Background Two imprinting control centres, H19/IGF2:IG-differentialy methylated region (DMR) and KCNQ1OT1:TSS-DMR, reside on chromosome 11p15.5. Paternal deletions involving the KCNQ1OT1:TSS-DMR result in variable phenotypes, namely, normal phenotype, Silver-Russel syndrome (SRS) and fetal demise. However, expression analyses for CDKN1C in these patients are very limited.
Cases Patient 1 (adult woman) and patient 2 (boy in early childhood) showed prenatal and postnatal growth failure and clinical suspicion of SRS.
Molecular analyses Both patients showed hypermethylation of the KCNQ1OT1:TSS-DMR caused by the paternal heterozygous de novo deletions involving the KCNQ1OT1:TSS-DMR, but not including CDKN1C enhancers. The deletion sizes were 5 kb and 12 kb for patients 1 and 2, respectively. CDKN1C gene expressions in immortalised leucocytes of both patients were increased compared with those of controls.
Conclusion Paternal deletions involving the KCNQ1OT1:TSS-DMR, but not including CDKN1C enhancers, disrupt KCNQ1OT1 expression, strongly activate CDKN1C expression and consequently cause severe growth failure.
- human genetics
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Contributors KH-I performed the molecular analyses and wrote the manuscript. ST and EN provided detailed clinical data and materials for molecular analyses. KY and MF supervised the study. MK designed the project, wrote the manuscript and gave the final approval of the version to be published.
Funding This work was supported by grants from the National Center for Child Health and Development (2019B-4), the Japan Agency for Medical Research and Development (AMED) (20ek0109373h0003) and the Takeda Science Foundation.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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