A novel frameshift deletion in in a patient with Kleefstra Syndrome results in decreased H3K9 dimethylation.

Background: Kleefstra Syndrome (KS) (MIM# 610253) is an autosomal dominant disorder caused by haploinsufficiency of euchromatic histone methyltransferase-1 ( GLP). (MIM# 607001) encodes a histone methyltransferase that heterodimerizes with EHMT2 (also known as G9a, MIM# 604599), which together are responsible for mono- and dimethylation of H3 lysine 9 (H3K9me1 and -me2), resulting in transcriptional repression of target genes.

Methods: This report describes an 18-year-old woman with intellectual disability, severely limited speech, hypotonia, microcephaly, and facial dysmorphisms, who was found to have a novel single-base frameshift deletion in .

Results: Functional studies using patient fibroblasts showed decreased H3K9me2 compared to wild-type control cells, thus providing a rapid confirmatory test that complements molecular studies.

Conclusion: Whole exome sequencing revealed a novel frameshift deletion in after a lengthy diagnostic odyssey in this patient. Functional testing using this patient's fibroblasts provides proof-of-concept for the analysis of variants of uncertain significance that are predicted to impact EHMT1 enzymatic activity.