The ability to sequence whole exomes and genomes of individual people has revolutionised our ability to explore the full spectrum of genetic mutations causing serious human diseases. Working closely with the craniofacial teams based in Oxford and other UK units, we specialise in the application of these methods to children born with a serious malformation of the skull termed craniosynostosis.
It started with Apert syndrome
In 1995 we 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. We identified two specific mutations within the gene encoding fibroblast growth factor receptor type 2 (FGFR2), accounting for ~99% of affected individuals. Other FGFR2 mutations are associated with different congenital syndromes and complete mutation screens show that the mutations are non-random, with some being highly recurrent. A similar spectrum of mutations occur somatically in specific cancers. Over the past two decades we have investigated the mechanisms by which these apparent mutation hotspots arise, leading us to propose a novel process occurring in the testes, which we term selfish spermatogonial selection. Prof Anne Goriely now leads this work.
Genetic analysis of skull malformations
Extending out from this discovery, we have worked on many other genetic conditions. During the era of “classical” human genetics, our novel findings included 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, RAB23 in Carpenter syndrome and ALX3 in a newly recognised disorder, which we termed frontorhiny. Genetic testing for all of these conditions is now available at the NHS Genetics lab in Oxford and elsewhere.
Next generation sequencing (NGS)
In the current decade, the rate of progress in discovery has been accelerated dramatically by whole exome and whole genome sequencing (WGS). We contributed to the first large scale application of WGS in a clinical setting, with one of our patients gaining publicity on the front page of the Times (3 August 2011) as the first within the UK to have a clinically applied whole genome sequence (mutation in HUWE1). We continue to use NGS to give better, more accurate genetic diagnoses for our patients. We have reported six further genes in craniosynostosis, MEGF8, ERF, TCF12, ZIC1, CDC45 and SMO, with others in the pipeline. This makes possible for the first time a comprehensive catalogue of mutated genes, allowing us to build towards a more complete picture of the multiple complex processes by which craniosynostosis occurs.
Mechanistic understanding (led by Stephen Twigg)
We also work on mice, because the key events in development craniosynostosis occur during fetal life, so it is not ethical to study this in humans. Using CRISPR-Cas9 genome editing we recently generated a novel mouse line containing a Zic1 mutation equivalent to one we had identified in humans. We plan to use a combination of single cell analysis with the study of a craniosynostosis model to gain new insights into the mechanisms of suture development. In parallel we are mapping regulatory elements that control the expression of genes involved in suture development at different timepoints in both human and murine fetal sutures. By intersecting these data with genome sequences (for example from the 100,000 Genomes project), we will try to identify regulatory mutations in some of our unsolved patients.
Irene Mathijssen, Dept. of Plastic and Reconstructive Surgery and Hand Surgery, Erasmus MC Rotterdam, The Netherlands
Louise Wilson, Clinical Genetics, Great Ormond Street Hospital NHS Trust