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Comparative tissue gene expression profiling and alternative splicing by exon-sensitive microarrays in non-syndromic craniosynostosis

ABSTRACT: Craniosynostosis (CS) is the congenital premature fusion of one or more cranial sutures and represents the more prevalent craniofacial malformation in humans, with an overall incidence of 1 out of 2000-3000 live births. Non-syndromic craniosynostoses (NSC) are believed to be multifactorial disorders, with a strong genetic component, due to possible gene–gene or gene–environment interactions that remain to be clearly identified. In this study we delved into the molecular signaling acting in calvarial tissue and cells from patients affected by nonsynodromic midline craniosynostosis, using a comparative analysis between fused and unfused sutures of each affected individuals. Using comparative microarray tissue gene expression profiling we have identified a subset of genes involved in the structure and function of the primary cilium, including the Bardet-Biedl syndrome 9 (BBS9) gene, which was recently associated to sagittal synostosis in a GWAS study. We therefore characterized BBS9 expression and cilium-related signaling in cells isolated from patients’ calvarial bone.

ORGANISM(S): Homo sapiens

PROVIDER: GSE79386 | GEO | 2018/05/31

REPOSITORIES: GEO

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Skeletal Stem Cell Powering Cranial Suture Fate: An Answer to Craniosynostosis (scRNA-seq)

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Single cell RNA-sequencing of Bardet Biedl Syndrome iPSC-derived hypothalamic neurons

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Project description:Craniosynostosis (CS) is the premature fusion of the cranial sutures,occurring either in isolated or syndromic form. CS was described in over 180 genetic syndromes that comprise 15-30% of all CS cases. Syndromic CS usually has a monogenic inheritance and originates in most of the patients from mutations within the FGFR1, FGFR2, FGFR3, and TWIST1 genes. Causative alterations in other genes, or rarely copy number variations (CNVs) were also reported. In this paper, we describe a patient with Noonan-like facial dysmorphism accompanied by intellectual disability, and compound CS, involving coronal, sagittal, and squamous sutures. We 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. The 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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