Monogenic defects in Russian children with autism spectrum disorders

Autism spectrum disorders (ASD) represent a substantial social problem affecting at least 1 in 100 children worldwide. These conditions are very often accompanied by intellectual disability (ID) and speech delay; thus, they can be considered within a clinical continuum of neurodevelopmental disorders. Given the high heterogeneity of ASD, the subjective nature of diagnostic criteria, and the presence of phenocopies, identifying genetic determinants of these disorders remains a challenge.

To investigate the spectrum and frequency of rare genetic variants in genes with proven association with ASD in Russian children.

110 patients from 106 families were recruited into the study (mean age at diagnosis 6 years; boy-to-girl ratio 3:1. Most of the patients (84%) demonstrated a combination of ASD with developmental delay (DD) or ID. Patients with syndromic features were subjected to the chromosomal microarray analysis. The remained children underwent clinical exome sequencing aimed at identifying presumably monogenic causes of ASD. The study focused on rare (minor allele frequency ≤ 0.001) variants affecting high-confidence ASD-associated genes.

Pathogenic copy number variations were detected in three (7%) of the patients examined. Clinical exome sequencing revealed pathogenic/likely pathogenic variants in 12 of 105 cases (11%), indicating the presence of monogenic syndromes with established clinical significance (Pitt-Hopkins syndrome, ZTTK syndrome, syndromic X-linked ID of Billuart type, Snijders-Blok-Campeau, Helsmoortel-van der Aa, Coffin-Siris, Clark-Baraitser, Keefstra syndromes, etc.). In addition, 27 patients (26%) had 37 rare variants of unknown clinical significance in DSCAM, SHANK2, AUTS2, ADNP, ANKRD11, APBA2, ARID1B, ASTN2, ATRX, SCN1A, CHD2, DEAF1, EHMT1, GRIN2B, NBEA, NR4A2, TRIO, TRIP12, POGZ, EP300, FOXP1, PCDH19, GRIN2A, NCKAP1, and CHD8 genes. No specific variant was detected more than once in unrelated patients. Among the genes with rare variants found in 2 or more patients were TRIP12 (n = 4), AUTS2 (n = 3), ARID1B (n = 3), PCDH19 (n = 3), EP300 (n = 3), TRIO (n = 2), ASTN2 (n = 2), EHMT1 (n = 2), and CHD2 (n = 2). Of note, 5 male ASD/DD patients from 3 unrelated families had PCDH19 missense variants, confirming that at least some hemizygous males with non-mosaic PCDH19 variants may present with neurobehavioral abnormalities. These variants did not cause epilepsy restricted to females in patients' mothers or sisters.

These data confirm a tremendous diversity of genetic causes of ASD. Clinical exome sequencing may serve as a reasonable alternative to whole-exome sequencing.