Genome-wide analysis of copy-number variation in humans with cleft lip and/or cleft palate identifies COBLL1, RIC1, and ARHGEF38 as clefting genes

Lansdon, Lisa A.; Dickinson, Amanda J.G.; Arlis, Sydney; Liu, Huan; Hlas, Arman; Hahn, Alyssa; Bonde, Greg; Long, Abby; Standley, Jennifer; Tyryshkina, Anastasia; Wehby, George L.; Lee, Nanette R.; Daack‐Hirsch, Sandra; Mohlke, Karen L.; Girirajan, Santhosh; Darbro, Benjamin W.; Cornell, Robert A.; Houston, Douglas; Murray, Jeffrey C.; Manak, J. Robert

doi:10.1016/j.ajhg.2022.11.012

Cited by 4 publications

(3 citation statements)

References 141 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Another limitation of this study is that Copy Number Variants (CNVs) were not included in the analysis. Although it is unlikely that, with the present small sample size, we could identify a CNV contribution, it has been recently suggested [51] that their role in orofacial clefts has been relatively overlooked.…”

mentioning

confidence: 66%

Ultra-Rare Variants Identify Biological Pathways and Candidate Genes in the Pathobiology of Non-Syndromic Cleft Palate Only

et al. 2023

View full text Add to dashboard Cite

In recent decades, many efforts have been made to elucidate the genetic causes of non-syndromic cleft palate (nsCPO), a complex congenital disease caused by the interaction of several genetic and environmental factors. Since genome-wide association studies have evidenced a minor contribution of common polymorphisms in nsCPO inheritance, we used whole exome sequencing data to explore the role of ultra-rare variants in this study. In a cohort of 35 nsCPO cases and 38 controls, we performed a gene set enrichment analysis (GSEA) and a hypergeometric test for assessing significant overlap between genes implicated in nsCPO pathobiology and genes enriched in ultra-rare variants in our cohort. GSEA highlighted an enrichment of ultra-rare variants in genes principally belonging to cytoskeletal protein binding pathway (Probability Density Function corrected p-value = 1.57 × 10−4); protein-containing complex binding pathway (p-value = 1.06 × 10−2); cell adhesion molecule binding pathway (p-value = 1.24 × 10−2); ECM-receptor interaction pathway (p-value = 1.69 × 10−2); and in the Integrin signaling pathway (p-value = 1.28 × 10−2). Two genes implicated in nsCPO pathobiology, namely COL2A1 and GLI3, ranked among the genes (n = 34) with nominal enrichment in the ultra-rare variant collapsing analysis (Fisher’s exact test p-value < 0.05). These genes were also part of an independent list of genes highly relevant to nsCPO biology (n = 25). Significant overlap between the two sets of genes (hypergeometric test p-value = 5.86 × 10−3) indicated that enriched genes are likely to be implicated in physiological palate development and/or the pathological processes of oral clefting. In conclusion, ultra-rare variants collectively impinge on biological pathways crucial to nsCPO pathobiology and point to candidate genes that may contribute to the individual risk of disease. Sequencing can be an effective approach to identify candidate genes and pathways for nsCPO.

show abstract

mentioning

confidence: 66%

Ultra-Rare Variants Identify Biological Pathways and Candidate Genes in the Pathobiology of Non-Syndromic Cleft Palate Only

et al. 2023

View full text Add to dashboard Cite

show abstract

“…Specific recommendations for diagnostic testing will continue to evolve as more data on the contribution of rare variants to both isolated and familial clefting accrues. Recent data supporting a role for rare copy number variants (Lansdon et al, 2023) and how to incorporate other genomic variants, including those in non-coding regions (Zieger et al, 2023), will require additional data and validation through analytic trials. But as some individuals with a positive family history will have questions about risks consideration should be given to sequencing studies to identify variants that might suggest higher than what epidemiologic recurrence risks alone would support.…”

Section: Discussionmentioning

confidence: 99%

Rare variants found in multiplex families with orofacial clefts: Does expanding the phenotype make a difference?

Perez

Chung

Head

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

Whole-exome sequencing (WES) is now a relatively straightforward process to identify causal variants in Mendelian disorders. However, the same is not true for WES in families where the inheritance patterns are less clear, and a complex etiology is suspected. Orofacial clefts (OFCs) are highly heritable birth defects with both Mendelian and complex etiologies. The phenotypic spectrum of OFCs may include overt clefts and several subclinical phenotypes, such as discontinuities in the orbicularis oris muscle (OOM) in the upper lip, velopharyngeal insufficiency (VPI), microform clefts or bifid uvulas. We hypothesize that expanding the OFC phenotype to include these phenotypes can clarify inheritance patterns in multiplex families, making them appear more Mendelian. We performed whole-exome sequencing to find rare, likely causal genetic variants in 31 multiplex OFC families, which included families with multiple individuals with OFCs and individuals with subclinical phenotypes. We identified likely causal variants in COL11A2, IRF6, KLF4, SHROOM3, SMC3, TP63, and TBX3 in seven families. Although we did not find clear evidence supporting the subclinical phenotype hypothesis, our findings support a role for rare variants in the etiology of OFCs.

show abstract

“…Specific recommendations for diagnostic testing will continue to evolve as more data on the contribution of rare and common variants to both isolated and familial clefting accrues. Recent data supporting a role for rare copy number variants (Lansdon et al, 2023) and how to incorporate other genomic variants, including those in non‐coding regions (Zieger et al, 2023), will require additional data and validation through analytic trials. As individuals with a positive family history might have questions about risks, consideration should be given to sequencing studies to identify variants that might suggest higher recurrence risks than what epidemiologic studies alone would support.…”

Section: Discussionmentioning

confidence: 99%

Rare variants found in multiplex families with orofacial clefts: Does expanding the phenotype make a difference?

Perez

Chung

Head

et al. 2023

American J of Med Genetics Pt A

Self Cite

View full text Add to dashboard Cite

Exome sequencing (ES) is now a relatively straightforward process to identify causal variants in Mendelian disorders. However, the same is not true for ES in families where the inheritance patterns are less clear, and a complex etiology is suspected. Orofacial clefts (OFCs) are highly heritable birth defects with both Mendelian and complex etiologies. The phenotypic spectrum of OFCs may include overt clefts and several subclinical phenotypes, such as discontinuities in the orbicularis oris muscle (OOM) in the upper lip, velopharyngeal insufficiency (VPI), microform clefts or bifid uvulas. We hypothesize that expanding the OFC phenotype to include these phenotypes can clarify inheritance patterns in multiplex families, making them appear more Mendelian. We performed exome sequencing to find rare, likely causal genetic variants in 31 multiplex OFC families, which included families with multiple individuals with OFCs and individuals with subclinical phenotypes. We identified likely causal variants in COL11A2, IRF6, SHROOM3, SMC3, TBX3, and TP63 in six families. Although we did not find clear evidence supporting the subclinical phenotype hypothesis, our findings support a role for rare variants in the etiology of OFCs.

show abstract

Genome-wide analysis of copy-number variation in humans with cleft lip and/or cleft palate identifies COBLL1, RIC1, and ARHGEF38 as clefting genes

Cited by 4 publications

References 141 publications

Ultra-Rare Variants Identify Biological Pathways and Candidate Genes in the Pathobiology of Non-Syndromic Cleft Palate Only

Ultra-Rare Variants Identify Biological Pathways and Candidate Genes in the Pathobiology of Non-Syndromic Cleft Palate Only

Rare variants found in multiplex families with orofacial clefts: Does expanding the phenotype make a difference?

Rare variants found in multiplex families with orofacial clefts: Does expanding the phenotype make a difference?

Contact Info

Product

Resources

About