Intellectual disability update Jan 2018

Gene: NR1I3

Red List (low evidence)

Comment on publications: added publications for the single de novo case and also supports inclusion of this gene on the ID panel, although currently there is not enough evidence to upgrade the rating

Created: 28 Feb 2018, 2:58 p.m.

From Koemans et al., 2017 (PMID: 29069077) Kleefstra syndrome, caused by haploinsufficiency of euchromatin histone methyltransferase 1 (EHMT1), is characterized by intellectual disability (ID), autism spectrum disorder (ASD), characteristic facial dysmorphisms, and other variable clinical features. In addition to EHMT1 mutations, de novo variants were reported in four additional genes (MBD5, SMARCB1, NR1I3, and KMT2C), in single individuals with clinical characteristics overlapping Kleefstra syndrome.

Created: 28 Feb 2018, 2:53 p.m.

This is a possible DD gene in Gene2Phenotype for EHMT1-LIKE INTELLECTUAL DISABILITY.

Created: 28 Feb 2018, 2:52 p.m.

In a girl with a syndromic form of mental retardation, Kleefstra et al., 2012 (PMID:22726846) identified a de novo heterozygous T-to-C transition at nucleotide 740 of the NR1I3 gene that resulted in a phe-to-ser substitution at codon 247 (F247S). They found a small number (4 cases) that were EHMT1 gene mutation-negative patients with core phenotypic features of Kleefstra syndrome but with phenotypic heterogeneity, referred to as Kleefstra syndrome spectrum (KSS), identifing de novo mutations in 4 genes, MBD5, MLL3, SMARCB, and NR1I3, that encode epigenetic regulators. Shared phenotypic features among these patients include intellectual disability and childhood hypotonia, present in all, and behavioral problems, synophrys, and midface hypoplasia, present in a majority. Otherwise the phenotypes were quite variable. Using Drosophila, Kleefstra et al. (2012) demonstrated that MBD5, MLL3, and NR1I3, cooperate with EHMT1; SMARCB1 was known to interact directly with MLL3.

Created: 28 Feb 2018, 2:46 p.m.

Comment on phenotypes: added phenotype from G2P

Created: 27 Feb 2018, 5:22 p.m.