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

Background 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. Results 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. Conclusion 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.

Different Mechanisms Cause Hypomethylation of Both H19 and KCNQ1OT1 Imprinted Differentially Methylated Regions in Two Cases of Silver–Russell Syndrome Spectrum

“…In SRS-MLID, the most affected DMRs other than IC1 are MEST :alt-TSS-DMR and GRB10 :alt-TSS-DMR [ 12 ] ( Table 1 ), although we did not find abnormal methylation at these loci in our patient. Some cases of BWS and SRS with MLID have been associated with maternal variants of the SCMC genes [ 9 , 12 , 22 , 23 , 24 , 25 , 26 , 27 ], but the whole-exome sequencing did not identify any such variant in our case.…”

Molecular characterisation of 36 multilocus imprinting disturbance (MLID) patients: a comprehensive approach

“…In 25% (6/24) of the tested MLID mothers putative pathogenic maternal effect variants were identified. The determination of the aberrant imprinting pattern of children in a family with PADI6 mutations (BWS-15 [ 16 ]) confirmed the observation that PADI6 associated MLIDs exhibit severe epigenotypes [ 9 , 19 , 28 ]. However, comparably severely aberrant MLID profiles were also detected in a patient from a NLRP2 family (SRS-1), and in other patients without proven maternal effect gene variants (SRS-5, BWS-14).…”

Co-Occurrence of Beckwith–Wiedemann Syndrome and Early-Onset Colorectal Cancer

“…The methylation profile of each iDMR was calculated as the average of the CpG methylation levels within the iDMR. PBL methylation values of the patient were compared with those of 8 age-matched controls of the same batch downloaded from GSE195873 (C5 to C12) [ 22 ]. The values, deviating ± 3 s.d.…”

“…Whole-genome copy number variants (CNVs) were analysed by single nucleotide polymorphism (SNP)-array that was carried out as previously reported [ 22 , 23 ].…”

“…Whole-genome single nucleotide variants were analysed by Whole Exome Sequencing (WES) as previously described [ 22 , 24 ]. In silico prediction of variant pathogenicity on the CFTR protein was studied by Polyphen-2 ( (accessed on 11 January 2023) and following the guidelines of the American College Medical Genetics (ACMG) reported in [ 25 ].…”