Clinical genetics of craniosynostosis

Abstract

Purpose of review: When providing accurate clinical diagnosis and genetic counseling in craniosynostosis, the challenge is heightened by knowledge that etiology in any individual case may be entirely genetic, entirely environmental, or anything in between. This review will scope out how recent genetic discoveries from next-generation sequencing have impacted on the clinical genetic evaluation of craniosynostosis.

Recent findings: Survey of a 13-year birth cohort of patients treated at a single craniofacial unit demonstrates that a genetic cause of craniosynostosis can be identified in one quarter of cases. The substantial contributions of mutations in two genes, TCF12 and ERF, is confirmed. Important recent discoveries are mutations of CDC45 and SMO in specific craniosynostosis syndromes, and of SMAD6 in nonsyndromic midline synostosis. The added value of exome or whole genome sequencing in the diagnosis of difficult cases is highlighted.

Summary: Strategies to optimize clinical genetic diagnostic pathways by combining both targeted and next-generation sequencing are discussed. In addition to improved genetic counseling, recent discoveries spotlight the important roles of signaling through the bone morphogenetic protein and hedgehog pathways in cranial suture biogenesis, as well as a key requirement for adequate cell division in suture maintenance.

Figure 1. Classification and causes of craniosynostosis in a prospectively ascertained 13-year cohort

Data are based on a cohort of patients with craniosynostosis (n = 666) born between 1998 and 2010 inclusive, presenting to a single specialized unit (Oxford, UK) and requiring at least one major craniofacial procedure by the end of 2015. The pie chart on the left shows a broad classification according to presence or absence of syndromic features and identification of a likely secondary or genetic cause. The grid on the right provides a more detailed breakdown according to the pattern of suture involvement and precise diagnosis. Abbreviations for different suture fusions as follows: S, sagittal; M, metopic; UC, unilateral coronal; BC, bilateral coronal; L, unilateral or bilateral lambdoid; MS, multiple suture fusion excluding bilateral coronal or lambdoid. AN, acanthosis nigricans. Data updated from previously published 5-year cohort [7].

Figure 2. Genetic testing in craniosynostosis

The cohort described in Fig. 1 (n = 666) was analyzed in terms of the number of successes in achieving a positive diagnosis for different genetic tests. The tests are arranged hierarchically with those yielding the highest number of diagnoses at the left.