Syndromic Craniosynostosis Can Define New Candidate Genes for Suture Development or Result from the Non-specifc Effects of Pleiotropic Genes: Rasopathies and Chromatinopathies as Examples

Abstract

Craniosynostosis is a heterogeneous condition caused by the premature fusion of cranial sutures, occurring mostly as an isolated anomaly. Pathogenesis of non-syndromic forms of craniosynostosis is largely unknown. In about 15–30% of cases craniosynostosis occurs in association with other physical anomalies and it is referred to as syndromic craniosynostosis. Syndromic forms of craniosynostosis arise from mutations in genes belonging to the Fibroblast Growth Factor Receptor (FGFR) family and the interconnected molecular pathways in most cases. However it can occur in association with other gene variants and with a variety of chromosome abnormalities as well, usually in association with intellectual disability (ID) and additional physical anomalies. Evaluating the molecular properties of the genes undergoing intragenic mutations or copy number variations (CNVs) along with prevalence of craniosynostosis in different conditions and animal models if available, we made an attempt to define two distinct groups of unusual syndromic craniosynostosis, which can reflect direct effects of emerging new candidate genes with roles in suture homeostasis or a non-specific phenotypic manifestation of pleiotropic genes, respectively. RASopathies and 9p23p22.3 deletions are reviewed as examples of conditions in the first group. In particular, we found that craniosynostosis is a relatively common component manifestation of cardio-facio-cutaneous (CFC) syndrome. Chromatinopathies and neurocristopathies are presented as examples of conditions in the second group. We observed that craniosynostosis is uncommon on average in these conditions. It was randomly associated with Kabuki, Koolen-de Vries/KANSL1 haploinsufficiency and Mowat–Wilson syndromes and in KAT6B-related disorders. As an exception, trigonocephaly in Bohring-Opitz syndrome reflects specific molecular properties of the chromatin modifier ASXL1 gene. Surveillance for craniosynostosis in syndromic forms of intellectual disability, as well as ascertainment of genomic CNVs by array-CGH in apparently non-syndromic craniosynostosis is recommended, to allow for improvement of both the clinical outcome of patients and the accurate individual diagnosis.

Structural Genome Variations Related to Craniosynostosis

“…Findings in 2 patients with large deletions close to TWIST1 suggested that haploinsufficiency of neighboring genes may also contribute to developmental delay in these cases [Johnson et al, 1998]. These observations are in agreement with the notion of a contiguous gene syndrome as a possible genomic cause for complex disorders, which include craniosynostosis as one of its phenotypes, such as Kabuki, 17q21.31 deletion (Koolen-De-Vries/KANSL1 syndrome), and 9p23p22.3 deletion syndrome [Koolen et al, 2008;Sharkey et al, 2009;Dubourg et al, 2011;Koolen et al, 2016;Topa et al, 2017;Zollino et al, 2017].…”

“…Nonsyndromic cases of sagittal and/or metopic craniosynostosis should first be screened for SMAD6 mutations, and nonsyndromic coronal craniosynostosis be investigated for TCF12 and TWIST1 mutations and the FGFR3 P250R variant [Timberlake and Persing, 2018]. Cases of sporadic, nonsyndromic midline craniosynostosis negative for TCF12 and TWIST1 mutations and the FGFR3 P250R variant as well as their parents should preferably be investigated by array-CGH, WES, or WGS [Zollino et al, 2017;Kutkowska-Kaźmierczak et al, 2018;Timberlake and Persing, 2018]. The thus found de novo CNVs and SNVs may then be prioritized for adhering to the GO category of skeletal development (GO:0001501) or the wider category of development (GO:0007275).…”

“…This approach was extended to so-called RASopathies and 9p23p22.3 deletion cases as examples of conditions of intragenic mutations or CNVs provoking craniosynostosis [Zollino et al, 2017]. Trigonocephaly due to craniosynostosis in cases with 9p23p22.3 deletions probably has an oligogenic pathogenesis, involving the receptor-type protein tyrosine phosphatase ( PTPRD ) and the FRAS1-related extracellular matrix protein 1 ( FREM1 ) genes Mitsui et al, 2013].…”

“…In patients with 17q21.31 deletion (Koolen-De-Vries/ KANSL1 syndrome), sagittal craniosynostosis, scaphocephaly, dolichocephaly, metopic ridges, bitemporal narrowing, trigonocephaly, brachycephaly, and frontal bossing have been described [Koolen et al, 2008[Koolen et al, , 2016Sharkey et al, 2009;Dubourg et al, 2011]. Since also lossof-function mutations in KANSL1 (e.g., c.1652+2T>C; p.L552FfsX14) are sufficient to cause the full clinical phenotype associated with 17q21.31 deletions, it remains unclear whether craniosynostosis results only by haploinsufficiency for the genes in this deletion [Zollino et al, 2017]. In the Bohring-Opitz syndrome, trigonocephaly and craniosynostosis apparently reflect specific molecular properties of the causative gene, ASXL1 , which is involved in activation and silencing of HOX genes and in chromatin remodeling [Hoischen et al, 2011].…”

“…Craniosynostosis occurs either as an isolated nonsyndromic phenotype, or may be part of a syndrome including anomalies of the eyes, nose, palate, hands, and feet as well as impairment of vision, hearing, and intellectual development. Syndromic forms of craniosynostosis, occurring in association with other physical anomalies and intellectual disability, comprise approximately 15% of the cases and follow mendelian rules of inheritance [Wilkie et al, 2010;Zollino et al, 2017]. In approximately 85% of the patients, craniosynostosis occurs sporadically due to de novo genome rearrangements or gene mutations [Timberlake and Persing, 2018].…”