Cryptic and complex chromosomal aberrations in early-onset neuropsychiatric disorders

Area of Science:

• Genetics
• Genomics
• Neuroscience

Background:

• Structural variations (SVs) are key genetic causes of neurodevelopmental and psychiatric disorders, but clinical screening is limited.
• Current methods like chromosomal microarray (CMA) and karyotyping miss certain SVs, including balanced chromosomal abnormalities (BCAs) and cryptic copy-number variants (CNVs).

Purpose of the Study:

• To evaluate whole-genome sequencing (WGS) with large-insert jumping libraries for comprehensive detection of both visible and cryptic SVs in youth with severe neuropsychiatric conditions.
• To assess the diagnostic yield and clinical significance of SVs identified by WGS.

Main Methods:

• Whole-genome sequencing (WGS) using large-insert jumping libraries was performed on 30 clinically referred youth with severe neuropsychiatric conditions.
• Detected SVs were filtered based on confidence and resolution thresholds.
• Genomic profiling was used to analyze complex rearrangements and compare findings with existing clinical CNV data.

Main Results:

• An average of 96 high-confidence SVs (>6,305 bp) and 111 lower-resolution SVs per person were detected.
• These SVs affected 3.8 Mb of genomic sequence, yielding 42 putative loss-of-function (LoF) or gain-of-function mutations per person.
• An estimated 80% of LoF variants were cryptic to clinical CMA. Complex rearrangements, including a recurrent inversion, were identified. Three SVs were deemed clinically significant.

Conclusions:

• WGS with large-insert jumping libraries provides a comprehensive approach to detect the full spectrum of SVs, including cryptic ones, in individuals with neuropsychiatric disorders.
• This method has the potential to improve diagnostic yield and understanding of the genetic basis of these conditions.
• Sequence-based delineation of the SV mutational spectrum should be explored for broader clinical diagnostic screening in youth referred for neuropsychiatric evaluation.