Refining analyses of copy number variation identifies specific genes associated with developmental delay

Abstract

Copy number variants (CNVs) are associated with many neurocognitive disorders; however, these events are typically large, and the underlying causative genes are unclear. We created an expanded CNV morbidity map from 29,085 children with developmental delay in comparison to 19,584 healthy controls, identifying 70 significant CNVs. We resequenced 26 candidate genes in 4,716 additional cases with developmental delay or autism and 2,193 controls. An integrated analysis of CNV and single-nucleotide variant (SNV) data pinpointed 10 genes enriched for putative loss of function. Follow-up of a subset of affected individuals identified new clinical subtypes of pediatric disease and the genes responsible for disease-associated CNVs. These genetic changes include haploinsufficiency of SETBP1 associated with intellectual disability and loss of expressive language and truncations of ZMYND11 in individuals with autism, aggression and complex neuropsychiatric features. This combined CNV and SNV approach facilitates the rapid discovery of new syndromes and genes involved in neuropsychiatric disease despite extensive genetic heterogeneity.

Figure 1. Truncating SETBP1 mutations and phenotypes

CNV data define a focal CNV region around SETBP1 (a). Combining a focal de novo deletion observed in our study (9886269) and CNVs from Filges and Marseglia et al.^, (red bars) highlights minimal common regions, including SETBP1 and LOC101927921. Targeted resequencing identified eight truncating variants in SETBP1 and none in controls. Integration of published exome data identified one additional case, and no truncating events in controls (b). Phenotypic assessment of these cases identified a recognizable phenotype (c-d), including IQ deficits ranging from mild to severe, impaired speech, and distinctive facial features. See the Supplementary Note for additional patient photos and write-ups. We obtained informed consent to publish the photographs.

Figure 2. Truncating ZMYND11 mutations and phenotypes

CNV data refines a focal CNV deletion region (red bars) containing two genes: ZMYND11 and DIP2C (a). Targeted resequencing identified five truncating variants and one single amino acid deletion predicted to behave as LoF variants by removing a critical binding residue in the MYND domain (Gln587) (b). Analysis of control resequencing and exome data identified no additional truncating events in ZMYND11 but highlighted two truncating mutations in DIP2C. Phenotypic assessment revealed a consistent phenotype characterized by mild ID concurrent with speech and motor delays, as well as complex neuropsychiatric behavioral and characteristic facial features (c-d). See the Supplementary Note for additional patient photos and write-ups. We obtained informed consent to publish the photographs.