic causes of developmental disabilities.
• To evaluate the effectiveness of large-scale sequencing, including whole-genome sequencing (WGS), as a diagnostic tool.
• To improve the interpretation and reclassification of genetic variants.

Main Methods:

• Whole-exome sequencing (WES) was performed on 365 individuals (127 affected).
• Whole-genome sequencing (WGS) was performed on 612 individuals (244 affected).
• Systematic reanalysis of genetic variants was conducted to improve interpretation.

Main Results:

• Pathogenic or likely pathogenic variants were identified in 27% of cases (100 individuals).
• Variants of uncertain significance (VUS) were found in an additional 11.3% (42 individuals).
• Reanalysis led to reclassification of 15 variants, improving diagnostic yield for families with initially negative or VUS results.

Conclusions:

• Large-scale sequencing, especially WGS in proband-parent trios, is a valuable diagnostic tool for pediatric neurological diseases.
• Ongoing reanalysis and data sharing are crucial for advancing genetic understanding and diagnosis.
• This study highlights the importance of genomic data for both clinical diagnosis and research progress.