Genome‐wide DNA methylation and RNA analyses enable reclassification of two variants of uncertain significance in a patient with clinical Kabuki syndrome. Issue 10 (3rd July 2019)

• Record Type: Journal Article
• Authors: Aref‐Eshghi, Erfan; Bourque, Danielle K.; Kerkhof, Jennifer; Carere, Deanna Alexis; Ainsworth, Peter; Sadikovic, Bekim; Armour, Christine M.; Lin, Hanxin
• Is Part Of: Human mutation. Volume 40:Issue 10(2019)
• Page Start: 1684
• Page End: 1689
• Publication Date: 2019-07-03
• Subjects: discordant variant classification -- DNA methylation -- episignature -- Kabuki syndrome -- KMT2D -- nontruncating variant -- RNA analysis -- splice variant -- variant of unknown significance; Human chromosome abnormalities -- Periodicals; Mutation (Biology) -- Periodicals; 616.04205
• DOI: 10.1002/humu.23833
• Languages: English
• ISSNs: 1059-7794

Abstract

Abstract: Nontruncating sequence variants represent a major challenge in variant interpretation and classification. Here, we report a patient with features of Kabuki syndrome who carries two rare heterozygous variants in KMT2D : c.12935C>T, p.(Ser4312Phe) and c.15785‐10T>G. The clinical significance of these variants were discordantly interpreted by different diagnostic laboratories. Parental testing showed that the missense variant was inherited from the father with a mild Kabuki phenotype and the intronic variant from the mother with mosaic status. Through genome‐wide DNA methylation analysis of peripheral blood, we confirmed that the proband exhibited a previously described episignature of Kabuki syndrome. Parental samples had normal DNA methylation profiles, thus ruling out the involvement of the paternally inherited missense variant. RNA analysis revealed that the intronic change resulted in exon 49 skipping and frameshift, thereby providing a molecular diagnosis of Kabuki syndrome. This study demonstrates the utility of epigenomic and RNA analyses in resolving ambiguous clinical cases.