Beckwith-Wiedemann syndrome due to imprinting defect of 11p15
General Information (adopted from Orphanet):
| Synonyms, Signs: |
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| Number of Symptoms | 39 |
| OrphanetNr: | 231117 |
| OMIM Id: |
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| ICD-10: |
Q87.3 |
| UMLs: |
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| MeSH: |
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| MedDRA: |
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| Snomed: |
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Prevalence, inheritance and age of onset:
| Prevalence: | No data available. |
| Inheritance: |
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| Age of onset: |
Antenatal Neonatal 25898929 [IBIS] |
Disease classification (adopted from Orphanet):
| Parent Diseases: |
Beckwith-Wiedemann syndrome
-Rare cardiac disease -Rare developmental defect during embryogenesis -Rare genetic disease -Rare maxillo-facial surgical disease -Rare oncologic disease -Rare otorhinolaryngologic disease -Rare renal disease |
Comment:
| Imprinted gene(s) involved in the aetiology of Beckwith-Wiedemann syndrome (BWS) have been mapped to chromosome 11p15.5 by family linkage studies and the identification of chromosomal rearrangements in sporadic cases. In both mouse and man several imprinted genes are clustered within this region including the candidate BWS genes IGF2, H19, CDKN1C (p57KIP2), and KCNQ1 (KVLQT1) (PMID:10424811). Multiple (epi)genetic defects can alter the expression of imprinted genes included in two domains on chromosome 11p15.5 and are found in approximately 80% of Beckwith-Wiedemann syndrome (BWS) patients. Differently from the majority of genes expressed from both alleles on maternally and paternally inherited chromosomes, imprinted genes are expressed monoallelically based on their parental origin. This phenomenon is regulated epigenetically through imprinting centers (ICs) acquiring DNA methylation during the gametogenesis and maintain it on the maternal or paternal allele in the somatic cells. At 11p15.5, two differentially methylated ICs (IC1 and IC2) control the expression of genes included in closely located domains. In BWS, abnormal ICs methylation cause quantitatively altered expression of controlled genes. BWS molecular defects are classified in centromeric and telomeric ones, including IC2 and IC1, respectively. (PMID:25898929). A cluster of imprinted genes within 11p15 is thought to be coordinately regulated via the imprinted expression of KCNQ1OT1, which encodes an untranslated RNA. In skin fibroblasts from five monozygotic twin pairs discordant for Beckwith-Wiedemann syndrome (BWS), each affected twin had an imprinting defect at KCNQ1OT1 on 11p15, whereas the unaffected twin did not. Five additional monozygotic twin pairs, for whom only blood was available, also displayed an imprinting defect at KCNQ1OT1 (PMID:12019213). Sporadic cases with putative imprinting defects may be subdivided into (a) those with loss of imprinting (LOI) of IGF2 and H19 hypermethylation and silencing due to a defect in a distal 11p15.5 imprinting control element (IC1) and (b) those with loss of methylation at KvDMR1, LOI of KCNQ1OT1 (LIT1) and variable LOI of IGF2 in whom there is a defect at a more proximal imprinting control element (IC2) (PMID:15999116). Genomic imprinting refers to an epigenetic marking resulting in monoallelic gene expression and has a critical role in fetal development. Various imprinting diseases have been reported in humans and animals born after the use of assisted reproductive technology (ART). All the epimutations implicated involve a loss of methylation of the maternal allele (demethylation of KvDMR1/KCNQ1OT1 in Beckwith–Wiedemann syndrome (BWS), demethylation of SNRPN in Angelman syndrome and demethylation of DMR2/IGF2R in large offspring syndrome), suggesting that ART impairs the acquisition or maintenance of methylation marks on maternal imprinted genes. Some patients with BWS show abnormal methylation at loci other than the 11p15 region, and the involvement of other loci is not restricted to patients with BWS born after ART was used. Moreover, the mosaic distribution of epimutations suggests that imprinting is lost after fertilisation owing to a failure to maintain methylation marks during pre-implantation development (PMID:16825435). |
Symptom Information:
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(HPO:0001627) | Abnormal heart morphology | Occasional [IBIS] | 25898929 | IBIS | 19 / 7739 | |
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(HPO:0001520) | Large for gestational age | Frequent [IBIS] | 25898929; 11181570; 15999116; 19513094 | IBIS | 34 / 7739 | |
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(HPO:0001943) | Hypoglycemia | Frequent [IBIS] | 25898929; 16825435 | IBIS | 131 / 7739 | |
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(HPO:0001998) | Neonatal hypoglycemia | 12019213; 15999116; 18245780 | IBIS | 22 / 7739 | ||
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(HPO:0001629) | Ventricular septal defect | 16825435 | IBIS | 316 / 7739 | ||
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(HPO:0000158) | Macroglossia | Frequent [IBIS] | 25898929; 11181570; 12019213; 15999116; 16825435; 18245780; 19513094 | IBIS | 119 / 7739 | |
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(HPO:0001324) | Muscle weakness | 11181570; 16825435 | IBIS | 859 / 7739 | ||
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(HPO:0000729) | Autistic behavior | 25898929 | IBIS | 27 / 7739 | ||
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(HPO:0000750) | Delayed speech and language development | 16825435 | IBIS | 197 / 7739 | ||
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(HPO:0001250) | Seizures | 18245780 | IBIS | 1245 / 7739 | ||
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(HPO:0001561) | Polyhydramnios | 25898929; 18245780 | IBIS | 191 / 7739 | ||
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(HPO:0001528) | Hemihypertrophy | Frequent [IBIS] | 25898929; 12019213; 15999116; 16825435; 18245780 | IBIS | 13 / 7739 | |
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(HPO:0002240) | Hepatomegaly | 18245780 | IBIS | 467 / 7739 | ||
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(HPO:0001744) | Splenomegaly | 18245780 | IBIS | 337 / 7739 | ||
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(HPO:0003271) | Visceromegaly | Frequent [IBIS] | 25898929; 12019213; 16825435 | IBIS | 8 / 7739 | |
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(HPO:0010866) | Abdominal wall defect | Frequent [IBIS] | 25898929; 12019213; 15999116; 16825435; 19513094 | IBIS | 5 / 7739 | |
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(HPO:0001540) | Diastasis recti | 25898929; 18245780 | IBIS | 23 / 7739 | ||
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(HPO:0001537) | Umbilical hernia | Occasional [IBIS] | 12019213; 15999116; 16825435; 18245780; 19513094 | IBIS | 206 / 7739 | |
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(HPO:0000023) | Inguinal hernia | 18245780 | IBIS | 181 / 7739 | ||
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(HPO:0001539) | Omphalocele | 25898929; 11106355; 12019213; 15999116; 16825435 | IBIS | 102 / 7739 | ||
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(HPO:0000054) | Micropenis | 16825435 | IBIS | 257 / 7739 | ||
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(HPO:0000028) | Cryptorchidism | 25898929 | IBIS | 347 / 7739 | ||
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(HPO:0000271) | Abnormality of the face | Frequent [IBIS] | 18245780 | IBIS | 108 / 7739 | |
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(HPO:0000324) | Facial asymmetry | 18245780 | IBIS | 57 / 7739 | ||
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(HPO:0000175) | Cleft palate | 16825435 | IBIS | 349 / 7739 | ||
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(HPO:0000356) | Abnormality of the outer ear | Frequent [IBIS] | 25898929; 11181570; 12019213; 15999116; 16825435 | IBIS | 85 / 7739 | |
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(HPO:0009908) | Anterior creases of earlobe | 12019213; 15999116; 18245780 | IBIS | 10 / 7739 | ||
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(HPO:0001052) | Nevus flammeus | Occasional [IBIS] | 25898929; 11181570; 15999116; 16825435; 18245780 | IBIS | 88 / 7739 | |
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(HPO:0000077) | Abnormality of the kidney | Occasional [IBIS] | 25898929; 12019213; 18245780 | IBIS | 73 / 7739 | |
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(HPO:0000105) | Enlarged kidneys | 25898929 | IBIS | 30 / 7739 | ||
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(HPO:0002667) | Nephroblastoma | 25898929; 11181570; 18245780 | IBIS | 30 / 7739 | ||
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(HPO:0000069) | Abnormality of the ureter | 25898929; 18245780 | IBIS | 47 / 7739 | ||
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(HPO:0002664) | Neoplasm | 25898929; 15999116 | IBIS | 111 / 7739 | ||
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(HPO:0002859) | Rhabdomyosarcoma | 16825435 | IBIS | 10 / 7739 | ||
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(HPO:0002898) | Embryonal neoplasm | Occasional [IBIS] | 12019213 | IBIS | 6 / 7739 | |
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(HPO:0001548) | Overgrowth | Frequent [IBIS] | 25898929; 12019213; 18245780 | IBIS | 27 / 7739 | |
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(HPO:0001622) | Premature birth | 25898929 | IBIS | 100 / 7739 | ||
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(HPO:0030025) | Auricular pit | 12019213; 15999116; 18245780 | IBIS | 3 / 7739 | ||
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(HPO:0030084) | Clinodactyly | 16825435 | IBIS | 90 / 7739 |
Associated genes:
ClinVar (via SNiPA)
| Gene symbol | Variation | Clinical significance | Reference |
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