A copy number variation morbidity map of developmental delay

Abstract

To understand the genetic heterogeneity underlying developmental delay, we compare copy-number variants (CNVs) in 15,767 children with intellectual disability and various congenital defects to 8,329 adult controls. We estimate that ~14.2% of disease in these individuals is due to large CNVs > 400 kbp. We find greater CNV enrichment in patients with craniofacial anomalies and cardiovascular defects than epilepsy or autism. We identify 59 pathogenic CNVs including 14 novel or previously weakly supported candidates. We refine the critical interval for several genomic disorders such as the 17q21.31 microdeletion syndrome and identify 940 candidate dosage-sensitive genes. We also develop methods to opportunistically discover small, disruptive CNVs within the large and growing diagnostic array datasets. This evolving CNV morbidity map combined with exome/genome sequencing will be critical for deciphering the genetic basis of developmental delay, intellectual disability, and autism spectrum disorders.

Copy number variations in 375 patients with oesophageal atresia and/or tracheoesophageal fistula

“…For instance, the 15q13.3 deletion seen in male patient SKZ_0856 overlaps with a known deleterious CNV 18 seen in patients with a highly variable phenotype, which include mild to moderate intellectual disability and variable dysmorphic features. 49 Other CNVs with overlap in our study are the gain involving FAT1 on 4q35.2 in patient SKZ_1248, the 6p22 deletion in patient SKZ_1856, 18 the 2q13 duplication seen in patient DE61OSOUKBD100197 19 and 22q11 gain 18 seen in female patient SKZ_1780. Interestingly, two additional published EA/TEF patients have a 22q11 duplication overlapping the one seen in patient SKZ_1780.…”

“…We classified CNVs to be rare if they were absent or present once in our in-house cohort of unaffected individuals (n = 3235 individuals). We searched for overlap in large CNV cohorts of control individuals published by Cooper et al, 18 Coe et al 19 and Kaminsky et al 20 We also evaluated the CNVs significantly different in these studies between patients and controls. To confirm the putative de novo and putative deleterious CNVs, patient and parental DNAs were tested with either additional SNP array, real-time quantitative PCR, fluorescence in situ hybridization (FISH) and/or multiplex amplicon quantification (MAQ; Multiplicon N.V., Gent, Belgium).…”

“…However, we can look for overlap with CNVs described previously in CNV burden studies and inspect whether OA/TOF has been described in patients with such a CNV. Therefore, we used the CNV burden studies published by Cooper et al, 18 Coe et al 19 and Kaminsky et al 20 as a proxy (developmental delay vs controls) after filtering all common CNVs. Here, they did use sufficient numbers of patients and controls and find an enrichment of a small number of loci in this heterogeneous patient population of developmental delay and/or congenital anomalies.…”

The Immune Signaling Adaptor LAT Contributes to the Neuroanatomical Phenotype of 16p11.2 BP2-BP3 CNVs

“…2 Deletions (MIM: 611913) and duplications (MIM: 614671) of the 16p11.2 600 kb BP4-BP5 region are among the most frequent causes of neurodevelopmental and neuropsychiatric disorders. [2][3][4][5][6][7] They are associated with Rolandic epilepsy 8 and mirror phenotypes on body mass index (BMI), head circumference (HC), and brain volume. [9][10][11][12] The deletion of the distal 16p11.2 220 kb BP2-BP3 locus (MIM: 613444) is likewise enriched in individuals with early-onset obesity and is also associated with developmental delay, intellectual disability, autism spectrum disorders (ASD), and schizophrenia.…”

“…[9][10][11][12] The deletion of the distal 16p11.2 220 kb BP2-BP3 locus (MIM: 613444) is likewise enriched in individuals with early-onset obesity and is also associated with developmental delay, intellectual disability, autism spectrum disorders (ASD), and schizophrenia. 3,[13][14][15][16] Moreover, the BP2-BP3 deletion and reciprocal duplication have mirror effects on BMI and HC, whereas the duplication of this interval, like the deletion, is associated with ASD. 17 Thus, genomic rearrangements at both the 16p11.2 600 kb BP4-BP5 and the 220 kb BP2-BP3, two loci 650 kb apart, present similar clinical patterns: large effect sizes on BMI and HC, as well as association with ASD and other neuropsychiatric traits.…”