Breakpoint Mapping by Whole Genome Sequencing Identifies PTH2R Gene Disruption in a Patient with Midline Craniosynstosis and a De Novo Balanced Chromosomal Arrangement

2015-06-04 00:01:15

Journal of Medical Genetics; 4 June 2015; DOI: 10.1136/jmedgenet-2015-103001

Juwon Kim, Hong-Hee Won, Yoonjung Kim, Jong Rak Choi, Nae Yu, Kyung-A Lee



Craniosynostosis (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 Results

Conventional 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.


We 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.


Craniosynostosis (CRS) is defined by the premature osseous obliteration of one or more of the cranial vault sutures. The disruption of a fine balance between proliferation and differentiation during embryogenesis or early childhood can alter the patency of these sutures. Non-syndromic CRS (NSC) cases, which occur as an isolated anomaly, account for >80% of all CRS cases and most com-
monly affect sagittal sutures. Although multiple reports have identified mutations in several genes such as FGFR1-3, TWIST1/2, MSX2, FGFRL1, SNAIL, SLUG, NELL1 and RUNX2 in NSC, only a small proportion of patients have a known genetic cause, which indicates that in addition to strong genetic components the premature closure of the sutures is a complex trait. Recently, in an attempt
to find a genetic cause of NSC, a locus near BMP2 and within BBS9 was implicated in the association of non-syndromic sagittal suture. Each sutural synostosis shows distinct characteristics, even among cases with known genetic components. Of note, chromosomal aberrations and submicroscopic chromosomal rearrangements have been associated more frequently with midline synostoses. Recent
advances in whole genome sequencing (WGS) technologies have made it possible to identify genomic rearrangements and breakpoints involved in these rearrangements, facilitating rapid identification of disease genes in chromosomal breakpoint regions. Here, our objective is to identify a gene that is disrupted to cause the disease in a patient with midline NSC using cytogenetic analysis and WGS.

To Read Full Article, Click Here