Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome

By Sarah B. H. Ng, Abigail W. Bigham, K. Buckingham, M. Hannibal, M. McMillin, Heidi I. S. Gildersleeve, A. Beck, H. Tabor, Gregory M. Cooper, H. Mefford and 11 more. Nature Genetics, 2010

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We demonstrate the successful application of exome sequencing to discover a gene for an autosomal dominant disorder, Kabuki syndrome (OMIM%147920). We subjected the exomes of ten unrelated probands to massively parallel sequencing. After filtering against existing SNP databases, there was no compelling candidate gene containing previously unknown variants in all affected individuals. Less stringent filtering criteria allowed for the presence of modest genetic heterogeneity or missing data but also identified multiple candidate genes. However, genotypic and phenotypic stratification highlighted MLL2, which encodes a Trithorax-group histone methyltransferase: seven probands had newly identified nonsense or frameshift mutations in this gene. Follow-up Sanger sequencing detected MLL2 mutations in two of the three remaining individuals with Kabuki syndrome (cases) and in 26 of 43 additional cases. In families where parental DNA was available, the mutation was confirmed to be de novo (n = 12) or transmitted (n = 2) in concordance with phenotype. Our results strongly suggest that mutations in MLL2 are a major cause of Kabuki syndrome.

Subfields: Genetics, Pharmacy

View Paper: https://www.semanticscholar.org/paper/ba96f27a9d945c9ca3e689a553bb99b946c9e350

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Citations in the corpus

Dynamic and Coordinated Epigenetic Regulation of Developmental Transitions in the Cardiac Lineage (2012, neutral): “Mutations in the histone methyltransferase MLL2 in 206 Cell 151, 206–220, September 28, 2012 ª2012 Elsevier Inc. humans cause congenital heart defects in Kabuki syndrome (Ng et al., 2010).”
The Next-Generation Sequencing Revolution and Its Impact on Genomics (2013, neutral): “…few unrelated individuals (Gilissen et al., 2010; Hoischen et al., 2010; Lalonde et al., 2010; Ng et al., 2010a, 2010b) or affected family members (Bilgü var et al., 2010; Bolze et al., 2010; Johnson et al., 2010; Krawitz et al., 2010; Musunuru et al., 2010; Walsh et al., 2010; Wang et al., 2010).”
Improved exome prioritization of disease genes through cross-species phenotype comparison (2014, background): “…a number of the disease-gene discoveries reported to date have exploited the availability of multiple unrelated individuals with the same, clinically easily recognizable syndrome (Ng et al. 2010a) or the identification of de novo heterozygous mutations by trio analysis (Vissers et al. 2010).”
Analysis of the Coding Genome of Diffuse Large B-Cell Lymphoma (2011, background): “The pattern of monoallelic somatic inactivation observed in DLBCL suggests a role for MLL2 as a haploinsufficient tumor suppressor, consistent with the observation that monoallelic MLL2 truncating mutations leading to decreased gene dosage have a pathogenic effect in Kabuki syndrome, a congenita”
Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing (2012, background): “As has been suggested previously, our data suggest that MLL2 may function as an important tumor suppressor in DLBCL (17, 29).”
Comparative analysis of RNA-Seq alignment algorithms and the RNA-Seq unified mapper (RUM) (2011, methodology): “This pipeline, the RNA-Seq Unified Mapper (RUM), performs comparably to the best current aligners and provides an advantageous combination of accuracy, speed and usability.”
A general framework for estimating the relative pathogenicity of human genetic variants (2014, background): “Second, it is well established that annotations like PolyPhen and conservation are valuable in the sequencing-based identification of disease-causal genes by virtue of their ability to highly rank pathogenic variants 1,2,38 .”
Predicting the Functional Effect of Amino Acid Substitutions and Indels (2012, background): “Exome capture and high-throughput sequencing has become a popular approach to discover and associate genetic variants with common genetic diseases [25,26,27,28,29,30].”
The impact of next-generation sequencing on genomics (2011, background): “…strategy, the mutations in DHODH from four individuals from three unrelated families with Miller syndrome have been successfully identified (Ng et al., 2010a), illustrating that selective DNA enrichment techniques will dramatically reduce overall cost and accelerate discovery of genetic…”
A survey of tools for variant analysis of next-generation genome sequencing data (2013, background): “disorders [6, 7], for elucidating some genetically het-”
Exome sequencing identifies somatic mutations of DNA methyltransferase gene DNMT3A in acute monocytic leukemia (2011, background): “Recently, mutations of histone methyltransferase genes, such as EZH2 in some hematological malignancies and MLL2 in Kabuki syndrome (an inherited disorder), have been reporte”