Breakpoint mapping by whole genome sequencing identifiesPTH2Rgene disruption in a patient with midline craniosynostosis and a de novo balanced chromosomal rearrangement

Abstract

BackgroundCraniosynostosis (CRS) is a premature closure of calvarial sutures caused by gene mutation or environmental factors or interaction between the two. Only a small proportion of non-syndromic CRS (NSC) patients have a known genetic cause, and thus, it would be meaningful to search for a causative gene disruption for the development NSC. We applied a whole genome sequencing approach on a 15-month-old boy with sagittal and metopic synostosis to identify a gene responsible for the development of the disease.Methods and resultsConventional chromosome study revealed a complex paracentric inversion involving 2q14.3 and 2q34. Array comparative genomic hybridisation did not show any copy number variation. Multicolour banding analysis was carried out and the breakpoints were refined to 2q14 and 2q34. An intronic break of the PTH2R gene was detected by whole genome sequencing and fluorescence in situ hybridisation analysis confirmed disruption of PTH2R.ConclusionsWe report PTH2R as a gene that is disrupted in NSC. The disruption of the PTH2R gene may cause uncontrolled proliferation and differentiation of chondrocytes, which in turn results in premature closure of sutures. This addition of PTH2R to the list of genes associated with NSC expands our understanding of the development of NSC.

Genetic advances in craniosynostosis

“…FREM1 mutations were identified in eight out of 104 (5.8%) patients with metopic CS, including two patients with mNCS [Vissers et al, 2011]. Finally, premature closure of the sagittal and metopic sutures has been found associated with hearing impairment, crumpled ear, widely spaced eyes, and developmental delay in the syndromic phenotype associated with an intronic breakpoint in PTH2R [Kim et al, 2015]. …”

A Higher Proportion of Craniosynostosis Genes Are Cancer Driver Genes

“…These 17 new genes found through this process were added to the CRS genes list: AXIN2 (Yilmaz et al, 2018), BBS9 (Justice et al, 2012; Sewda et al, 2019), BCOR (O’Byrne et al, 2017) (for Oculo-facio-cardio-dental syndrome, or microphthalmia syndrome), BGLAP (Sowińska-Seidler et al, 2018), COLEC10 (for 3MC syndrome) (Munye et al, 2017), FGFRL1 (Rieckmann et al, 2009) (for Antley-Bixler syndrome), GCK (for Greig cephalopolysyndactyly syndrome) (Zung et al, 2011), LMNA (Sowińska-Seidler et al, 2018), PPP3CA (Mizuguchi et al, 2018), PTH2R (Kim et al, 2015), RAF1 (for Noonan syndrome with multiple lentigines, or leopard syndrome) (Rodríguez et al, 2019), SIX2 (for frontonasal dysplasia syndrome) (Hufnagel et al, 2016), SMURF1, SPRY1, SPRY4 (Timberlake et al, 2016, 2017), TCOF1 (for Treacher Collins syndrome) (Horiuchi et al, 2004), TNFRSF11B (for Juvenile Paget disease) (Saki et al, 2013).…”

“…The involvement of FGF (fibroblast growth factor), FGFR (fibroblast growth factor receptor), and MAPK/ERK signaling pathways in CRS has long been discussed in the literature (Marie et al, 2005; Shukla et al, 2007; Kim et al, 2015; Kosty and Vogel, 2015; Pfaff et al, 2016; Timberlake et al, 2017). However, our top hit gene-set is KEGG’s cancer pathway, and this link between CRS and cancer is to our knowledge rarely discussed in the literature.…”

Joint Multi-Ancestry and Admixed GWAS Reveals the Complex Genetics behind Human Cranial Vault Shape

“…We also identified BCL11B , a transciption factor involved in keeping suture patency by preventing expression of RUNX2 and FGFR2 in the suture mesenchyme 100 and for which de novo mutations have been observed in several craniosynostosis cases 101,102 . In addition, we identified PTHLH, whose associated receptor, PTH2R is implicated in syndromic craniosynostosis 103 . While no significant associations were found near FGFR1 , FGFR2 , or FGFR3 , all implicated in syndromic and non-syndromic craniosynostosis, we found associations with genes encoding their ligands, FGF10 and FGF18 13 .…”