Whole-Exome Sequencing Reveals Rare Germline Mutations in Patients With Hemifacial Microsomia

Overview

Journal Front Genet

Date 2021 Jun 3

PMID 34079577

Citations 2

Authors

Xiaojun Chen

Fatao Liu

Zin Mar Aung

Yan Zhang

Gang Chai

Affiliations

Soon will be listed here.

Abstract

Hemifacial microsomia (HFM) is a rare congenital disease characterized by a spectrum of craniomaxillofacial malformations, including unilateral hypoplasia of the mandible and surrounding structures. Genetic predisposition for HFM is evident but the causative genes have not been fully understood. Thus, in the present study, we used whole-exome sequencing to screen 52 patients with HFM for rare germline mutations. We revealed 3,341 rare germline mutations in this patient cohort, including those in 13 genes previously shown to be associated with HFM. Among these HFM-related genes, was most frequently mutated (in 3/52 patients). , which has not been previously associated with HFM, exhibited rare variants most frequently (in 7/52 patients). Pathway enrichment analysis of genes that were mutated in >2 patients predicted the "laminin interactions" pathway to be most significantly disrupted, predominantly by mutations in , , or . In summary, this study is the first to identify rare germline mutations in HFM. The likely disruptions in the signaling pathways due to the mutations reported here may be considered potential causes of HFM.

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References

Rooryck C, Souakri N, Cailley D, Bouron J, Goizet C, Delrue M . Array-CGH analysis of a cohort of 86 patients with oculoauriculovertebral spectrum. Am J Med Genet A. 2010; 152A(8):1984-9. DOI: 10.1002/ajmg.a.33491. View

Snuderl M, Kannan K, Pfaff E, Wang S, Stafford J, Serrano J . Recurrent homozygous deletion of DROSHA and microduplication of PDE4DIP in pineoblastoma. Nat Commun. 2018; 9(1):2868. PMC: 6054684. DOI: 10.1038/s41467-018-05029-3. View

Bilguvar K, Ozturk A, Louvi A, Kwan K, Choi M, Tatli B . Whole-exome sequencing identifies recessive WDR62 mutations in severe brain malformations. Nature. 2010; 467(7312):207-10. PMC: 3129007. DOI: 10.1038/nature09327. View

Su P, Liu Y, Yu J, Chen J, Chen S, Lai Y . Facial asymmetry and clinical manifestations in patients with novel insertion of the TCOF1 gene. Clin Genet. 2011; 82(5):460-5. DOI: 10.1111/j.1399-0004.2011.01765.x. View

Er T, Su Y, Wu C, Chen C, Wang J, Hsieh T . Targeted next-generation sequencing for molecular diagnosis of endometriosis-associated ovarian cancer. J Mol Med (Berl). 2016; 94(7):835-47. DOI: 10.1007/s00109-016-1395-2. View

Kamburov A, Stelzl U, Lehrach H, Herwig R . The ConsensusPathDB interaction database: 2013 update. Nucleic Acids Res. 2012; 41(Database issue):D793-800. PMC: 3531102. DOI: 10.1093/nar/gks1055. View

Koboldt D, Zhang Q, Larson D, Shen D, McLellan M, Lin L . VarScan 2: somatic mutation and copy number alteration discovery in cancer by exome sequencing. Genome Res. 2012; 22(3):568-76. PMC: 3290792. DOI: 10.1101/gr.129684.111. View

Ballesta-Martinez M, Lopez-Gonzalez V, Dulcet L, Rodriguez-Santiago B, Garcia-Minaur S, Guillen-Navarro E . Autosomal dominant oculoauriculovertebral spectrum and 14q23.1 microduplication. Am J Med Genet A. 2013; 161A(8):2030-5. DOI: 10.1002/ajmg.a.36007. View

Tuin A, Tahiri Y, Paine K, Paliga J, Taylor J, Bartlett S . Clarifying the relationships among the different features of the OMENS+ classification in craniofacial microsomia. Plast Reconstr Surg. 2014; 135(1):149e-156e. DOI: 10.1097/PRS.0000000000000843. View

10.

Kumar P, Henikoff S, Ng P . Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc. 2009; 4(7):1073-81. DOI: 10.1038/nprot.2009.86. View

11.

Rooryck C, Stef M, Burgelin I, Simon D, Souakri N, Thambo J . 2.3 Mb terminal deletion in 12p13.33 associated with oculoauriculovertebral spectrum and evaluation of WNT5B as a candidate gene. Eur J Med Genet. 2009; 52(6):446-9. DOI: 10.1016/j.ejmg.2009.08.005. View

12.

Zhang Y, Hu J, Zhang J, Zhou X, Li X, Gu C . Genome-wide association study identifies multiple susceptibility loci for craniofacial microsomia. Nat Commun. 2016; 7:10605. PMC: 4748111. DOI: 10.1038/ncomms10605. View

13.

McClellan J, King M . Genetic heterogeneity in human disease. Cell. 2010; 141(2):210-7. DOI: 10.1016/j.cell.2010.03.032. View

14.

Li H, Durbin R . Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009; 25(14):1754-60. PMC: 2705234. DOI: 10.1093/bioinformatics/btp324. View

15.

Terhal P, Rosler B, Kohlhase J . A family with features overlapping Okihiro syndrome, hemifacial microsomia and isolated Duane anomaly caused by a novel SALL4 mutation. Am J Med Genet A. 2006; 140(3):222-6. DOI: 10.1002/ajmg.a.31060. View

16.

Zhu L, Peng J, Harutyunyan K, Garcia M, Justice M, Belmont J . Craniofacial, skeletal, and cardiac defects associated with altered embryonic murine Zic3 expression following targeted insertion of a PGK-NEO cassette. Front Biosci. 2006; 12:1680-90. DOI: 10.2741/2180. View

17.

Ala-Mello S, Siggberg L, Knuutila S, von Koskull H, Taskinen M, Peippo M . Further evidence for a relationship between the 5p15 chromosome region and the oculoauriculovertebral anomaly. Am J Med Genet A. 2008; 146A(19):2490-4. DOI: 10.1002/ajmg.a.32479. View

18.

McLaren W, Gil L, Hunt S, Riat H, Ritchie G, Thormann A . The Ensembl Variant Effect Predictor. Genome Biol. 2016; 17(1):122. PMC: 4893825. DOI: 10.1186/s13059-016-0974-4. View

19.

Abul-Husn N, Manickam K, Jones L, Wright E, Hartzel D, Gonzaga-Jauregui C . Genetic identification of familial hypercholesterolemia within a single U.S. health care system. Science. 2016; 354(6319). DOI: 10.1126/science.aaf7000. View

20.

Colovati M, Bragagnolo S, Guilherme R, Dantas A, Soares M, Kim C . Atypical 581-kb 22q11.21 Deletion in a Patient with Oculo-Auriculo-Vertebral Spectrum Phenotype. Cytogenet Genome Res. 2016; 147(2-3):130-4. DOI: 10.1159/000444228. View