TY - JOUR T1 - Diagnostic value of exome and whole genome sequencing in craniosynostosis JF - Journal of Medical Genetics JO - J Med Genet SP - 260 LP - 268 DO - 10.1136/jmedgenet-2016-104215 VL - 54 IS - 4 AU - Kerry A Miller AU - Stephen R F Twigg AU - Simon J McGowan AU - Julie M Phipps AU - Aimée L Fenwick AU - David Johnson AU - Steven A Wall AU - Peter Noons AU - Katie E M Rees AU - Elizabeth A Tidey AU - Judith Craft AU - John Taylor AU - Jenny C Taylor AU - Jacqueline A C Goos AU - Sigrid M A Swagemakers AU - Irene M J Mathijssen AU - Peter J van der Spek AU - Helen Lord AU - Tracy Lester AU - Noina Abid AU - Deirdre Cilliers AU - Jane A Hurst AU - Jenny E V Morton AU - Elizabeth Sweeney AU - Astrid Weber AU - Louise C Wilson AU - Andrew O M Wilkie Y1 - 2017/04/01 UR - http://jmg.bmj.com/content/54/4/260.abstract N2 - Background Craniosynostosis, the premature fusion of one or more cranial sutures, occurs in ∼1 in 2250 births, either in isolation or as part of a syndrome. Mutations in at least 57 genes have been associated with craniosynostosis, but only a minority of these are included in routine laboratory genetic testing.Methods We used exome or whole genome sequencing to seek a genetic cause in a cohort of 40 subjects with craniosynostosis, selected by clinical or molecular geneticists as being high-priority cases, and in whom prior clinically driven genetic testing had been negative.Results We identified likely associated mutations in 15 patients (37.5%), involving 14 different genes. All genes were mutated in single families, except for IL11RA (two families). We classified the other positive diagnoses as follows: commonly mutated craniosynostosis genes with atypical presentation (EFNB1, TWIST1); other core craniosynostosis genes (CDC45, MSX2, ZIC1); genes for which mutations are only rarely associated with craniosynostosis (FBN1, HUWE1, KRAS, STAT3); and known disease genes for which a causal relationship with craniosynostosis is currently unknown (AHDC1, NTRK2). In two further families, likely novel disease genes are currently undergoing functional validation. In 5 of the 15 positive cases, the (previously unanticipated) molecular diagnosis had immediate, actionable consequences for either genetic or medical management (mutations in EFNB1, FBN1, KRAS, NTRK2, STAT3).Conclusions This substantial genetic heterogeneity, and the multiple actionable mutations identified, emphasises the benefits of exome/whole genome sequencing to identify causal mutations in craniosynostosis cases for which routine clinical testing has yielded negative results. ER -