The genetic basis for Weaver syndrome recently has been identified (Tatton-Brown et al., Oncotarget, 2011, 2:1127-1133 and Gibson et al., Am. J. Hum. Genet. 2012, 90:110-118) allowing now for the possibility of genetic testing for this disorder.  Weaver syndrome is a rare congenital developmental disorder that was first identified and described in two unrelated males in 1974 by Dr. David Weaver and associates.  Clinical features include generalized overgrowth, advanced bone age, marked macrocephaly, and characteristic facial features.  Among the facial features seen are a broad forehead, ocular hypertelorism, long philtrum, retrognathia with a prominent chin crease that has sometimes been described as a ‘stuck-on’ chin, and large ears.  Several of the patients also have intellectual disability generally in the mild to moderate range.  Weaver syndrome is generally a sporadic condition although some familial cases have been described.

Many of the clinical features of Weaver syndrome overlap with Sotos syndrome, another overgrowth condition, and include in particular macrocephaly, overgrowth, and developmental delay.  Mutations and deletions of the NSD1 gene, which codes for a histone methyl transferase, have been identified in the majority of patients with Sotos syndrome, and a few patients thought to have Weaver syndrome also have had NSD1 mutations.  These latter findings have raised the question of whether Weaver and Sotos syndromes represent allelic disorders with variable expressivity or if they are distinct conditions with different underlying genetic bases. 

A defective gene in Weaver syndrome has recently been identified.  Two groups (Tatton-Brown et al., Oncotarget, 2011, 2:1127-1133 and Gibson et al., Am. J. Hum. Genet. 2012, 90:110-118) used exome sequencing of selected patients with Weaver syndrome and their parents to look for de novo mutations.  One of the patients used in these studies included the original patient described by Dr. Weaver et al. in 1974.  Both studies identified mutations in the EZH2 gene, a gene that codes for a histone modification enzyme.  Specifically, the EZH2 protein catalyzes the trimethylation of lysine 27 of histone H3 (H3K27), thereby playing a key role in the shutting down of transcription of genes that are bound by this histone complex.  The majority of EZH2 mutations identified in patients with Weaver syndrome so far include missense mutations, some in-frame mutations, and very few nonsense/frameshift mutations.  Altogether, EZH2 mutations in 22 unrelated patients with Weaver syndrome have been identified of which one was identified in a familial case.  It is uncertain as to whether the mutations lead to gain or loss of function, but the speculation is that the mutations are more likely to be gain of function mutations.

It is interesting to note that somatic mutations of EZH2 previously have been identified in patients with lymphoid and myeloid malignancies.  In fact some of the same mutations identified in patients with Weaver syndrome have been seen somatically in patients with myeloid malignancies.  Some patients with Weaver syndrome have developed tumors and malignancies leading to the speculation that constitutive EZH2 mutations may confer a predisposition to malignancy.  These observations are still preliminary and more long-term clinical studies of patients with Weaver syndrome will be required to make more definite conclusions about the gene and malignancies in this condition.

EZH2 is the second histone methyl transferase, after NSD1, connected to overgrowth disorders and both are SET-domain containing proteins.  Somatic mutations affecting both the EZH2 and NSD1 genes have been identified in hematologic malignant conditions.  This observation raises the importance of the role of histone-modifying proteins in neurodevelopmental disorders and hematologic malignancies.  With the similarity in phenotype between Weaver and Sotos syndrome, it is satisfying to observe a similar molecular basis for both disorders.

Mutation analysis of the EZH2 and NSD1 genes is available at the University of Chicago Genetic Services Laboratory.  As more patients with mutations in EZH2 are identified through genetic testing, it will be interesting to see if the clinical spectrum of this condition expands.