Genetic Causes of Craniosynostosis: An Update

Goos, Jacqueline A.C.; Mathijssen, Irene M J

doi:10.1159/000492266

Cited by 54 publications

(57 citation statements)

References 203 publications

(255 reference statements)

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“…In 2015, a set of 57 genes are summarized as being genetically associated with craniosynostosis (CRS) (Twigg and Wilie, 2015), i.e., variants/mutations are observed in these genes in CRS patients that are less likely to be observed in people without CRS. A more recent paper adds 39 more CRS genes published from 2015-2017 (Goos and Mathijssen, 2019), resulting in a total of 96 genes. The reason for so many genes being linked to the disease can be understood by the perspective of heterogeneity (McClellan and King, 2010).…”

Section: Resultsmentioning

confidence: 99%

“…The three compilations ((Twigg and Wilie, 2015), (Goos and Mathijssen, 2019), and here) add up to 113 genes that are genetically associated with craniosynostosis. These 113 craniosynostosis genes are: ABCC9, ADAMTSL4, AHDC1, ALPL, ALX4, ASXL1, ATR, AXIN2, B3GAT3, BBS9, BCOR, BGLAP, BMP2, BRAF, CD96, CDC45, CHST3, COLEC10, COLEC11, CRTAP, CTSK, CYP26B1, DPH1, EFNA4, EFNB1, ERF, ESCO2, FAM20C, FBN1, FGF9, FGFR1, FGFR2, FGFR3, FGFRL1, FLNA, FREM1, FTO, GCK, GLI3, GLIS3, GNAS, GNPTAB, GPC3, HNRNPK, HUWE1, IDS, IDUA, IFT122, IFT140, IFT43, IGF1R, IHH, IL11RA, IL6ST, IRX5, JAG1, KANSL1, KAT6A, KAT6B, KMT2D, KRAS, LMNA, LMX1B, LRP5, MASP1, MED13L, MEGF8, MSX2, NFIA, NTRK2, OSTM1, P4HB, PHEX, POR, PPP1CB, PPP3CA, PTH2R, PTPN11, PTPRD, RAB23, RAF1, RECQL4, RSPRY1, RUNX2, SCARF2, SCN4A, SEC24D, SH3PXD2B, SHOC2, SIX2, SKI, SLC25A24, SMAD6, SMC1A, SMO, SMURF1, SOX6, SPECC1L, SPRY1, SPRY4, STAT3, TCF12, TCOF1, TGFBR1, TGFBR2, TMCO1, TNFRSF11B, TWIST1, WDR19, WDR35, ZEB2, ZIC1, and ZNF462.…”

Section: Resultsmentioning

confidence: 99%

“…More detailed information on the newly added 17 CRS genes are summarized in the Appendix. The gene OSTM1 is labeled as OSTEM1 in (Mahmoud Adel et al, 2013; Goos and Mathijssen, 2019) which is not a HGNC approved name. Also note that BGLAP and LMNA in our new addition are within a 1.26 Mb deletion and each gene was hypothesized as causing the disease (Sowińska-Seidler et al, 2018).…”

Section: Resultsmentioning

confidence: 99%

“…Towards this goal, we would like to have a more up-to-date list of genes that are genetically associated with craniosynostosis (i.e., genes that contain, uniquely or preferably, germline mutations in craniosynostosis patients). Previously, there have been two attempts to collect craniosynostosis genes: one in 2015 with 57 genes (Twigg and Wilie, 2015) and a more recent one in 2019 with 39 genes (Goos and Mathijssen, 2019).…”

Section: Introductionmentioning

confidence: 99%

“… ABSTRACT Craniosynostosis (CRS) is a congenital abnormality deformity with a heterogenous genetic contribution. Previously, there are two attempts to collect genes that are genetically associated with craniosynostosis and some related syndromes with 57 (Twigg and Wilkie, 2015) and 39 (Goos and Mathijssen, 2019) genes identified, respectively. We expanded this list of craniosynostosis genes by adding another 17 genes with an updated literature search.…”

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confidence: 99%

See 4 more Smart Citations

A Higher Proportion of Craniosynostosis Genes Are Cancer Driver Genes

Misra

Shih

Yan

et al. 2019

Preprint

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Craniosynostosis (CRS) is a congenital abnormality deformity with a heterogenous genetic contribution. Previously, there are two attempts to collect genes that are genetically associated with craniosynostosis and some related syndromes with 57 (Twigg and Wilkie, 2015) and 39 (Goos and Mathijssen, 2019) genes identified, respectively. We expanded this list of craniosynostosis genes by adding another 17 genes with an updated literature search. These genes are shown to be more likely to be intolerant to functional mutations. Of these 113 craniosynostosis genes, 21 (19% vs. 1.5% baseline frequency) are cancer driver genes, a 14-fold enrichment. The cancer-craniosynostosis connection is further validated by an over-representation analysis of craniosynostosis genes in KEGG cancer pathway and several cancer related gene-sets. Many cancer-craniosynostosis overlapping genes participate in intracellular signaling pathways, which play a role in both development and cancer. This connection can be viewed from the oncogenesis recapitulates ontogenesis framework. Nineteen craniosynostosis genes are transcription factor genes (16.8% vs. 8.2% baseline), and craniosynostosis genes are also enriched in targets of certain transcription factors or micro RNAs.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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A Higher Proportion of Craniosynostosis Genes Are Cancer Driver Genes

Misra

Shih

Yan

et al. 2019

Preprint

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

Tønne

Due-Tønnessen

Vigeland

et al. 2022

American J of Med Genetics Pt A

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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.

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Compound craniosynostosis, intellectual disability, and Noonan‐like facial dysmorphism associated with 7q32.3‐q35 deletion

Bukowska‐Olech

Dmitrzak‐Węglarz

Larysz

et al. 2020

Birth Defects Research

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ObjectiveCraniosynostosis (CS) is the premature fusion of the cranial sutures, occurring either in isolated or syndromic form. Syndromic CS, which was described in over 180 genetic syndromes, accounts for 15–30% of all CS cases and usually originates from mutations within the FGFR1, FGFR2, FGFR3, and TWIST1 genes. However, causative alterations in other genes, or rarely copy number variations (CNVs) were also reported. In this article, we describe a patient with Noonan‐like facial dysmorphism accompanied by intellectual disability and compound CS, involving coronal, sagittal, and squamous sutures.MethodsWe applied karyotyping, copy number variations analysis using array comparative genomic hybridization, and microarray‐based genes expresion analysis.ResultsWe have shown that the index carried a large and rare heterozygous deletion, which encompassed 12.782 Mb and mapped to a chromosomal region of 7q32.3‐q35 (HG38 – chr7:131837067‐144607071). The aberration comprised 109 protein‐coding genes, including BRAF, that encodes serine/threonine‐protein kinase B‐Raf, being a part of the RAS/MAPK signaling pathway.DiscussionThe RAS/MAPK pathway plays an essential role in human development; hence, its dysregulation not surprisingly results in severe congenital anomalies, such as phenotypically overlapping syndromes termed RASopathies. To our best knowledge, we report here the first CNV causing haploinsufficiency of BRAF, resulting in dysregulation of the RAS/MAPK cascade, and consequently, in the phenotype observed in our patient. To conclude, with this report, we have pointed to the involvement of the RAS/MAPK signaling pathway in CS development. Moreover, we have shown that the molecular analysis based on both DNA and RNA profiling, undoubtedly constitutes a comprehensive diagnostic and research strategy for elucidating a cause of genetic diseases.

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Genetic Causes of Craniosynostosis: An Update

Cited by 54 publications

References 203 publications

A Higher Proportion of Craniosynostosis Genes Are Cancer Driver Genes

A Higher Proportion of Craniosynostosis Genes Are Cancer Driver Genes

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

Compound craniosynostosis, intellectual disability, and Noonan‐like facial dysmorphism associated with 7q32.3‐q35 deletion

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