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Novel genetic variants of KHDC3L and other members of the subcortical maternal complex associated with Beckwith-Wiedemann syndrome or Pseudohypoparathyroidism 1B and multi-locus imprinting disturbances

ABSTRACT: Novel genetic variants of KHDC3L and other members of the subcortical maternal complex associated with Beckwith-Wiedemann syndrome or Pseudohypoparathyroidism 1B and multi-locus imprinting disturbances

PROVIDER: PRJNA802536 | ENA |

REPOSITORIES: ENA

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Novel genetic variants of KHDC3L and other members of the subcortical maternal complex associated with Beckwith-Wiedemann syndrome or Pseudohypoparathyroidism 1B and multi-locus imprinting disturbances

Project description:Beckwith–Wiedemann syndrome (BWS) and Pseudohypoparathyroidism type 1B (PHP1B) are imprinting disorders (ID) caused by deregulation of the imprinted gene clusters located at 11p15.5 and 20q13.32, respectively. In both of these diseases a subset of the patients is affected by multi-locus imprinting disturbances (MLID). In several families, MLID is associated with damaging variants of maternal-effect genes encoding protein components of the subcortical maternal complex (SCMC). However, frequency, penetrance and recurrence risks of these variants are still undefined. In this study, we screened two cohorts of BWS patients and one cohort of PHP1B patients for the presence of MLID, and analysed the positive cases for the presence of maternal variants in the SCMC genes by whole exome-sequencing and in silico functional studies. We identified 10 new cases of MLID associated with the clinical features of either BWS or PHP1B, in which segregate 13 maternal putatively damaging missense variants of the SCMC genes. The affected genes also included KHDC3L that has not been associated with MLID to date. Moreover, we highlight the possible relevance of relatively common variants in the aetiology of MLID. Our data further add to the list of the SCMC components and maternal variants that are involved in MLID, as well as of the associated clinical phenotypes. Also, we propose that in addition to rare variants, common variants may play a role in the aetiology of MLID and imprinting disorders by exerting an additive effect in combination with rarer putatively damaging variants. These findings provide useful information for the molecular diagnosis and recurrence risk evaluation of MLID-associated IDs in genetic counselling.

2022-06-02 | GSE195873 | GEO

Co-occurrence of Beckwith-Wiedemann syndrome and Pseudohypoparathyroidism type 1B: coincidence or common molecular mechanism?

Project description:Imprinting disorders are congenital diseases caused by dysregulation of genomic imprinting, affecting growth, neurocognitive development, metabolism and cancer predisposition. Overlapping clinical features are often observed among this group of diseases. In rare cases, two fully expressed imprinting disorders may coexist in the same patient. A dozen cases of this type have been reported so far. Most of them are represented by individuals affected by Beckwith-Wiedemann spectrum (BWSp) and Transient Neonatal Diabetes Mellitus (TNDM) or BWSp and Pseudo-hypoparathyroidism type 1B (PHP1B). All these patients displayed multilocus imprinting disturbances (MLID). Here, we report the first case of co-occurrence of BWS and PHP1B in the same individual in absence of MLID. Genome-wide methylation and SNP-array analyses demonstrated loss of methylation of the KCNQ1OT1:TSS-DMR on chromosome 11p15.5 as molecular cause of BWSp, and upd(20)pat as cause of PHP1B. The absence of MLID and the heterodisomy of chromosome 20 suggests that BWSp and PHP1B arose through distinct and independent mechanism in our patient.

2023-08-01 | GSE237676 | GEO

imprinting disorders: Beckwith–Wiedemann, Silver–Russell, and Prader-Willi syndromes in Egyptian patients

Project description:19 patients with syndromic ImpDis were 8 clinically diagnosed with Silver-Russell syndrome (SRS), 7 with Prader-Willi syndrome (PWS), and 4 with Beckwith-Wiedemann syndrome (BWS).array chromosomal microarray (CMA) was performed for 12 patients

2025-03-15 | GSE282080 | GEO

Loss-of-function maternal-effect mutations of PADI6 are associated with familial and sporadic Beckwith-Wiedemann Syndrome with multi-locus imprinting disturbance

Project description:PADI6 is a component of the subcortical maternal complex (SCMC) which is a group of proteins that are abundantly expressed in the oocyte cytoplasm and essential for the proper development of the early embryo. The mutation(s) in the components of the subcortical maternal complex have been associated with reproductive failures, including formation of hydatidiform mole, female infertility and imprinting disorders with multi-locus imprinting disturbance (MLIDs).In the current study by using whole-exome sequencing analysis, we identified four cases of Beckwith-Wiedemann Syndrome with multi-locus imprinting disturbance while their mothers were carriers of variants in PADI6 gene. Genome-wide methylation profiling using Methylation EPIC array depicted the loss of methylation specifically at several known imprinted loci in affected individuals as compared to healthy siblings, parents and controls. Our findings firmly establish the role of PADI6 in imprinting disorders.

2020-10-02 | GSE153211 | GEO

Clinical spectrum of multi-locus imprinting disturbances associated with maternal-effect variants range from overt Beckwith-Wiedemann syndrome to apparently healthy phenotype

Project description:Multi-locus imprinting Disturbances (MLID) are methylation defects affecting germline-derived Differentially Methylated Regions (gDMRs) and they have been associated with maternal-effect variants causing imprinting disorders in the offspring. In a family with multiple pregnancy losses, a child with Beckwith-Wiedemann syndrome (BWS) and a further child without any features of imprinting disorders, novel compound heterozygous variants in the NLRP5 gene of the mother were found. Locus-specific and whole-genome methylation analysis by using Infinium MethylationEPIC BeadChip (WG-317-1001, Illumina) revealed MLID with different methylation profiles in both the siblings. The proband and the normal sibling were found to cluster with other MLID cases as shown by principal component analysis and unsupervised hierarchical clustering and remain distinct from controls. However, we were unable to cluster MLID cases associated with specific clinical phenotypes. The identification of two novel maternal-effect variants of NLRP5 associated with poly-abortivity and MLID add further evidence to the role of NLRP5 in the maintenance of genomic imprinting in early embryos. Furthermore, our results demonstrate that within these pedigrees MLID can also be present in the progeny with healthy phenotype, indicating that some sort of compensation occurs between altered imprinted loci in these individuals.

2019-10-01 | GSE133774 | GEO

Multi-omic Investigation of Beckwith-Wiedemann Syndrome Hepatoblasto

Project description:Multi-omic Investigation of Beckwith-Wiedemann Syndrome Hepatoblasto

| PRJNA764785 | ENA

Multi-omic Investigation of Beckwith-Wiedemann Syndrome Hepatoblasto

Project description:Multi-omic Investigation of Beckwith-Wiedemann Syndrome Hepatoblasto

| PRJNA764786 | ENA

Project description:BackgroundBeckwith-Wiedemann syndrome (BWS) and Pseudohypoparathyroidism type 1B (PHP1B) are imprinting disorders (ID) caused by deregulation of the imprinted gene clusters located at 11p15.5 and 20q13.32, respectively. In both of these diseases a subset of the patients is affected by multi-locus imprinting disturbances (MLID). In several families, MLID is associated with damaging variants of maternal-effect genes encoding protein components of the subcortical maternal complex (SCMC). However, frequency, penetrance and recurrence risks of these variants are still undefined. In this study, we screened two cohorts of BWS patients and one cohort of PHP1B patients for the presence of MLID, and analysed the positive cases for the presence of maternal variants in the SCMC genes by whole exome-sequencing and in silico functional studies.ResultsWe identified 10 new cases of MLID associated with the clinical features of either BWS or PHP1B, in which segregate 13 maternal putatively damaging missense variants of the SCMC genes. The affected genes also included KHDC3L that has not been associated with MLID to date. Moreover, we highlight the possible relevance of relatively common variants in the aetiology of MLID.ConclusionOur data further add to the list of the SCMC components and maternal variants that are involved in MLID, as well as of the associated clinical phenotypes. Also, we propose that in addition to rare variants, common variants may play a role in the aetiology of MLID and imprinting disorders by exerting an additive effect in combination with rarer putatively damaging variants. These findings provide useful information for the molecular diagnosis and recurrence risk evaluation of MLID-associated IDs in genetic counselling.

| S-EPMC9148495 | biostudies-literature

Multi-omic Investigation of Beckwith-Wiedemann Syndrome Wilms Tumor

Project description:Multi-omic Investigation of Beckwith-Wiedemann Syndrome Wilms Tumor

| PRJNA798492 | ENA

Multi-omic Investigation of Beckwith-Wiedemann Syndrome Wilms Tumor

Project description:Multi-omic Investigation of Beckwith-Wiedemann Syndrome Wilms Tumor

| PRJNA798493 | ENA