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Select assembly: (NC_000007.13) (NC_000007.14)
Evidence for haploinsufficiency phenotype
PubMed ID Description
23375656 Girirajan et al. (2013) conducted a large-scale case-control study (2588 patients; 580 controls) of an autism patient cohort to identify segmental duplication mediated and associated recurrent genomic hotspots for copy number variants, and dosage sensitive genes, using custom targeted high density array. De novo deletion (51.5 kb) involving KMT2C (MLL3) was seen in a single patient (12957.p1) with autism phenotype. This deletion appears to be intragenic and includes at least 5 exons (based on the coordinates in supplemental table S10: novel gene-disrupting smaller hotspot events exclusive to autism cases).
22726846 Kleefstra et al. (2012) used NGS to sequence 316 putative EHMT1-interacting genes in a cohort of 9 individuals with core features of Kleefstra syndrome (i.e. ID, hypotonia, and distinctive facial features), without EHMT1 disrupting alterations (the only gene known to be disrupted in the Kleefstra syndrome phenotypic spectrum (KSS)). They detected de novo mutations in four genes, MBD5, KMT2C (MLL3), SMARCB1, and NR1I3 (all of which encode epigenetic regulators) and hypothesized that the ?EHMT1 negative? individuals have a mutation in one of these four genes that share a biological function with EHMT1. One individual (KS113) from this cohort carried a de novo nonsense mutation in KMT2C (p.ARG1481*) which was predicted to result in a loss-of-function. Functional studies demonstrating reduced gene dosage effect of this mutation were not performed.
29069077 Koemans et al. (2017), presented a novel cohort of five patients with de novo loss of function mutations affecting KMT2C. Mutations in these 5 patients were predicted to cause loss of function and included, c.5216del (p.Pro1739Leufs*2) in individual 1, c.7550C>G (p.Ser2517*) in mosaic (?30% of blood cells) in individual 2, c.1690A>T (p.Lys564*) in individual 3, and c.10812_10815del (p.Lys3605fs) in individual 4. In patient 5, microarray detected an intragenic 203kb de novo deletion (Chr7: 151858920?152062163)x1 and was confirmed by locus-specific qPCR. All individuals had ID, ranging from mild to severe, language and motor delay, and autism or Pervasive Developmental Disorder (PDD) (see their Table 1 for additional clinical features). Functional studies using the Drosophila KMT2C ortholog, trithorax related (trr), was conducted. Knockdown of trr was targeted specifically to the mushroom body (MB), the learning and memory center of the fly brain. Similar to the Drosophila EHMT1 ortholog, G9a, trr is required in the MB for short term memory. Their data showed that trr is required in the mushroom body for short term memory as studied by measuring the courtship index. In order to identify genomic binding regions of trr and to gain insight into its target genes and the processes that it regulates in the nervous system, chromatin immunoprecipitation combined with next generation sequencing (ChIP-seq) using wildtype adult Drosophila heads and a validated ChIP grade antibody directed against trr were conducted. Based on these studies it was concluded that, trr binds to the promoter of many genes involved in neuronal processes. In addition, whole-transcriptome mRNA sequencing (RNA-seq) on wildtype and mutant fly heads revealed a large and significant overlap between genes and biological pathways that are differentially expressed upon loss of trr and G9a, suggesting functional convergence between these two proteins in the fly brain.

Haploinsufficiency phenotype comments:

The KMT2C (also known as MLL3) encodes a histone methyltransferase that regulates gene transcription by modifying chromatin structure and also mediates mono- and tri-methylation of histone H3 at lysine 4 (H3K4me1 and H3K4me3). Multiple de novo alterations (one multi-exonic deletion, a non-focal deletion, and many sequence-level mutations, some of which are predicted to result in a loss-of-function) have been identified in association with constitutional phenotypes, many such variants have been identified within large-scale studies, where limited phenotypic and clinical information are provided. Amongst KMT2C variant carriers reported in the literature, considerable phenotypic variability exists, including autism, a Kleefstra syndrome-like developmental phenotype, schizophrenia susceptibility, bipolar disorder, and cancer predisposition (colorectal and AML in one family and nasopharyngeal carcinoma in another). There is also some common variation affecting this gene in the DGV, along with segmental duplications within the gene. Additional relevant literature is summarized below: PMID: 21792059: Sahoo et al (2011), from a cohort of >30,000 patients referred for diagnostic microarray testing, searched for CNVs associated with schizophrenia susceptibility. The authors identified a hotspot with multiple CNVs at 7q36.1 (including KMT2C), including one non-focal deletion. PMID: 27217147: Kataoka et al. (2016) performed trio-based WES (79 trios; 237 exomes) of a Bipolar Disorder (BD) cohort to identify de novo protein-altering mutations across the genome. Seventy-one de novo point mutations were identified and validated by Sanger sequencing. A nonsense mutation affecting KMT2C (MLL3), resulting in an amino acid alteration (p.K3601X) was detected in a single patient with BD type I. Properties of genes hit by de novo mutations in the context of ?gene intolerance? were analyzed using a scoring system (Residual Variation Intolerance Score (RVIS), published by Petrovski et al.). Enrichment data was also computed by combining this BD data set with an existing cohort of published data on schizoaffective disorder and examined by one-tailed Fisher exact test. Findings from this study were in accordance with the results of previous WES studies for other neuropsychiatric disorders such ASD and schizophrenia. Furthermore, KMT2C (MLL3) was found to be among the genes hit by de novo loss of function mutation despite its extremely high intolerance to protein-altering variants and was suggested as a candidate for disease susceptibility. PMID 23429989: Li et al. (2013), in a letter to editor, described a germline mutation in KMT2C (MLL3) in four individuals from a multigenerational Chinese family with colorectal cancers and acute myeloid leukemia. Exome sequencing revealed a heterozygous insertion mutation resulting in frameshift and premature truncation at codon 827. Functional studies were not performed, no additional phenotypic information was reported. PMID 26014803: Sasaki et al. (2015) used family-based WES reported three different variants in KMT2C (MLL3) in three closely related family members with familial nasopharyngeal carcinoma. One variant Y816* was predicted to result in a premature stop codon and loss-of-function, the other two variants were missense mutations. They hypothesized that inactivating mutations of MLL3 may be associated with a highly penetrant and previously unknown cancer-predisposition syndrome. No functional studies were performed.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity