Whole‐exome sequencing in syndromic craniosynostosis increases diagnostic yield and identifies candidate genes in osteogenic signaling pathways

Abstract

Craniosynostosis (CS) is a common congenital anomaly defined by premature fusion of one or more cranial sutures. Syndromic CS involves additional organ anomalies or neurocognitive deficits and accounts for 25%–30% of the cases. In a recent population‐based study by our group, 84% of the syndromic CS cases had a genetically verified diagnosis after targeted analyses. A number of different genetic causes were detected, confirming that syndromic CS is highly heterogeneous. In this study, we performed whole‐exome sequencing of 10 children and parents from the same cohort where previous genetic results were negative. We detected pathogenic, or likely pathogenic, variants in four additional genes (NFIA, EXTL3, POLR2A, and FOXP2) associated with rare conditions. In two of these (POLR2A and FOXP2), CS has not previously been reported. We further detected a rare predicted damaging variant in SH3BP4, which has not previously been related to human disease. All findings were clustered in genes involved in the pathways of osteogenesis and suture patency. We conclude that whole‐exome sequencing expands the list of genes associated with syndromic CS, and provides new candidate genes in osteogenic signaling pathways.

Novel FOXP2 variant associated with speech and language dysfunction in a Chinese family and literature review

“…For instance, a family harboring the c.484delC(p.Q162Nfs*100) variant of FOXP2 displayed striking discrepancies in clinical manifestations and severity levels between genotype-identical mothers and offspring. The proband and the mother both exhibited craniosynostosis; however, the extent of language impairment diverged substantially, and the proband's sister displayed only progressive language retardation [25]. An analogous pattern of disparity in linguistic and intellectual faculties was observed in the family subject to the present study; the affected mother exhibited far less severe linguistic and cognitive impairments than the proband and was capable of regular educational engagement, whereas the proband was markedly compromised in communicative abilities.…”

The value of genome-wide analysis in craniosynostosis

“…Additionally, we found novel variants in POLR2A and PRRX1 ( Supplementary Table S3 ) genes that have recently been associated with metopic and lambdoid synostosis, respectively ( Tønne et al, 2022 ; Timberlake et al, 2023 ). Interestingly, previous studies demonstrated that PRRX1 is expressed in calvarial sutural mesenchymal stem cells ( Wilk et al, 2017 ).…”

“…However, recent transcriptome studies show that neural crest-derived cells from the sagittal suture of human embryonic calvaria are highly enriched for the FOXP1/2 transcriptional network ( He et al, 2021 ). Moreover, a truncating variant in FOXP2 inherited from an affected parent was recently reported in a patient with sagittal SCS ( Tønne et al, 2022 ). This further supports the involvement of FOXP1/2 in midline synostosis.…”

“…Furthermore, WES and WGS enable targeted in silico analysis of a custom-designed CS-related gene panel and performance of a broader exome/genome analysis in cases returning negative results. This is a cost-effective strategy that increases the diagnostic yield and can be adapted to the phenotypic presentation ( Miller et al, 2017 ; Tønne et al, 2020 ; Hyder et al, 2021 ; Bukowska-Olech et al, 2022 ; Tønne et al, 2022 ).…”

Metopic and Sagittal Craniosynostosis in Williams Syndrome

“…Multisuture craniosynostosis has been associated with many genetic syndromes and is proposed to increase the risk of raised intracranial pressure when untreated 1 . Currently, over 80% of syndromic craniosynostosis have a known genetic change 2 …”