Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome.
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.
Ng
Sarah B
SB
Department of Genome Sciences, University of Washington, Seattle, Washington, USA.
Bigham
Abigail W
AW
Buckingham
Kati J
KJ
Hannibal
Mark C
MC
McMillin
Margaret J
MJ
Gildersleeve
Heidi I
HI
Beck
Anita E
AE
Tabor
Holly K
HK
Cooper
Gregory M
GM
Mefford
Heather C
HC
Lee
Choli
C
Turner
Emily H
EH
Smith
Joshua D
JD
Rieder
Mark J
MJ
Yoshiura
Koh-Ichiro
K
Matsumoto
Naomichi
N
Ohta
Tohru
T
Niikawa
Norio
N
Nickerson
Deborah A
DA
Bamshad
Michael J
MJ
Shendure
Jay
J
D000015:Abnormalities, Multiple / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005787:Gene Frequency; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D006801:Humans; D009154:Mutation / Q000502:physiology; D009363:Neoplasm Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA / Q000379:methods*; D013577:Syndrome; D054928:Validation Studies as Topic
D004268:DNA-Binding Proteins; C120898:KMT2D protein, human; D009363:Neoplasm Proteins