Monogenic defects in Russian children with autism spectrum disorders

Area of Science:

• Genetics
• Neurodevelopmental Disorders
• Pediatrics

Background:

• Autism spectrum disorders (ASD) affect over 1% of children globally, often co-occurring with intellectual disability and speech delay.
• The high heterogeneity and phenotypical overlap of ASD present challenges in identifying specific genetic determinants.
• Understanding the genetic basis of ASD is crucial for diagnosis and potential therapeutic strategies.

Purpose of the Study:

• To investigate the spectrum and frequency of rare genetic variants in ASD-associated genes within a Russian pediatric cohort.
• To identify monogenic causes and variants of unknown significance contributing to ASD.
• To assess the utility of clinical exome sequencing in diagnosing genetic causes of ASD.

Main Methods:

• Recruited 110 patients (106 families) with ASD, predominantly with co-occurring developmental delay or intellectual disability.
• Utilized chromosomal microarray analysis for patients with syndromic features.
• Performed clinical exome sequencing on remaining patients, focusing on rare variants (MAF ≤ 0.001) in high-confidence ASD-associated genes.

Main Results:

• Pathogenic copy number variations were identified in 7% of patients.
• Clinical exome sequencing detected pathogenic/likely pathogenic variants in 11% of cases, revealing various monogenic syndromes.
• Rare variants of unknown significance were found in 26% of patients across numerous ASD-associated genes, including recurrent variants in *TRIP12*, *AUTS2*, *ARID1B*, *PCDH19*, and *EP300*.
• Confirmed that hemizygous males with *PCDH19* variants can exhibit neurobehavioral abnormalities.

Conclusions:

• The genetic causes of ASD are highly diverse, underscoring the complexity of these neurodevelopmental disorders.
• Clinical exome sequencing is a valuable diagnostic tool for ASD, offering a viable alternative to whole-exome sequencing.
• Further research into variants of unknown significance is warranted to elucidate their role in ASD pathogenesis.