Abstract
BackgroundKleefstra Syndrome (KS) (MIM# 610253) is an autosomal dominant disorder caused by haploinsufficiency of euchromatic histone methyltransferase‐1 (EHMT1, GLP). EHMT1 (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.MethodsThis 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 de novo single‐base frameshift deletion in EHMT1.ResultsFunctional studies using patient fibroblasts showed decreased H3K9me2 compared to wild‐type control cells, thus providing a rapid confirmatory test that complements molecular studies.ConclusionWhole exome sequencing revealed a novel frameshift deletion in EHMT1 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.
Highlights
Kleefstra syndrome (KS) (MIM# 610253, known as 9q subtelomeric deletion syndrome) is characterized by severe developmental delay, absent or limited speech, hypotonia, brachycephaly, distinctive facial features, congenital heart defects, and behavioral problems (Kleefstra et al 2006)
We describe an 18-year-old woman with global developmental delay, severely limited speech, hypotonia, microcephaly, and facial dysmorphisms, who was found to have a novel de novo single-base frameshift deletion in EHMT1 (Chr9(GRCh37): g.140637927_ 140637928del; NM_024757.4(EHMT1): c.928_929del; NP_079033.4: p.Arg310Aspfs*4) by whole exome sequencing (WES) after a protracted diagnostic odyssey
The patient underwent whole exome sequencing at the age of 17 (Baylor Miraca Genetics, Houston, TX, USA), which revealed a novel de novo single-base frameshift deletion (Chr9(GRCh37): g.140637927_140637928del; NM_024757.4(EHMT1): c.928_929del; NP_079033.4: p.Arg310Aspfs*4) in the EHMT1 gene that is implicated in KS
Summary
Kleefstra syndrome (KS) (MIM# 610253, known as 9q subtelomeric deletion syndrome) is characterized by severe developmental delay, absent or limited speech, hypotonia, brachycephaly, distinctive facial features, congenital heart defects, and behavioral problems (Kleefstra et al 2006). Studies of individuals with 9q subtelomeric a 2017 The Authors. Characterization of a Novel EHMT1 Variant deletions showed that the euchromatic histone methyltransferase-1 gene (EHMT1, MIM# 607001) falls within the critical region deleted in these patients, and further investigations revealed small interstitial deletions affecting EHMT1 (Kleefstra et al 2006). Subsequent studies on additional individuals with intragenic mutations in EHMT1, including nonsense, splice site, and missense variants, confirmed that haploinsufficiency of EHMT1 results in KS (Kleefstra et al 2009). EHMT1 (MIM# 607001) encodes a histone methyltransferase that heterodimerizes with EHMT2 ( known as G9a, MIM# 604599), which together are responsible for mono- and dimethylation of H3 lysine 9 (H3K9me and -me2), resulting in transcriptional repression of target genes
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