RNF135 is responsible for a new overgrowth syndrome

Dr Deirdre Cilliers has won the inaugural Alan Emery Prize for her paper 'Mutations in RNF135, a gene within the NFL microdeletion region, cause phenotypic abnormalities including overgrowth' (1). The award is made by the Royal Society of Medicine's Medical Genetics Section. Professor Alan Emery, a distinguished geneticist with over 200 scientific papers to his name and the author of many books, was founding President of the Section. He led pioneering work in understanding muscular dystrophies and is notably the 'Emery' in Emery-Dreyfus and the emerin gene. He is equally at ease discussing medicine in art, fly-fishing and marine biology. Details of how to apply for next year's prize (deadline March 31 2009) may be found online.

Mutations in RNF135, a gene from within the NF1 microdeletion region on chromosome 17q11.2, have been identified in six patients with overgrowth and learning difficulties. This new syndrome was identified during a study performed for the Childhood Overgrowth Study, led by Professor Nazneen Rahman, at the Institute of Cancer Research, UK. The study was set up for the identification of genes found in patients with non-specific overgrowth. A report of the condition was recently published in Nature Genetics (2007).

Childhood overgrowth syndromes are a heterogeneous group of conditions that share excess growth as a feature and are associated with various problems in childhood, including developmental delay, congenital anomalies and an increased risk of cancer. Several genes associated with childhood overgrowth syndromes have recently been identified, for example NSD1 (Sotos syndrome) and GPC3 (Simpson-Golabi-Behmel syndrome). Despite these recent advances, the molecular basis of overgrowth in a large proportion of patients remains undetermined.

One approach to finding novel genes is to investigate chromosomal deletion syndromes associated with overgrowth to determine if a specific gene within the deleted region is causative of the overgrowth in these cases and may also be mutated in other overgrowth cases. An example of a genomic deletion associated with overgrowth is the microdeletion at 17q11.2, which includes the NF1 gene.  

A total of 245 patients with overgrowth of unknown cause were recruited through the Childhood Overgrowth Study. Of these, five patients were found to have mutations in RNF135, a gene within the 17q11.2 microdeletion region. A 5-gene deletion, which included RNF135 but excluded the NF1 gene, was identified in a sixth patient.

Characteristics of the patients with RNF135 mutations included overgrowth, distinct facial features, developmental delay and other variable features including deafness, eye abnormalities and congenital heart anomalies. All the mutations were inherited and this new overgrowth syndrome displays an autosomal dominant inheritance pattern. Parents and siblings had similar features to the patients, although some family members were only mildly affected.

In the future, this overgrowth gene may also lead to a better understanding of the molecular control of growth and the dysregulation of growth in patients with cancer and other undiagnosed overgrowth conditions.