Sequencing Chromosomal Abnormalities Reveals Neurodevelopmental Loci that Confer Risk across Diagnostic Boundaries

Abstract

SUMMARY Balanced chromosomal abnormalities (BCAs) represent a reservoir of single gene disruptions in neurodevelopmental disorders (NDD). We sequenced BCAs in autism and related NDDs, revealing disruption of 33 loci in four general categories: 1) genes associated with abnormal neurodevelopment (e.g., AUTS2, FOXP1, CDKL5), 2) single gene contributors to microdeletion syndromes (MBD5, SATB2, EHMT1, SNURF-SNRPN), 3) novel risk loci (e.g., CHD8, KIRREL3, ZNF507), and 4) genes associated with later onset psychiatric disorders (e.g., TCF4, ZNF804A, PDE10A, GRIN2B, ANK3). We also discovered profoundly increased burden of copy number variants among 19,556 neurodevelopmental cases compared to 13,991 controls (p = 2.07×10−47) and enrichment of polygenic risk alleles from autism and schizophrenia genome-wide association studies (p = 0.0018 and 0.0009, respectively). Our findings suggest a polygenic risk model of autism incorporating loci of strong effect and indicate that some neurodevelopmental genes are sensitive to perturbation by multiple mutational mechanisms, leading to variable phenotypic outcomes that manifest at different life stages.

Detection of copy-number variation in AUTS2 gene by targeted exonic array CGH in patients with developmental delay and autistic spectrum disorders

“…30,32,34,38 Our results are consistent with this observation as patients 3 and 4 with duplication of exon 5 have ASDs. Both these duplications are not expected to alter the reading frame, but can result in addition of amino-acid residues to the amino terminus of the protein.…”

“…25 Haploinsufficiency of AUTS2 (three reports of apparently balanced translocation and two reports of inversion) has been associated with ASDs, ID, seizures, and attention deficit hyperactivity disorder. [26][27][28][29][30][31]34 Sultana et al 30 reported monozygotic twins with ID and autism with an apparently balanced t(7;20) (q11.2; p11.2) that disrupted AUTS2. Kalscheuer et al 32 described translocations involving AUTS2 in three unrelated individuals with mild to moderate ID.…”

“…An inversion disrupting both the AUTS2 and contactin-associated protein-like 2 (CNTNAP2) genes was reported in a child with ASD and ID. 31 More recently, by sequencing patients with balanced chromosomal abnormalities, Talkowski et al 34 showed the disruption of AUTS2 in a subject with ASD, mild learning disability, poor oral motor coordination, tongue protrusion, and flexion contractures. The disruption of AUTS2 in this patient because of an inversion was in intron 4 with the other breakpoint disrupting PTPRN2.…”

“…The oligonucleotide coverage in the 180k exon-targeted array clearly shows more oligos per exon as compared to the 105k genome array. The previously published reports on either translocation breakpoints (Huang et al, 33 Sultana et al, 30 Kalscheuer et al 32 ) or inversion breakpoints (Talkowski et al, 34 Bakkaloglu et al 31 …”

Discovery of Rare Mutations in Autism: Elucidating Neurodevelopmental Mechanisms

“…Recent studies of simplex families using microarrays with greater resolution found a burden rate of de novo CNVs from 5.8-7.9% in probands to 1.7-2.0% in unaffected siblings [97,98]. Furthermore, an increased CNV burden was identified in the same loci encompassing balanced chromosomal abnormalities, such as translocations and inversions, in an autism/neurodevelopmental disorder cohort [99].…”