Selected publications

• Goriely Anne and Wilkie Andrew OM (2012) Paternal age effect mutations and selfish spermatogonial selection: causes and consequences for human disease. Am J Hum Genet, 90(2):175-200.

• Wilkie Andrew OM, Byren Jo C, Hurst Jane A, Jayamohan Jayaratnam, Johnson David, Knight Samantha JL, Lester Tracy, Richards Peter G, Twigg Stephen RF, and Wall Steven A (2010) Prevalence and complications of single-gene and chromosomal disorders in craniosynostosis. Pediatrics, 126(2):e391-400.

• Twigg Stephen RF, Versnel Sarah L, Nurnberg Gudrun, Lees Melissa M, Bhat Meenakshi, Hammond Peter, Hennekam Raoul CM, Hoogeboom A JM, Hurst Jane A, Johnson David, Robinson Alexis A, Scambler Peter J, Gerrelli Dianne, Nurnberg Peter, Mathijssen Irene MJ, and Wilkie Andrew OM (2009) Frontorhiny, a distinctive presentation of frontonasal dysplasia caused by recessive mutations in the ALX3 homeobox gene. Am J Hum Genet, 84(5):698-705.

• Goriely Anne, Hansen Ruth MS, Taylor Indira B, Olesen Inge A, Jacobsen Grete K, McGowan Simon J, Pfeifer Susanne P, McVean Gilean AT, Meyts Ewa R, and Wilkie Andrew OM (2009) Activating mutations in FGFR3 and HRAS reveal a shared genetic origin for congenital disorders and testicular tumors. Nat Genet, 41(11):1247-52.

• Furniss Dominic, Lettice Laura A, Taylor Indira B, Critchley Paul S, Giele Henk, Hill Robert E, and Wilkie Andrew OM (2008) A variant in the sonic hedgehog regulatory sequence (ZRS) is associated with triphalangeal thumb and deregulates expression in the developing limb. Hum Mol Genet, 17(16):2417-23.

Prof Andrew Wilkie

In 1995 our group discovered the cause of Apert syndrome, a severe condition characterised by craniosynostosis (early closure of the cranial sutures) and syndactyly (fusion between the digits) of the hands and feet (Fig 1). We identified two specific mutations within the gene for fibroblast growth factor receptor type 2 (FGFR2), one or other of which is present in ~99% of affected individuals. Other FGFR2 mutations are associated with different congenital syndromes and complete screens show that the mutations are non-random, with some being highly recurrent. It is now apparent that a similar spectrum of mutations occur somatically in specific cancers.

Figure 1

In cases where the mutation has arisen de novo, it always originates from the unaffected father, who tends to be older than average (paternal age effect). We have extended this observation by developing a method to measure the level of the most common Apert mutation in sperm (Fig 2). This has led us to propose that these mutations confer a growth advantage to the testis cells in which they arise (Goriely et al 2003, 2005). Recently we demonstrated a direct link between the occurrence in sperm of a specific mutation in a related gene, FGFR3, and a rare type of testicular tumour (spermatocytic seminoma). We propose that paternal age-effect mutations arise through a shared mechanism involving activation of Ras signalling within the spermatogonial cell (Goriely et al 2009). This work and its significance has been comprehensively reviewed (Goriely and Wilkie 2012). 

Figure 2

Apart from the work on Apert syndrome we have investigated the molecular basis of many other conditions with craniofacial and/or limb malformations. Discoveries in the past few years include the identification of mutations of ROR2 in brachydactyly type B and recessive Robinow syndrome, of MSX2 and ALX4 in parietal foramina, of FLNA in the otopalatodigital spectrum disorders, of EFNB1 in craniofrontonasal syndrome (Twigg et al 2004, 2006), EFNA4 in craniosynostosis (Merrill et al 2006), RAB23 in Carpenter syndrome (Jenkins et al 2007), the ZRS of SHH in triphalangeal thumb (Furniss et al 2008), and ALX3 in a newly recognised disorder, frontorhiny (Twigg et al 2009).