IADR Abstract Archives
Whole Exome Sequencing Identifies Damaging Variants in Indonesians With Clefts
Objectives: Approximately 70% of cleft lip with or without palate and 50% of cleft palate cases are non-syndromic (nsOFC). The interaction between genomics, genetic and environmental factors have been implicated in the etiology of nsOFC.
In the current study, we investigated the contributions of rare and novel genetic variants in known cleft genes using whole exome sequencing data of Indonesians with nsOFC
Methods: Whole exome sequencing was conducted on 6 individuals (5 with nsOFC and 1 unaffected). Called variants were annotated using Annovar. SNVs and indels in known cleft candidate genes were identified among the exonic variants. These variants were further filtered for novelty and rarity using MAF of 0 and 1% as reported in genome aggregate database, exome aggregate consortium and 1000 genome project database. Deleteriousness of these filtered variants were predicted using polyphen, SIFT and a CADD score cutoff of ≥ 15.Variants were prioritized if they were predicted to be deleterious by CADD, SIFT and PolyPhen2. ACMG criteria was also used to assess pathogenicity using VARSOME. Pathogenic amino acid changes effect on protein structure and function were identified using HOPE.
Results: We identified a novel variant in CORIN that was deleterious across all the 3 prediction tools and predicted to be likely damaging by HOPE. Rare deleterious variants (MAF <1%) were also identified in 5 genes (PAX7, SOS1, TULP4, MTHFD1L and MMACHC).
Conclusions: Our study provides additional evidence for the role of PAX7, TULP4, SOS1 and MTHFD1L in nsOFC development. We also identified a novel variant in CORIN. This is the first time CORIN is implicated in nsOFC development in humans. The identification of rare variants (<1%) in these genes could explain the missing heritability for nsOFC not explained by common variants in GWAS.
In the current study, we investigated the contributions of rare and novel genetic variants in known cleft genes using whole exome sequencing data of Indonesians with nsOFC
Methods: Whole exome sequencing was conducted on 6 individuals (5 with nsOFC and 1 unaffected). Called variants were annotated using Annovar. SNVs and indels in known cleft candidate genes were identified among the exonic variants. These variants were further filtered for novelty and rarity using MAF of 0 and 1% as reported in genome aggregate database, exome aggregate consortium and 1000 genome project database. Deleteriousness of these filtered variants were predicted using polyphen, SIFT and a CADD score cutoff of ≥ 15.Variants were prioritized if they were predicted to be deleterious by CADD, SIFT and PolyPhen2. ACMG criteria was also used to assess pathogenicity using VARSOME. Pathogenic amino acid changes effect on protein structure and function were identified using HOPE.
Results: We identified a novel variant in CORIN that was deleterious across all the 3 prediction tools and predicted to be likely damaging by HOPE. Rare deleterious variants (MAF <1%) were also identified in 5 genes (PAX7, SOS1, TULP4, MTHFD1L and MMACHC).
Conclusions: Our study provides additional evidence for the role of PAX7, TULP4, SOS1 and MTHFD1L in nsOFC development. We also identified a novel variant in CORIN. This is the first time CORIN is implicated in nsOFC development in humans. The identification of rare variants (<1%) in these genes could explain the missing heritability for nsOFC not explained by common variants in GWAS.