BACKGROUND: Overgrowth conditions are a heterogeneous group of disorders 
characterised by increased growth and variable features, including macrocephaly, 
distinctive facial appearance and various degrees of learning difficulties and 
intellectual disability. Among them, Sotos and Weaver syndromes are clinically 
well defined and due to heterozygous mutations in NSD1 and EZH2, respectively. 
NSD1 and EZH2 are both histone-modifying enzymes. These two epigenetic writers 
catalyse two specific post-translational modifications of histones: methylation 
of histone 3 lysine 36 (H3K36) and lysine 27 (H3K27). We postulated that 
mutations in writers of these two chromatin marks could cause overgrowth 
conditions, resembling Sotos or Weaver syndromes, in patients with no NSD1 or 
EZH2 abnormalities.
METHODS: We analysed the coding sequences of 14 H3K27 methylation-related genes 
and eight H3K36 methylation-related genes using a targeted next-generation 
sequencing approach in three Sotos, 11 'Sotos-like' and two Weaver syndrome 
patients.
RESULTS: We identified two heterozygous mutations in the SETD2 gene in two 
patients with 'Sotos-like' syndrome: one missense p.Leu1815Trp de novo mutation 
in a boy and one nonsense p.Gln274* mutation in an adopted girl. SETD2 is 
non-redundantly responsible for H3K36 trimethylation. The two probands shared 
similar clinical features, including postnatal overgrowth, macrocephaly, 
obesity, speech delay and advanced carpal ossification.
CONCLUSIONS: Our results illustrate the power of targeted next-generation 
sequencing to identify rare disease-causing variants. We provide a compelling 
argument for Sotos and Sotos-like syndromes as epigenetic diseases caused by 
loss-of-function mutations of epigenetic writers of the H3K36 histone mark.