Table 1.
Overview of established and assumed imprinting disorders for which prenatal features and complications have been reported. (a These genes on chromosome 7 are targeted using routine diagnostic testing, but their role in the etiology of SRS is currently unclear. b The MEG3/DLK1:IG-DMR is the more relevant DMR in 14q32, but is not routinely targeted due to its molecular complexity. c This DMR has been suggested to be relevant to aupd(16)mat phenotype. d Reports on placental morphology for upd(16)mat are not available, but due to the origin of upd(16)mat from trisomy 16 rescue and associated placental trisomy 16 (mosaicism), a placental phenotype might be delineated. NR, not yet reported; ND, not determined; upd(6)pat, paternal uniparental disomy of chromosome 6 (abbrevations are similar for other upds); DMR, differentially methylated region; LOM, loss of methylation; GOM, gain of methylation; LOI, loss of imprinting; GoF, gain of function; LoF, loss of function; SNVs, single nucleotide variant; CNV, copy number variant).
| Imprinting Disorder OMIM |
Chromosome | ImpDis-Specific DMR | Intrauterine Phenotype | Preterm Delivery | Placental Phenotype | Molecular Defects | Frequencies among Molecularly Confirmed Cases |
|---|---|---|---|---|---|---|---|
| Transient neonatal diabetes mellitus (TNDM) 601410 |
6q24 | PLAGL1:alt-TSS-DMR | Growth restriction, abdominal wall defects | 30% < 37 gw [6] | upd(6)pat | 41% | |
| dup(6q24)pat | 29% | ||||||
| PLAGL1:alt-TSS-DMR: LOM | 30% | ||||||
| Silver–Russell syndrome (SRS) 180860 |
7 | GRB10:alt-TSS-DMR a, MEST:alt-TSS-DMR a | Growth restriction | Yes [7] | Calcification [8] | upd(7)mat | 15.8% |
| 11p15.15 | H19/IGF2:IG-DMR | Mice: placental undergrowth, defective vascularization [9] | upd(11p15)mat | single cases | |||
| del(11p15)pat | single cases | ||||||
| dup(11p15)mat | 2.3% | ||||||
| H19/IGF2:IG:DMR: LOM | 67.6% | ||||||
| CDKN1C (GoF), IGF2, HMGA2, PLAG1: SNVs, CNVs | several cases | ||||||
| Beckwith–Wiedemann syndrome (BWS) 130650 |
11p15.5 | H19/IGF2:IG-DMR | Overgrowth, polyhydramnion, abdominal wall defects, placental mesenchymal dysplasia, (mother: preeclampsia) | Yes [10] | Placental mesenchymal dysplasia; placentomegaly | upd(11p15)pat | 19.5% |
| KCNQ1OT1:TSS-DMR | dup(11p15)pat | <1% | |||||
| H19/IGF2:IG-DMR: GOM | 11.8% | ||||||
| KCNQ1OT1:TSS-DMR: LOM | 64.0% | ||||||
| CDKN1C: (LoF) SNVs: sporadic, familial | 5%, 40% | ||||||
| Temple syndrome (TS14) 616,222 |
14q32 | MEG3/DLK1:IG-DMR | Growth restriction | 30% [11] | upd(14)mat | 54.0% | |
| MEG3:TSS-DMR | del(14q32)pat | 12.2% | |||||
| MEG3/DLK1:IG-DMR: LOM | 33.8% | ||||||
| Kagami–Ogata syndrome (KOS14) 608149 |
14q32 | MEG3/DLK1:IG-DMR b | Overgrowth, polyhydramnion, abdominal wall defects, placentomegaly | Yes [11] | Placentomegaly | upd(14)pat | 51.5% |
| MEG3:TSS-DMR b | del(14q32)mat | 21.9% | |||||
| MEG3/DLK1:IG-DMR: GOM | 26.6% | ||||||
| Prader–Willi syndrome (PWS) 176270 |
15q11q13 | SNRPN:alt-TSS-DMR | SGA: 53% [12] | 26% [13] | del(15q11q13)pat | 70–75% | |
| upd(15)mat | 25–30% | ||||||
| SNURF:TSS-DMR: GOM | 1% | ||||||
| upd(16)mat | 16 | ZNF597:TSS-DMR c | Growth restriction (mother: preeclampsia [14]) | Small placenta? d [15] | upd(16)mat | 100% | |
| Pseudohypoparathyroidism: | 20q13 | GNAS-NESP:TSS-DMR | Growth restriction | NR | |||
| PHP1B (iPPSD3) 603233 |
upd(20q13)pat | 2.7% | |||||
| GNAS-AS1:TSS-DMR | broad LOI (all GNAS DMRs) | 38% | |||||
| GNAS-XL:Ex1-DMR | broad LOI (all GNAS DMRs) | rare | |||||
| GNAS A/B:TSS-DMR | GNAS A/B:TSS-DMR: LOM | 13.5% | |||||
| PHP1A/PPHP/POH (iPPSD2) 103580/612463 |
GNAS: LoF SNVs and CNVs | 37.7% | |||||
| Mulchandani–Bhoj–Conlin syndrome (MBCS) 617352 |
20 | ? | Growth restriction [16] | NR | upd(20)mat | ND |