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Review
. 2025 Apr 29;16(5):521.
doi: 10.3390/genes16050521.

A Novel Frameshift Variant and a Partial EHMT1 Microdeletion in Kleefstra Syndrome 1 Patients Resulting in Variable Phenotypic Severity and Literature Review

Maria Tzetis  1   2 , Anastasios Mitrakos  1   3 , Ioanna Papathanasiou  4 , Vasiliki Koute  5 , Konstantina Kosma  1 , Roser Pons  6 , Aspasia Michoula  7 , Ioanna Grivea  7 , Aspasia Tsezou  2   4
Affiliations
Review

A Novel Frameshift Variant and a Partial EHMT1 Microdeletion in Kleefstra Syndrome 1 Patients Resulting in Variable Phenotypic Severity and Literature Review

Maria Tzetis et al. Genes (Basel). .

Abstract

Background: Kleefstra syndrome 1(KLEFS1, OMIM#610253) is a rare neurodevelopmental disorder (NDD) instigated by heterozygous variants or microdeletions occurring in the 9q34.4 genomic region of the euchromatic histone methyltransferase-1 (EHMT1) gene and is inherited in an autosomal dominant (AD) manner. The clinical phenotype of KLEFS1 includes moderate to severe intellectual disability (ID), hypotonia, and distinctive facial features and additionally involves other organ systems (heart, renal, genitourinary, sensory) albeit with phenotypic heterogeneity between patients. The purpose of this study is to expand the genotypic spectrum of KLEFS1 and compare phenotypic features of the syndrome of already published cases.

Methods: Exome sequencing (ES), chromosomal microarray analysis (CMA), as well as sanger sequencing, for confirmation of the de novo status of the frameshift variant, were used.

Results: Here we describe two more cases, both males with a similar age and carriers of novel variants; one with a frameshift variant involving exon 13: p.Val692Glyfs*64 and the other with the smallest so far described, 11 Kb (exons 19-25), 9q34.4 microdeletion: 9q34.3 (140703393-140714454). Both presented with an NDD disorder with one showing more severe ID with significant social disabilities, while the other with the microdeletion had mild ID and following a normal education curriculum. Neither of them were obese nor had any other significant organ system disorder.

Conclusions: The observed phenotypic variability due to genotypic differences in the two children contributes to the expanding spectrum of KLEFS1 disease phenotypes.

Keywords: Kleefstra 1 syndrome (KLEFS1); array comparative genomic hybridization (aCGH); exome sequencing (ES); microdeletion 9q34.4.

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Conflict of interest statement

Authors Maria Tzetis and Aspasia Tsezou were employed by the company GeneTech Analytics Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
EHMT1: c.2075-2097del (p.Val692Glyfs*64), identified in P1 by ES (IGV image).
Figure 2
Figure 2
EHMT1 microdeletion in P2 identified by CMA, spanning exons 19-25 (arr[GRCh37] 9q34.3(140703393-140714454)x1; 11Kb).
See this image and copyright information in PMC

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