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

## TL;DR

This study reports two new genetic variants in Kleefstra syndrome 1 and shows how they lead to different symptom severities in patients.

## Contribution

The study identifies a novel frameshift variant and the smallest reported EHMT1 microdeletion in Kleefstra syndrome 1.

## Key findings

- One patient had a frameshift variant (p.Val692Glyfs*64) in exon 13 of the EHMT1 gene.
- The other patient had an 11 Kb microdeletion in exons 19-25 of the 9q34.4 region.
- The two patients showed different levels of intellectual disability despite similar ages and no other major health issues.

## 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.