De Novo Mutations in MLL Cause Wiedemann-Steiner Syndrome

Global transcriptional disturbances underlie Cornelia de Lange syndrome and related phenotypes

“…We analyzed the patients in the Turkish CdLS cohort in whom molecular diagnosis was inconclusive from known CdLS-associated genes (total number = 18/32 with no molecular diagnosis) in order to identify potential disease genes. Remarkably, in 1 female patient (CdLS-3) we identified a heterozygous nonsense mutation (Chr11: g.118344107 C>T [hg19]; c.C2233T, p.Arg745Ter) in KMT2A (NM_005933), the causal gene for WDSTS (21). Segregation analysis in the family confirmed that this mutation was not present in the parents or the healthy elder brother, indicating it to be a de novo mutation in the patient (Figure 4).…”

“…Also known as "hairy elbows syndrome," it is characterized by excessive hair growth around the distal third of the upper arm and the proximal third of the forearm and occasionally on other parts of the body (e.g., sacrum) along with short stature, distinctive facial features, and DD/ID. De novo deleterious mutations in lysine-specific methyltransferase 2A (KMT2A) were identified in patients with a clinical diagnosis of WDSTS (21). However, these patients show a moderately different spectrum of clinical findings, indicating that different mutations in KMT2A, or allelic heterogeneity, contribute to a spectrum of phenotypes.…”

“…However, these patients show a moderately different spectrum of clinical findings, indicating that different mutations in KMT2A, or allelic heterogeneity, contribute to a spectrum of phenotypes. To date, a wide spectrum of abnormalities in WDSTS is observed, among which hairy elbows is found as the most prominent shared clinical feature (21)(22)(23).…”

Enhanced utility of family-centered diagnostic exome sequencing with inheritance model–based analysis: results from 500 unselected families with undiagnosed genetic conditions

“…For example, there was only one report published in 2012 regarding the identification of de novo mutations in KMT2A (MLL) in five patients with Wiedemann-Steiner syndrome. 21 In our first 500 unselected exome families, we detected mutations in this gene in four probands ( Table 4). Similar examples included recurrent 27 and we then identified another de novo mutation in this gene in another patient through retrospective data mining.…”

The histone methyltransferase activity of mll1 is dispensable for hematopoiesis and leukemogenesis

“…Mammals possess three pairs of related SET-domain containing histone methyltransferase (HMT) proteins, MLL1/2, SET1A/B, MLL3/4, and a divergent MLL5 protein. In addition to MLL1 translocations in leukemia, mutations in several trxG/MLL family members are associated with developmental disorders and cancer (Jones et al, 2012;Morin et al, 2011;Ng et al, 2010;Parsons et al, 2011;Pasqualucci et al, 2011). How these broadly expressed proteins influence particular physiologic and pathologic processes in specific cell types is largely unknown but, due to their enzymatic activities, represent attractive drug targets.…”