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Review of Recurrently Mutated Genes in Craniosynostosis Supports Expansion of Diagnostic Gene Panels.

ABSTRACT: Craniosynostosis, the premature fusion of the cranial sutures, affects ~1 in 2000 children. Although many patients with a genetically determined cause harbor a variant in one of just seven genes or have a chromosomal abnormality, over 60 genes are known to be recurrently mutated, thus comprising a long tail of rarer diagnoses. Genome sequencing for the diagnosis of rare diseases is increasingly used in clinical settings, but analysis of the data is labor intensive and involves a trade-off between achieving high sensitivity or high precision. PanelApp, a crowd-sourced disease-focused set of gene panels, was designed to enable prioritization of variants in known disease genes for a given pathology, allowing enhanced identification of true-positives. For heterogeneous disorders like craniosynostosis, these panels must be regularly updated to ensure that diagnoses are not being missed. We provide a systematic review of genetic literature on craniosynostosis over the last 5 years, including additional results from resequencing a 42-gene panel in 617 affected individuals. We identify 16 genes (representing a 25% uplift) that should be added to the list of bona fide craniosynostosis disease genes and discuss the insights that these new genes provide into pathophysiological mechanisms of craniosynostosis.

SUBMITTER: Tooze RS

PROVIDER: S-EPMC10048212 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Review of Recurrently Mutated Genes in Craniosynostosis Supports Expansion of Diagnostic Gene Panels.

Tooze Rebecca S RS Calpena Eduardo E Weber Astrid A Wilson Louise C LC Twigg Stephen R F SRF Wilkie Andrew O M AOM

Genes 20230228 3

Craniosynostosis, the premature fusion of the cranial sutures, affects ~1 in 2000 children. Although many patients with a genetically determined cause harbor a variant in one of just seven genes or have a chromosomal abnormality, over 60 genes are known to be recurrently mutated, thus comprising a long tail of rarer diagnoses. Genome sequencing for the diagnosis of rare diseases is increasingly used in clinical settings, but analysis of the data is labor intensive and involves a trade-off betwee ...[more]

PMID: 36980886

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Project description:BackgroundCancer genes tend to be highly mutated under positive selection. Better understanding the recurrently mutated genes (RMGs) in cancer is critical for explicating the mechanisms of tumorigenesis and providing vital clues for therapy. Although some studies have investigated functional impacts of RMGs in specific cancer types, a comprehensive analysis of RMGs and their mutational impacts across cancers is still needed.MethodsWe obtained data from The Cancer Genome Atlas (TCGA) and calculated mutation rate of each gene in 31 cancer types. Functional analysis was performed to identify the important signaling pathways and enriched protein types of RMGs. In order to evaluate functional impacts of RMGs, differential expression, survival, and pairwise mutation patterns analyses were performed.ResultsTotally, we identified 897 RMGs and 624 of them were specifically mutant in only a single cancer type. Functional analysis demonstrated that these RMGs were enriched in hydrolases, cytoskeletal protein, and pathways like MAPK, cell cycle, PI3K-Akt, ECM receptor interaction, and energy metabolism. The differentially expressed genes potentially affected by the same common RMG showed a relatively low overlap across different cancer types. For the 19 Mucin (MUC) family genes, nine of them were RMGs and four of them (MUC17, MUC5B, MUC4, and MUC16) were common RMGs shared in 8 to 17 cancer types. The results showed that recurrent mutations in MUC genes were significantly associated with better survival prognosis. Only a small part of RMGs was differentially expressed due to their own mutations and most of them were downregulated. In addition, pairwise mutation pattern analysis revealed the high frequency of co-occurred mutations among RMGs in STAD.ConclusionThrough the functional analysis of RMGs, we found that six signaling pathways were disrupted in most cancer types and that energy metabolism was abnormal in tumors. The results also revealed a strong correlation between recurrently mutated genes from MUC family and human survival. In addition, gene expression and survival prognosis were associated with different mutation types of RMGs.

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Review of Recurrently Mutated Genes in Craniosynostosis Supports Expansion of Diagnostic Gene Panels.

Publications

Review of Recurrently Mutated Genes in Craniosynostosis Supports Expansion of Diagnostic Gene Panels.

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