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 gene is unclear. We created an expanded CNV morbidity map from 29,085 children with developmental delay versus 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 ten genes enriched for putative loss of function. Patient follow-up on a subset identified new clinical subtypes of pediatric disease and the genes responsible for disease-associated CNVs. This includes haploinsufficiency of SETBP1 associated with intellectual disability and loss of expressive language and truncations of ZMYND11 in patients with autism, aggression and complex neuropsychiatric features. This combined CNV and SNV approach facilitates the rapid discovery of new syndromes and neuropsychiatric disease genes despite extensive genetic heterogeneity.

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.…”

“…LINC00114 is located between V-Ets Avian Erythroblastosis Virus E26 Oncogene Homolog (ERG) and V-Ets Avian Erythroblastosis Virus E26 Oncogene Homolog 2 (ETS2) within the Down's syndrome critical region. 19 The girl has OA/TOF and anal stenosis as main additional features. She does not have distinct Down's syndrome facial features or mental retardation.…”

“…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.…”

9q33.3q34.11 microdeletion: new contiguous gene syndrome encompassing STXBP1, LMX1B and ENG genes assessed using reverse phenotyping

“…23 It interacts with SETBP1, SET-binding protein, whose haploinsufficiency had been reported in association with ID and speech delay. 24 Recently, a de novo frameshift deletion resulting in a premature stop codon in SET has been identified in a patient with congenital microcephaly, normal brain and moderate ID. 25 SET is deleted in two of our four patients, but it is difficult to determine the weight of SET deletion in the phenotype of our patients, relative to the loss-of-function of other STXBP1, SPTAN1 and DNM1.…”