De novo mutations in MLL cause Wiedemann-Steiner syndrome.
Excessive growth of terminal hair around the elbows (hypertrichosis cubiti) has been reported both in isolation and in association with a variable spectrum of associated phenotypic features. We identified a cohort of six individuals with hypertrichosis cubiti associated with short stature, intellectual disability, and a distinctive facial appearance, consistent with a diagnosis of Wiedemann-Steiner syndrome (WSS). Utilizing a whole-exome sequencing approach, we identified de novo mutations in MLL in five of the six individuals. MLL encodes a histone methyltransferase that regulates chromatin-mediated transcription through the catalysis of methylation of histone H3K4. Each of the five mutations is predicted to result in premature termination of the protein product. Furthermore, we demonstrate that transcripts arising from the mutant alleles are subject to nonsense-mediated decay. These findings define the genetic basis of WSS, provide additional evidence for the role of haploinsufficency of histone-modification enzymes in multiple-congenital-anomaly syndromes, and further illustrate the importance of the regulation of histone modification in development.
South West Thames Regional Genetics Service, St George's Hospital, University of London, London SW17 0RE, UK.
Wendy D
WD
Jones
Dimitra
D
Dafou
Meriel
M
McEntagart
Wesley J
WJ
Woollard
Frances V
FV
Elmslie
Muriel
M
Holder-Espinasse
Melita
M
Irving
Anand K
AK
Saggar
Sarah
S
Smithson
Richard C
RC
Trembath
Charu
C
Deshpande
Michael A
MA
Simpson
D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology; D001483:Base Sequence; D059472:Exome / Q000235:genetics; D040461:Gene Components; D006130:Growth Disorders / Q000235:genetics* / Q000473:pathology; D057895:Haploinsufficiency / Q000235:genetics; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D006983:Hypertrichosis / Q000151:congenital* / Q000235:genetics / Q000473:pathology; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D017422:Sequence Analysis, DNA
C497422:KMT2A protein, human; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase