Clinical genetics of craniosynostosis

Abstract

Purpose of review When providing accurate clinical diagnosis and genetic counselling 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 non-syndromic midline synostosis. The added value of exome or whole genome sequencing in the diagnosis of difficult cases is highlighted. Summary Strategies to optimise clinical genetic diagnostic pathways by combining both targeted and next-generation sequencing are discussed. As well as improved genetic counselling, recent discoveries spotlight the important roles of signalling 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.

Syndromic Craniosynostosis: Complexities of Clinical Care

“…Muenke syndrome was genetically described in 1997 [Muenke et al, 1997] and is now the most common syndromic presentation with a prevalence of 1 in 10,000-30,000 live births [Doherty et al, 2007;Wilkie et al, 2017]. This syndrome results from mutation c.749C>G in the FGFR3 gene, resulting in p.Pro250Arg [Muenke et al, 1997].…”

“…This results in anomalies affecting bone and cartilage of the cranial vault, skull base, face, and joints -particularly apparent in the hands and feet. Apert is inherited in an autosomal dominant pattern but additionally presents with de novo mutations with an effect demonstrated with increasing paternal age [Wilkie et al, 2017].…”

“…The mutations comprise substitutions with the most common involving cysteine and include Trp290Cys, Trp340Cys, Cys342Arg, and Ser351Cys. These are gain-of-function mutations coding for tyrosine kinase [Wilkie and Johnson, 2017].…”

Genetic Causes of Craniosynostosis: An Update

“…But also, many of the gene defects may act through causing perturbations in osteogenesis, such as filaminopathies, hypophosphatasia [Currarino, 2007;Murthy, 2009], mucopolysaccharidoses [Ziyadeh et al, 2013], osteosclerosis [Kato et al, 2002;Kwee et al, 2005;Simpson et al, 2007Simpson et al, , 2009, and pycnodysostosis [Osimani et al, 2010;Bertola et al, 2011;Berenguer et al, 2012;Caracas et al, 2012;Twigg and Wilkie, 2015]. These diagnoses include potentially treatable conditions, for which early recognition is particularly important [Wilkie et al, 2017], and more and more mutations are being identified in genes that are involved in brain development or that are associated with intellectual disability and/or behavioral anomalies (such as ASXL1 , ANKDR11 , KAT6A , KMT2D , and ZEB2 ) [Twigg and Wilkie, 2015]. In the latter 2 groups, craniosynostosis often does not occur in all affected individuals.…”

“…Miller et al [2017] classified causative mutations according to 4 categories: mutations in commonly mutated craniosynostosis genes, in other core craniosynostosis genes, more rarely associated genes, and known disease genes not known to be associated with craniosynostosis . Next-generation sequencing of DNA of 40 probands and, if available, DNA of their parents, identified mutations in all 4 categories, making an argument for the value of next-generation sequencing instead of gene-specific testing Wilkie et al, 2017].…”