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The value of genome-wide analysis in craniosynostosis.

ABSTRACT: Background: This study assessed the diagnostic yield of high-throughput sequencing methods in a cohort of craniosynostosis (CS) patients not presenting causal variants identified through previous targeted analysis. Methods: Whole-genome or whole-exome sequencing (WGS/WES) was performed in a cohort of 59 patients (from 57 families) assessed by retrospective phenotyping as having syndromic or nonsyndromic CS. Results: A syndromic form was identified in 51% of the unrelated cases. A genetic cause was identified in 38% of syndromic cases, with novel variants detected in FGFR2 (a rare Alu insertion), TWIST1, TCF12, KIAA0586, HDAC9, FOXP1, and NSD2. Additionally, we report two patients with rare recurrent variants in KAT6A and YY1 as well as two patients with structural genomic aberrations: one with a 22q13 duplication and one with a complex rearrangement involving chromosome 2 (2p25 duplication including SOX11 and deletion of 2q22). Moreover, we identified potentially relevant variants in 87% of the remaining families with no previously detected causal variants, including novel variants in ADAMTSL4, ASH1L, ATRX, C2CD3, CHD5, ERF, H4C5, IFT122, IFT140, KDM6B, KMT2D, LTBP1, MAP3K7, NOTCH2, NSD1, SOS1, SPRY1, POLR2A, PRRX1, RECQL4, TAB2, TAOK1, TET3, TGFBR1, TCF20, and ZBTB20. Conclusion: These results confirm WGS/WES as a powerful diagnostic tool capable of either targeted in silico or broad genomic analysis depending on phenotypic presentation (e.g., classical or unusual forms of syndromic CS).

SUBMITTER: Topa A

PROVIDER: S-EPMC10839781 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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The value of genome-wide analysis in craniosynostosis.

Topa Alexandra A Rohlin Anna A Fehr André A Lovmar Lovisa L Stenman Göran G Tarnow Peter P Maltese Giovanni G Bhatti-Søfteland Madiha M Kölby Lars L

Frontiers in genetics 20240122

Background: This study assessed the diagnostic yield of high-throughput sequencing methods in a cohort of craniosynostosis (CS) patients not presenting causal variants identified through previous targeted analysis. Methods: Whole-genome or whole-exome sequencing (WGS/WES) was performed in a cohort of 59 patients (from 57 families) assessed by retrospective phenotyping as having syndromic or nonsyndromic CS. Results: A syndromic form was identified in 51% of the unrelated cas ...[more]

PMID: 38318288

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Project description:BackgroundCraniosynostosis (CS) conditions are included with the premature fusion of one or more multiple cranial sutures. As the second leading and most common craniofacial anomaly and orofacial clefts globally. Syndromic and nonsyndromic CS (NSCS) occur as a part of a genetic syndrome unlike Apert, Crouzon, Pfeiffer, Muenke, and Saethre-Chotzen syndromes. Approximately, 90% of the cases of CS arises from NSCS group and it is now a great challenge for the researcher and neurosurgeon for Indian-origin children, a great burden worldwide.Material and methodsStudy design: Prospective study of analysis sequence pattern on CS and NSCS from January 2007 to 2018 was carried out.Inclusion criteria: Diagnosed cases in syndromic and NSCS patients between 3 months and 14 years of age either preoperative or postoperative were included in the study of both groups (syndromic and NSCS).Exclusion criteria: Patients with primary microcephaly (secondary CS), postural plagiocephaly, incomplete data, no visual perception, and who were lost to follow-up, and who had no interest to participate the study were excluded from the study.Bioinformatic analysis: We have performed systematic bioinformatic analysis for all responsible genes by combining with using through the GeneDecks, Gene Runner, DAVID, and STRING databases.Genes testing: FGF family genes, MSX genes, such as Irf6, TP63, Dlx2, Dlx5, Pax3, Pax9, Bmp4, Tgf-beta2, and Tgf-beta3 were found to be involved in Cleft lip and cleft palate (CL/P), and Fgfr2, Fgfr1, Fgfr3, and TWIST, MSX, MSX1, 2 were found to be involved in both the groups of CS (SCS + NSCS).ResultsFGFR, MSX, Irf6, TP63, Dlx2, Dlx5, Pax3, Pax9, Bmp4, Tgf-beta2, and Tgf-beta3 demonstrated and find out that in CL/P, and Fgfr2, Fgfr1, Fgfr3, and Twist1 had accurate sequence data with more than accuracy of 95% reported with proper order with additional anomalies CS through newly developed tools.ConclusionNewly developed techniques of GeneDecks, Gene Runner, DAVID, and STRING databases gave better picture to analyze the larger population, patients (SCS + NSCS) with complex genetic, maternal, parental age, environmental, and stochastic factors contributing to NSCS networking, signaling, and pathways involvement. This bioinformatic tools analyzed better prediction of CS and NSCS sequences guiding us the newer invention modalities of pattern of screening and further development of recent future application.

Project description:Craniosynostosis refers to a condition during early development in which one or more of the fibrous sutures of the skull prematurely fuse by turning into bone, which produces recognizable patterns of cranial shape malformations depending on which suture(s) are affected. In addition to cases with isolated cranial dysmorphologies, craniosynostosis appears in syndromes that include skeletal features of the eyes, nose, palate, hands, and feet as well as impairment of vision, hearing, and intellectual development. Approximately 85% of the cases are nonsyndromic sporadic and emerge after de novo structural genome rearrangements or single nucleotide variation, while the remainders consist of syndromic cases following mendelian inheritance. By karyotyping, genome wide linkage, and CNV analyses as well as by whole exome and whole genome sequencing, numerous candidate genes for craniosynostosis belonging to the FGF, Wnt, BMP, Ras/ERK, ephrin, hedgehog, STAT, and retinoic acid signaling pathways have been identified. Many of the craniosynostosis-related candidate genes form a functional network based upon protein-protein or protein-DNA interactions. Depending on which node of this craniosynostosis-related network is affected by a gene mutation or a change in gene expression pattern, a distinct craniosynostosis syndrome or set of phenotypes ensues. Structural variations may alter the dosage of one or several genes or disrupt the genomic architecture of genes and their regulatory elements within topologically associated chromatin domains. These may exert dominant effects by either haploinsufficiency, dominant negative partial loss of function, gain of function, epistatic interaction, or alteration of levels and patterns of gene expression during development. Molecular mechanisms of dominant modes of action of these mutations may include loss of one or several binding sites for cognate protein partners or transcription factor binding sequences. Such losses affect interactions within functional networks governing development and consequently result in phenotypes such as craniosynostosis. Many of the novel variants identified by genome wide CNV analyses, whole exome and whole genome sequencing are incorporated in recently developed diagnostic algorithms for craniosynostosis.

Project description:BACKGROUND: Analyses of DNA sequences from cultivated microorganisms have revealed genome-wide, taxa-specific nucleotide compositional characteristics, referred to as genome signatures. These signatures have far-reaching implications for understanding genome evolution and potential application in classification of metagenomic sequence fragments. However, little is known regarding the distribution of genome signatures in natural microbial communities or the extent to which environmental factors shape them. RESULTS: We analyzed metagenomic sequence data from two acidophilic biofilm communities, including composite genomes reconstructed for nine archaea, three bacteria, and numerous associated viruses, as well as thousands of unassigned fragments from strain variants and low-abundance organisms. Genome signatures, in the form of tetranucleotide frequencies analyzed by emergent self-organizing maps, segregated sequences from all known populations sharing < 50 to 60% average amino acid identity and revealed previously unknown genomic clusters corresponding to low-abundance organisms and a putative plasmid. Signatures were pervasive genome-wide. Clusters were resolved because intra-genome differences resulting from translational selection or protein adaptation to the intracellular (pH approximately 5) versus extracellular (pH approximately 1) environment were small relative to inter-genome differences. We found that these genome signatures stem from multiple influences but are primarily manifested through codon composition, which we propose is the result of genome-specific mutational biases. CONCLUSIONS: An important conclusion is that shared environmental pressures and interactions among coevolving organisms do not obscure genome signatures in acid mine drainage communities. Thus, genome signatures can be used to assign sequence fragments to populations, an essential prerequisite if metagenomics is to provide ecological and biochemical insights into the functioning of microbial communities.

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The value of genome-wide analysis in craniosynostosis.

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The value of genome-wide analysis in craniosynostosis.

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