Table 1:
Examples of HARs, VEs, and CNEs that have more variants found in cases compared to controls.
| Element | Cohort | Variants found in cases and not controls (hg38) | Number of cases with variants | Number of controls with variants | Potential target genes | Disease and functional associations |
|---|---|---|---|---|---|---|
|
| ||||||
| HAR1362 | NIMH | chr2:44493977 (G->A) chr2:44494211 (G->A) |
2 | 0 | CAMKMT, SIX3*, PREPL | Required for development of anterior neural structures (SIX3) (Lagutin et al., 2003) |
| HAR1479 | NIMH | chr2:145221015 (G->A) chr2:145221025 (C->A) |
2 | 0 | ZEB2*, GTDC1, ARHGAP15 | Mutations cause Mowat-Wilson syndrome (ZEB2) (Epifanova et al., 2019) |
| HAR3094 | NIMH | chrX:30371544 (G->A) chrX:30371553 (A->G) |
2 | 0 | NR0B1*, CXorf21, IL1RAPL1*, MAGEB1, MAGEB2, MAGEB3 | Mutations associated with ASD and ID (IL1RAPL1) (Bhat et al., 2008; Mikhail et al., 2011) |
| HAR3134 | HMCA, NIMH | chrX:122662679 (T->C) chrX:122662692 (A->G) |
3 | 0 | GRIA3* | Mutations associated with ASD, X-linked syndromic ID, and schizophrenia (GRIA3) (Wu et al., 2007; Guilmatre et al., 2009; Singh et al., 2022) |
| HAR3162 | NIMH | chrX:144625836 (G->C) chrX:144625865 (A->G) chrX:144625878 (G->A) chrX:144625958 (G->A) |
4 | 1 | SLITRK2, SLITRK4 | Mutations associated with ID, DD, and neuropsychiatric symptoms (SLITRK2) (El Chehadeh et al., 2022) |
| VE15 | NIMH | chr1:10737260 (T->C) chr1:10737343 (G->C) |
2 | 0 | CASZ1* | Mutations associated with ASD, ID, and DD (CASZ1) (Coe et al., 2019) |
| VE162 | NIMH | chr1:213425381 (T->C) chr1:213425533 (A->C) |
2 | 0 | PROX1*, RPS6KC1, SMYD2 | Regulates interneuron differentiation (PROX1) (Miyoshi et al., 2015) |
| VE235 | NIMH | chr2:63049151 (C->A) | 1 | 0 | OTX1* | Mutations associated with ASD (Liu et al., 2011) |
| VE462 | NIMH | chr3:147847042 (T->C) chr3:147847133 (T->C) chr3:147847216 (T->C) |
3 | 0 | ZIC1*, ZIC4 | Involved in medial telencephalon development (ZIC1) (Inoue et al., 2007) |
| VE644 | NIMH | chr5:88396771 (G->T) chr5:88397035 (C->T) |
2 | 0 | MEF2C*, TMEM161B | Mutations associated with ASD (MEF2C) (Novara et al., 2010); Mutations associated with polymicrogyria (TMEM161B) (Akula et al., 2023; Wang et al., 2023) |
| CNE6445 | HMCA | chr17:69607668 (C->T) | 2 | 0 | KCNJ16, MAP2K6*, KCNJ2 | Member of MAP/ERK pathway, which has been linked to changes in social behavior (MAP2K6) (Albert-Gasco et al., 2020) |
| CNE7200 | HMCA | chrX:18424091 (T->C) | 2 | 0 | CDKL5* | Mutations associated with Rett syndrome and epilepsy (CDKL5) (Weaving et al., 2004) |
Full list in Table S4. Asterisks indicate genes that are loss-of-function intolerant (pLI > 0.9) (Lek et al., 2016). Potential target genes were determined by gene proximity and by location within the same topologically associated domain (Dixon et al., 2012, 2015). For HAR3162, one variant was observed in both a case and a control individual in HMCA and was excluded from the table. Coordinates are in hg19. ID: intellectual disability. DD: developmental disorders.