Open AccessA novel de novo frameshift deletion in EHMT 1 in a patient with Kleefstra Syndrome results in decreased H3K9 dimethylation
Author(s) -
Blackburn Patrick R.,
Williams Monique,
Cousin Margot A.,
Boczek Nicole J.,
Beek Geoffrey J.,
Lomberk Gwen A.,
Urrutia Raul A.,
BabovicVuksanovic Dusica,
Klee Eric W.
Publication year - 2017
Publication title -
molecular genetics and genomic medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.765
H-Index - 29
ISSN - 2324-9269
DOI - 10.1002/mgg3.268
Subject(s) - frameshift mutation , haploinsufficiency , genetics , histone methyltransferase , microcephaly , hypotonia , exome sequencing , biology , intellectual disability , medicine , microbiology and biotechnology , histone , gene , mutation , phenotype
Background Kleefstra Syndrome ( KS ) ( MIM # 610253) is an autosomal dominant disorder caused by haploinsufficiency of euchromatic histone methyltransferase‐1 ( EHMT 1, GLP ). EHMT 1 ( MIM # 607001) encodes a histone methyltransferase that heterodimerizes with EHMT 2 (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 de novo single‐base frameshift deletion in EHMT 1 . 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 EHMT 1 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 EHMT 1 enzymatic activity.