Mosaic Segmental and Whole-Chromosome Upd(11)mat in Silver-Russell Syndrome

Abstract

Molecular defects altering the expression of the imprinted genes of the 11p15.5 cluster are responsible for the etiology of two congenital disorders characterized by opposite growth disturbances, Silver–Russell syndrome (SRS), associated with growth restriction, and Beckwith–Wiedemann syndrome (BWS), associated with overgrowth. At the molecular level, SRS and BWS are characterized by defects of opposite sign, including loss (LoM) or gain (GoM) of methylation at the H19/IGF2:intergenic differentially methylated region (H19/IGF2:IG-DMR), maternal or paternal duplication (dup) of 11p15.5, maternal (mat) or paternal (pat) uniparental disomy (upd), and gain or loss of function mutations of CDKN1C. However, while upd(11)pat is found in 20% of BWS cases and in the majority of them it is segmental, upd(11)mat is extremely rare, being reported in only two SRS cases to date, and in both of them is extended to the whole chromosome. Here, we report on two novel cases of mosaic upd(11)mat with SRS phenotype. The upd is mosaic and isodisomic in both cases but covers the entire chromosome in one case and is restricted to 11p14.1-pter in the other case. The segmental upd(11)mat adds further to the list of molecular defects of opposite sign in SRS and BWS, making these two imprinting disorders even more specular than previously described.

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

“…Thus, it is possible that the KHDC3L variant is responsible for the occurrence of gametic non-disjunction and disomy in the maternal grandmother and upd(6) in the mother. Consistent with the finding that upd(6)mat is not necessarily associated with pathological conditions [ 47 , 49 ] ( http://upd-tl.com/upd.html ), no significant clinical feature was reported for this woman.…”

“…MS-MLPA analysis was performed by SALSA MS-MLPA Kit (MRC-Holland, Amsterdam, The Netherlands) according to the manufacturer’s protocol: Probemix ME034 for multi-locus imprinting was applied to BWS cases (probands 1–7) [ 49 ]. Probemix ME031for GNAS locus was applied to PHP1Bcases (probands 8–10).…”

“…SNP-array on DNA mother and maternal grandparents of proband 1 was performed as previously reported [ 49 ].…”

The kin selection theory of genomic imprinting and modes of reproduction in the eusocial Hymenoptera

“…This is the predicted phenotype for the paternal inheritance of two copies of Igf2 if humans have practiced polyandry throughout most of their history. By contrast, Silver–Russell syndrome, which involves prenatal and postnatal undergrowth, may be caused by maternal uniparental disomy of the same chromosome (Pignata et al ., 2021).…”

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

“…For the molecular diagnosis of the SRSp, it is recommended to test the DNA methylation of both IC1 and IC2 first, and in case of a positive result, determine if the epigenetic abnormality is associated with any CNV or UPD to estimate the recurrence risk [ 1 ]. Although IC1 loss of methylation (LOM) occurs most frequently as an isolated primary epimutation, it can be associated with IC2 gain of methylation (GOM) as consequence of upd(11)mat [ 5 ] or maternally inherited duplications of the entire cluster in rarer cases [ 6 ]. Isolated IC2 GOM is even rarer and can be associated with either maternally inherited duplications [ 7 ] or paternally inherited deletions [ 8 ].…”