Table 1. Identification of candidate HAR mutations.
The location of the HAR mutations with target genes and location relative to refSeq gene annotations with () indicating brain expression. Expression profiles were obtained from BrainSpan’s normalized LCM microarray values of the developing and adult human brain (Hughes-Benzie et al., 1996).
| Location (hg19) | Reference Allele | Alternate Allele | Gene Location | Interacting Gene* (brain expression) | Potential Target Genes (normalized brain expression level) | Family ID | Predicted Regulatory Activity+ | Phenotype | Diseases & Function |
|---|---|---|---|---|---|---|---|---|---|
| 7:101249641 | G | A | Intergenic | CUX1 (26.5) | LINC01007,MYL1 0 (0.3) | AU-20400 AU-13200 |
Brain enhancer | ASD with ID, (Epilepsy in 1 child) | Regulates synaptic spines and dendritic complexity in upper cortical layers (CUX1)(Cubelos et al., 2014; Nieto et al., 2004) |
| 5:87776690 | T | G | Intergenic | MEF2C (323.5), TMEM161B (2.9) | LINC00461 (88.0) | AU-9200 | Brain enhancer | ASD with ID, dysmorphic features (small pointed chin, large ears) | ASD, ID, dysmorphic features (e.g., small chin, prominent forehead, large ears)(Bienvenu et al., 2013; Morrow et al., 2008) |
| 1:97463563 | TGGGTAC | TA | Intergenic | PTBP2 (62.5) | DPYD (4.0) | AU-4700 | Brain enhancer | ASD with ID | Brain-specific splicing regulator; regulates neurogenesis; locus associated with ID (PTBP2) |
| X:132496780 | T | C | Intronic | GPC4 (89.9) | AU-16100 | Brain enhancer | ASD with ID | Regulates synapses (Kalscheuer et al., 2003); Simpson-Golabi-Behmel syndrome (ID in 47%)(Hughes-Benzie et al., 1996) | |
| X:132496834 | GT | G | Intronic | GPC4 (89.9) | AU-23200 | Brain enhancer | ASD with ID, Epilepsy, ACC | ||
| X:18445494 | G | GAGCTGTAG | Promoter | CDKL5 (28.7) | AU-13500 AU022203 | Brain enhancer | ASD with ID | Autism, Rett Syndrome, epilepsy and Angelman syndrome(Avino and Hutsler, 2010; Hutsler and Casanova, 2015) | |
| 4:145793760 | C | T | Intergenic | HHIP (13.8),ANAPC10 (5.0) | AU-13700 | Enhancer (stem cell, fetal lung) | ASD with ID | Deletion associated with ID (ANAPC10) | |
| 7:39073195 | T | TC | Intronic | POU6F2 (4.4),VPS41 (27.6) | AU-19000 | Brain enhancer | ASD | Strong association to ASD in GWAS and Wilms Tumor (POU6F2)(Mizuno et al., 2006) | |
| 17:55675858 | C | G | Intronic | USP32 (22.3) | MSI2 (21.1) | AU-24600 | Brain enhancer | ASD with ID | Regulation of neural precursors during CNS development (MSI2)(Gusev et al., 2014) |
| X:136372832 | C | T | Intergenic | GPR101 (11),ZIC3 (57.8) | AU-21500 | Repressed Polycomb (brain) | PDD-NOS, ADHD | Involved in adrenergic receptor activity in brain (GPR101); X-linked visceral heterotaxy and cerebellar dysgenesis (ZIC3) | |
| 4:30653187 | T | G | Intergenic | MIR4275,PCDH7 (29.7) | AU-5000 | Low H3K9ac in derived neural progenitor | ASD | Possible ASD; high expression in developing brain; regulated by MECP2 during establishment of synaptic connections (PCDH7) | |
| 5:39527315 | G | A | Intergenic | DAB2 (7.9) | PTGER4 (4.3) | AU-26800 | Enhancer: HESC, Mesendoderm, Trophoblast | ASD with ID | Essential for embryonic development (DAB2) |
Interacting genes determined from 4C-sequencing, ChIA-Pet (Fullwood et al., 2010; Li et al., 2010) and HiC data (Jin et al., 2013). The interaction distances are limited to 1Mb. Potential interacting genes represent those containing intronic HARs and, for intergenic HARs, the closest flanking upstream and downstream genes without clear link to HAR in existing chromatin interaction data. +Predicted regulatory activity was determined using Capra et. al. and ChromHMM predictions from Epigenomics Roadmap. See also Figure S5.
Avino, T.A., and Hutsler, J.J. (2010). Abnormal cell patterning at the cortical gray-white matter boundary in autism spectrum disorders. Brain research 1360, 138–146.
Bienvenu, T., Diebold, B., Chelly, J., and Isidor, B. (2013). Refining the phenotype associated with MEF2C point mutations. Neurogenetics 14, 71–75.
Cubelos, B., Briz, C.G., Esteban-Ortega, G.M., and Nieto, M. (2014). Cux1 and Cux2 selectively target basal and apical dendritic compartments of layer II–III cortical neurons. Developmental neurobiology.
Gusev, A., Lee, S.H., Trynka, G., Finucane, H., Vilhjalmsson, B.J., Xu, H., Zang, C., Ripke, S., Bulik-Sullivan, B., Stahl, E., et al. (2014). Partitioning heritability of regulatory and cell-type-specific variants across 11 common diseases. American journal of human genetics 95, 535–552.
Hughes-Benzie, R.M., Pilia, G., Xuan, J.Y., Hunter, A.G., Chen, E., Golabi, M., Hurst, J.A., Kobori, J., Marymee, K., Pagon, R.A., et al. (1996). Simpson-Golabi-Behmel syndrome: genotype/phenotype analysis of 18 affected males from 7 unrelated families. American journal of medical genetics 66, 227–234.
Hutsler, J.J., and Casanova, M.F. (2015). Cortical Construction in Autism Spectrum Disorder: Columns, Connectivity and the Subplate. Neuropathology and applied neurobiology.
Kalscheuer, V.M., Tao, J., Donnelly, A., Hollway, G., Schwinger, E., Kubart, S., Menzel, C., Hoeltzenbein, M., Tommerup, N., Eyre, H., et al. (2003). Disruption of the serine/threonine kinase 9 gene causes severe X-linked infantile spasms and mental retardation. American journal of human genetics 72, 1401–1411.
Mizuno, A., Villalobos, M.E., Davies, M.M., Dahl, B.C., and Muller, R.A. (2006). Partially enhanced thalamocortical functional connectivity in autism. Brain research 1104, 160–174.
Morrow, E.M., Yoo, S.Y., Flavell, S.W., Kim, T.K., Lin, Y., Hill, R.S., Mukaddes, N.M., Balkhy, S., Gascon, G., Hashmi, A., et al. (2008). Identifying autism loci and genes by tracing recent shared ancestry. Science 321, 218–223.
Nieto, M., Monuki, E.S., Tang, H., Imitola, J., Haubst, N., Khoury, S.J., Cunningham, J., Gotz, M., and Walsh, C.A. (2004). Expression of Cux-1 and Cux-2 in the subventricular zone and upper layers II–IV of the cerebral cortex. The Journal of comparative neurology 479, 168–180.