The origin of imprinting defects in Temple syndrome and comparison with other imprinting disorders

Abstract

Temple syndrome (TS14) is a rare imprinting disorder caused by genetic and epigenetic alterations on chromosome 14q32. A subset of these patients shows an imprinting defect (ID) where the paternal allele harbors a maternal epigenotype thus silencing the paternally expressed genes and leading to an increased expression of the maternally expressed genes. We investigated the grandparental origin of the incorrectly imprinted chromosome 14 in a cohort of 13 TS14 ID patients and their families. In seven families grandmaternal and, in six families, grandpaternal inheritance was observed. These results indicate that the ID occurred after imprint erasure in the paternal germ line. While the complete lack of methylation as observed in the majority of TS14 ID patients may be due to an imprint establishment error in the paternal germ line, cases with methylation mosaicism suggest that in general many IDs (TS14, AS, BWS, and SRS) are in fact of somatic origin in the early or late embryo.

Temple syndrome resulting from uniparental disomy is undiagnosed by a methylation assay due to low‐level mosaicism for trisomy 14

“…The analysis can detect the paternally inherited allele even if it is present in only a small percentage of cells. Further, Beygo et al (2018) estimate that about 50% of TS14 cases with imprinting defects are mosaic in their methylation pattern, with some cells having a normal imprint and other having an abnormal one. An endpoint methylation assay will fail to make the diagnosis in these cases also.…”

“…Salient features of the syndrome include pre‐ and post‐natal growth failure, hypotonia resulting in feeding difficulties, short stature, small hands and feet, precocious puberty, truncal obesity, and mild intellectual disability. Chromosome band 14q32 contains differentially methylated regions, including the genes DLK1 and RTL1 that are expressed only from the paternally inherited allele and MEG3 , RTL1as , and MEG8 , as well as miRNAs and snoRNAs that are expressed only from the maternally inherited allele (Beygo et al, 2018). Mechanistically, TS14 can be the result of three different etiologies: (1) maternal uniparental disomy of chromosome 14 [upd(14)mat] due to errors in chromosome segregation, (2) more localized imprinting defects, or (3) deletions of the paternally inherited region.…”

Establishment of mouse androgenetic embryonic stem cells by double sperm injection and differentiation into beating embryoid body

“…Uniparental embryos had aberrant genomic imprinting and unbalanced allele-specific expression of imprinted genes that disrupted fetal development, and was associated with genetic diseases, cancers and neurological disorders (Beygo et al, 2018;Jelinic and Shaw, 2007;Khosla et al, 2001). In the present research, we established AgES cells from mouse androgenetic embryos produced by injection of two sperm into an enucleated oocyte.…”

Temple Syndrome: Clinical Findings, Body Composition and Cognition in 15 Patients

“…TS14 can arise from several molecular causes, namely UPD(14)mat, with and without a Robertsonian translocation, paternal deletion and an isolated methylation defect [ 2 , 3 , 4 , 5 ]. All causes affect the 14q32.2 imprinted region, which is characterized by three differentially methylated regions (DMRs) and a cluster of paternally and maternally expressed genes [ 6 ]. The phenotype is caused by disruption of this region with loss of expression of the paternally inherited genes and overexpression of the maternally inherited genes [ 7 ].…”