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Whole-genome sequencing reveals de-novo mutations associated with nonsyndromic cleft lip/palate.

ABSTRACT: The majority (85%) of nonsyndromic cleft lip with or without cleft palate (nsCL/P) cases occur sporadically, suggesting a role for de novo mutations (DNMs) in the etiology of nsCL/P. To identify high impact protein-altering DNMs that contribute to the risk of nsCL/P, we conducted whole-genome sequencing (WGS) analyses in 130 African case-parent trios (affected probands and unaffected parents). We identified 162 high confidence protein-altering DNMs some of which are based on available evidence, contribute to the risk of nsCL/P. These include novel protein-truncating DNMs in the ACTL6A, ARHGAP10, MINK1, TMEM5 and TTN genes; as well as missense variants in ACAN, DHRS3, DLX6, EPHB2, FKBP10, KMT2D, RECQL4, SEMA3C, SEMA4D, SHH, TP63, and TULP4. Many of these protein-altering DNMs were predicted to be pathogenic. Analysis using mouse transcriptomics data showed that some of these genes are expressed during the development of primary and secondary palate. Gene-set enrichment analysis of the protein-altering DNMs identified palatal development and neural crest migration among the few processes that were significantly enriched. These processes are directly involved in the etiopathogenesis of clefting. The analysis of the coding sequence in the WGS data provides more evidence of the opportunity for novel findings in the African genome.

SUBMITTER: Awotoye W

PROVIDER: S-EPMC9273634 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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Whole-genome sequencing reveals de-novo mutations associated with nonsyndromic cleft lip/palate.

Awotoye Waheed W Mossey Peter A PA Hetmanski Jacqueline B JB Gowans Lord J J LJJ Eshete Mekonen A MA Adeyemo Wasiu L WL Alade Azeez A Zeng Erliang E Adamson Olawale O Naicker Thirona T Anand Deepti D Adeleke Chinyere C Busch Tamara T Li Mary M Petrin Aline A Aregbesola Babatunde S BS Braimah Ramat O RO Oginni Fadekemi O FO Oladele Ayodeji O AO Oladayo Abimbola A Kayali Sami S Olotu Joy J Hassan Mohaned M Pape John J Donkor Peter P Arthur Fareed K N FKN Obiri-Yeboah Solomon S Sabbah Daniel K DK Agbenorku Pius P Plange-Rhule Gyikua G Oti Alexander Acheampong AA Gogal Rose A RA Beaty Terri H TH Taub Margaret M Marazita Mary L ML Schnieders Michael J MJ Lachke Salil A SA Adeyemo Adebowale A AA Murray Jeffrey C JC Butali Azeez A

Scientific reports 20220711 1

The majority (85%) of nonsyndromic cleft lip with or without cleft palate (nsCL/P) cases occur sporadically, suggesting a role for de novo mutations (DNMs) in the etiology of nsCL/P. To identify high impact protein-altering DNMs that contribute to the risk of nsCL/P, we conducted whole-genome sequencing (WGS) analyses in 130 African case-parent trios (affected probands and unaffected parents). We identified 162 high confidence protein-altering DNMs some of which are based on available evidence, ...[more]

PMID: 35817949

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Project description:ObjectiveTo explore the association between de novo mutations (DNM) and non-syndromic cleft lip with or without palate (NSCL/P) using case-parent trio design.MethodsWhole-exome sequencing was conducted for twenty-two NSCL/P trios and Genome Analysis ToolKit (GATK) was used to identify DNM by comparing the alleles of the cases and their parents. Information of predictable functions was annotated to the locus with SnpEff. Enrichment analysis for DNM was conducted to test the difference between the actual number and the expected number of DNM, and to explore whether there were genes with more DNM than expected. NSCL/P-related genes indicated by previous studies with solid evidence were selected by literature reviewing. Protein-protein interactions analysis was conducted among the genes with protein-altering DNM and NSCL/P-related genes. R package "denovolyzeR" was used for the enrichment analysis (Bonferroni correction: P=0.05/n, n is the number of genes in the whole genome range). Protein-protein interactions among genes with DNM and genes with solid evidence on the risk factors of NSCL/P were predicted depending on the information provided by STRING database.ResultsA total of 339 908 SNPs were qualified for the subsequent analysis after quality control. The number of high confident DNM identified by GATK was 345. Among those DNM, forty-four DNM were missense mutations, one DNM was nonsense mutation, two DNM were splicing site mutations, twenty DNM were synonymous mutations and others were located in intron or intergenic regions. The results of enrichment analysis showed that the number of protein-altering DNM on the exome regions was larger than expected (P < 0.05), and five genes (KRTCAP2, HMCN2, ANKRD36C, ADGRL2 and DIPK2A) had more DNM than expected (P < 0.05/(2×19 618)). Protein-protein interaction analysis was conducted among forty-six genes with protein-altering DNM and thirteen genes associated with NSCL/P selected by literature reviewing. Six pairs of interactions occurred between the genes with DNM and known NSCL/P-related genes. The score measuring the confidence level of the predicted interaction between RGPD4 and SUMO1 was 0.868, which was higher than the scores for other pairs of genes.ConclusionOur study provided novel insights into the development of NSCL/P and demonstrated that functional analyses of genes carrying DNM were warranted to understand the genetic architecture of complex diseases.

Dataset Information

Whole-genome sequencing reveals de-novo mutations associated with nonsyndromic cleft lip/palate.

Publications

Whole-genome sequencing reveals de-novo mutations associated with nonsyndromic cleft lip/palate.

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