Novel protein-truncating variants of a chromatin-modifying gene MSL2 in syndromic neurodevelopmental disorders

Abstract

Numerous large scale genomic studies have uncovered rare but recurrent pathogenetic variants in a significant number of genes encoding epigenetic machinery in cases with neurodevelopmental disorders (NDD) especially autism spectrum disorder (ASD). These findings provide strong support for the functional importance of epigenetic regulators in neurodevelopment. After the clinical genomics evaluation of the patients using exome sequencing, we have identified, three novel protein-truncating variants (PTVs) in the MSL2 gene (OMIM: 614802) which encodes a chromatin modifying enzyme. MSL2 modifies chromatin through both mono-ubiquitination of histone 2B on lysine 34 (K34) and acetylation of histone H4 on lysine 16 (K16). We reported first time the detailed clinical features associated with 3 MSL2 PTVs. There are 15 PTVs (13 de novo) reported from the large genomics studies (12 cases) or ClinVar (3 cases) of NDD, ASD, and developmental disorders (DD) but the specific clinical features for these cases are not described. Taken together, our descriptions of dysmorphic face and other features support the causal role of MSL2 in a likely syndromic neurodevelopmental disorder and add MSL2 to a growing list of epigenetic genes implicated in ASD.

Fig. 1. Schematic illustrating MSL2 gene, mRNA, and protien structure and as well as annotatoins of pathogeneic variants.

A MSL2 gene structure and postions of pathogentic variants. B mRNA of MSL2 (Noted: NM_018133.3 was used to annotate the variant of patient #1 and NM_018133.4 was used for the patient #2 and #3). C MSL2 protein structure and pathogenic variants.

Fig. 2

Front and side facial profile of patient 2 showing slightly down-slanting palpebral fissures, flat midface, mild low-set ears, wide and smooth philtrum, and micrognathia.