Common<i>cis</i>-regulatory variation modifies the penetrance of pathogenic<i>SHROOM3</i>variants in craniofacial microsomia

Pathogenic coding variants have been identified in thousands of genes, yet the mechanisms underlying the incomplete penetrance in individuals carrying these variants are poorly understood. In this study, in a cohort of 2009 craniofacial microsomia (CFM) patients of Chinese ancestry and 2625 Han Chinese controls, we identified multiple predicted pathogenic coding variants in <i>SHROOM3</i> in both CFM patients and healthy individuals. We found that the penetrance of CFM correlates with specific haplotype combinations containing likely pathogenic-coding <i>SHROOM3</i> variants and CFM-associated expression quantitative trait loci (eQTLs) of <i>SHROOM3</i> expression. Further investigations implicate specific eQTL combinations, such as rs1001322 or rs344131, in combination with other significant CFM-associated eQTLs, which we term combined eQTL phenotype modifiers (CePMods). We additionally show that rs344131, located within a regulatory enhancer region of <i>SHROOM3</i>, demonstrates allele-specific effects on enhancer activity and thus impacts expression levels of the associated <i>SHROOM3</i> allele harboring any rare coding variant. Our findings also suggest that CePMods may serve as pathogenic determinants, even in the absence of rare deleterious coding variants in <i>SHROOM3</i> This highlights the critical role of allelic expression in determining the penetrance and severity of craniofacial abnormalities, including microtia and facial asymmetry. Additionally, using quantitative phenotyping, we demonstrate that both microtia and facial asymmetry are present in two separate <i>Shroom3</i> mouse models, the severity of which is dependent on gene dosage. Our study establishes <i>SHROOM3</i> as a likely pathogenic gene for CFM and demonstrates eQTLs as determinants of modified penetrance in the manifestation of the disease in individuals carrying likely pathogenic rare coding variants.

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Publication Details

Journal
Genome Research
Published
2025-04-15
DOI
https://doi.org/10.1101/gr.280047.124
Citations
1
Primary Topic
dental development and anomalies
Type
article

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article

Commoncis-regulatory variation modifies the penetrance of pathogenicSHROOM3variants in craniofacial microsomia

M. De Silva, Jie Mi, Changqing Zeng, Shouqin Zhao et al.
1 citations
Genome Research
dental development and anomalies
article

Commoncis-regulatory variation modifies the penetrance of pathogenicSHROOM3variants in craniofacial microsomia

M. De Silva, Jie Mi, Changqing Zeng, Shouqin Zhao, Matthew D. Durbin, Liza L. Cox, Hailin Shan, Tiong Yang Tan, Zhenni Shi, Jia Liu, Yong‐Biao Zhang, Lyndon Gallacher, Hao Zhu, Timothy C. Cox, Qingguo Zhang, Stylianos E. Antonarakis, Baichuan Xiao, Jiao Zhang, Jiaqiang Wang, Ying Li, Jiqiang Liu, Ziqiu Meng, Stephanie M. Ware, R. E. Lang, X. Tang, Hou-Feng Zheng, Soumya Rao
article en
1 citations

Abstract

Pathogenic coding variants have been identified in thousands of genes, yet the mechanisms underlying the incomplete penetrance in individuals carrying these variants are poorly understood. In this study, in a cohort of 2009 craniofacial microsomia (CFM) patients of Chinese ancestry and 2625 Han Chinese controls, we identified multiple predicted pathogenic coding variants in <i>SHROOM3</i> in both CFM patients and healthy individuals. We found that the penetrance of CFM correlates with specific haplotype combinations containing likely pathogenic-coding <i>SHROOM3</i> variants and CFM-associated expression quantitative trait loci (eQTLs) of <i>SHROOM3</i> expression. Further investigations implicate specific eQTL combinations, such as rs1001322 or rs344131, in combination with other significant CFM-associated eQTLs, which we term combined eQTL phenotype modifiers (CePMods). We additionally show that rs344131, located within a regulatory enhancer region of <i>SHROOM3</i>, demonstrates allele-specific effects on enhancer activity and thus impacts expression levels of the associated <i>SHROOM3</i> allele harboring any rare coding variant. Our findings also suggest that CePMods may serve as pathogenic determinants, even in the absence of rare deleterious coding variants in <i>SHROOM3</i> This highlights the critical role of allelic expression in determining the penetrance and severity of craniofacial abnormalities, including microtia and facial asymmetry. Additionally, using quantitative phenotyping, we demonstrate that both microtia and facial asymmetry are present in two separate <i>Shroom3</i> mouse models, the severity of which is dependent on gene dosage. Our study establishes <i>SHROOM3</i> as a likely pathogenic gene for CFM and demonstrates eQTLs as determinants of modified penetrance in the manifestation of the disease in individuals carrying likely pathogenic rare coding variants.

Genome ResearchVol. 35(5)
University of Geneva (CH), Beijing Tongren Hospital (CN), Army Medical University (CN), Capital Medical University (CN), Chinese Academy of Sciences (CN), Chinese Academy of Medical Sciences & Peking Union Medical College (CN), Beijing Institute of Genomics (CN), Westlake University (CN), Soochow University (CN), Daping Hospital (CN), Victorian Clinical Genetics Services (AU), Second Affiliated Hospital of Soochow University (CN), Beijing Children’s Hospital (CN), Indiana University School of Medicine, Indiana University – Purdue University Indianapolis (US), University of Missouri–Kansas City (US), Beihang University (CN), Ministry of Industry and Information Technology (CN)
National Natural Science Foundation of China, Beijing Municipal Commission of Education, Natural Science Foundation of Beijing Municipality, H2020 European Research Council
Good health and well-being
dental development and anomalies
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