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ABOUT
IMPRINTING
"Causative trans-acting factors in imprinting disorders have the potential to globally dysregulate epigenetic processes, thus affecting multiple DMRs across the genome. This is called a multi-locus imprinting disturbance (MLID). MLID is detected in over 10 % of patients with imprinting disorders such as TNDM, BWS, and SRS, which are frequently caused by epigenetic errors. It is often observed only in a fraction of somatic cells. Similar to UPDs, the mosaic nature of MLID argues for an origin of the underlying defect early in development." (Cited from {1279})
In 12/39 cases with UPD in any of the imprinted chromosomes (30.8%), skewed X-chromosome inactivation was observed {1176}.
In babies born after applying assisted reproductive techniques imprinting is 15x more frequent than in babies born after natural conception {879}; for BWS it was determined a 10 fold risk in ART - but no clear data on how many were due to UPD {1012}.
In {1227} the theory of Denise Barlow from 1993 is again revisited, where he proposed that genomic imprinting might have arisen from a host defense mechanism designed to inactivate retrotransposons.
Summary of all known imprinting disorders by 2016 see {987}.
Summary of all potentially imprinted regions in human (on all chromosomes) see {1074}.
A 'high-resolution map of genomic imprinting' was published in 2019 {1140}.
For known imprinted genes see http://www.geneimprint.com/site/genes-by-species.Homo+sapiens or http://igc.otago.ac.nz/Search.html.
Diagnostics for imprinting disorders is reviewed in 2020 in {1280}
It turns out that imprinting disorders show overlapping phenotypes {1266}.
Also, UPD(all)pat leads primarily to BWS like symptoms and UPD(all)mat leads to SRS-like phenotype.
First step towards a consensus strategy for multi-locus diagnostic testing of imprinting disorders were published in 2022 {1385}.
The following list of imprinting disorders is based on {1280; 1281}
(abbreviations in Table below: alt = altered; DMR = differentially methylated region; Ex1 = exon 1; GOM = gain of methylation, hypermethylation;
LOM = loss of methylation, hypomethylation; TSS = alternative transcription start site)
| imprinting
disorder |
gene(s)
involved |
locus |
mosaic |
mechanisms |
| Transient Neonatal Diabetes
mellitus (TNDM)(familial) |
PLAGL:alt-TSS-DMR, LOM* ZFP57+ |
6q24 |
no |
UPD(6)pat dup(6q)pat imprinting center defect* single nucleotid variant+ |
| Birk-Barel intellectual
disability syndrome (BBIDS) |
KCNK9+ | 8q24 |
no |
single nucleotid variants+ |
| Silver-Russell syndrome (SRS) |
GRB10:alt-TSS-DMR, GOM* |
7 |
no |
UPD(7)mat dup(7p and or q)mat imprinting center defect* |
| HG19/IGF2:TSS-DMR, LOM* KCNQ10T1:TSS-DMR, GOM* CDKN1C+ IGF2+ HMGA2+ PLAG1+ |
11p15.5 |
yes |
UPD(11p15)mat dup(11p)mat imprinting center defect* single nucleotid variant+ |
|
| Beckwith-Wiedemann syndrome
(BWS) |
GRB10:alt-TSS-DMR, GOM* HG19/IGF2:TSS-DMR, GOM* KCNQ10T1:TSS-DMR, LOM* CDKN1C+ mat |
11p15.5 |
yes |
UPD(11p15)pat dup(11p)pat imprinting center defect* single nucleotid variant+ |
| no syndrome yet but imprinting |
RB1 |
13q14.2 |
no |
UPD(13)mat
{1372} |
| Temple syndrome (TS14) |
MEG3/DLK1:TSS-DMR,
LOM* |
14q32 |
no |
UPD(14)mat del(14q32)pat imprinting center defect* |
| Kagami-Ogata syndrome (KOS14) |
MEG3/DLK1:TSS-DMR, GOM* | 14q32 | yes |
UPD(14)pat del(14q32)mat imprinting center defect* |
| (familial) Central Precocious
Puberty (CPPB) |
DLK1+ mat | 14q32 | no |
del or dup(14q32) single nucleotid variant+ |
| Prader-Willi syndrome (PWS) |
SNURF:TSS-DMR, GOM* |
15q11q13 |
yes |
UPD(15)mat del(15q11q13)pat imprinting center defect* |
| Angelman syndrome (AS) |
SNURF:TSS-DMR, LOM* UBE3A+ mat |
15q11q13 | yes | UPD(15)pat del(15q11q13)mat imprinting center defect* single nucleotid variant+ |
| Central Precocious Puberty 2
(CPPB2) |
MKRN3+ pat | 15q11.2 | no |
single nucleotid variant+ |
| Schaaf-Yang syndrome (SHFYNG) |
MAGEL2+ pat | 15q11.2 | no |
single nucleotid variant+ |
| Pseudo-hypoparathyoridism type
1B (PHP1B) |
GNAS-NESP:TSS-DMR, GOM* GNAS-AS1:TSS-DMR, LOM* GNAS-XL:Ex1-DMR, GOM* GNAS+ |
20q13 |
yes |
UPD(20)pat del(20q13)mat imprinting center defect* single nucleotid variant+ |
| Mulchandani-Bhoi-Conlin
syndrome (MBCS) |
n.a. |
6q24 |
no |
UPD(20)mat |
| multilocus imprinting disturbance (MLID) | they can
show mixture of all above mentioned imprinting
disorders or main features of only one of them see also {1429} |
|||
| Chromosomal region |
Gene |
Reference |
| 1p36.32 | TP73 | 1195 |
| 1p31.3 | DIRAS3 | 1195 |
| 6q25.3 | SLC22A3 | 1195 |
| 7p12.2 | DDC | 1195 |
| 7p12.1 | GRB10 | 1195 |
| 7q21.11 | MAGI2 | 1195 |
| 7q21.3 | PEG10 | 1195 |
| 7q21.3 | PPP1R9A | 1195 |
| 7q21.3 | CALCR | 1195 |
| 8p23.3 | DLGAP2 | 1195 |
| 9p24.2 | GLIS3 | 1195 |
| 10q26.11 | INPP5F | 1195 |
| 11q13.3 |
ANO1 | 1195 |
| 12q13.11 | SLC38A4 | 1195 |
| 15q21.1 |
GATM | 1195 |
| 16p13.3 |
NARFL | 1397 |
| 16p13.2 |
PMM2 | 1397 |
| 19q13.43 | PEG3 | 1195 |
| 19q13.42 | NLRP2 | 1195 |
In {1373} potential yet undetected regions in the genome with uniparental gene expression are summarized.
Neither the words 'epigenetics' nor 'UPD' are mentioned there, even though 'parent of origin-effects' are discussed.
In {1401} genes potentially underlying imprinting during development human neuronal differentiation are described.
