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. 2021 May 17:12:580761.
doi: 10.3389/fgene.2021.580761. eCollection 2021.

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

Xiaojun Chen  1 , Fatao Liu  2 , Zin Mar Aung  1 , Yan Zhang  1 , Gang Chai  1
Affiliations

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

Xiaojun Chen et al. Front Genet. .

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, NID2 was most frequently mutated (in 3/52 patients). PED4DIP, 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 ITGB4, NID2, or LAMA5. 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.

Keywords: hemifacial microsomia; mandibular hypoplasia; pathway enrichment analysis; rare germline mutations; whole-exome sequencing.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Typical photos and computed tomography scan images of a patient with hemifacial microsomia. From left to right: front, left-lateral, and upward view.
FIGURE 2
FIGURE 2
Gene mutations identified among the analyzed hemifacial microsomia (HFM) patient cohort. (A) A total of 13 known HFM genes were found to be mutated in the studied patient cohort, affecting 14 (16.92%) of the 52 analyzed patients. These included (B) three NID2 mutations, Asn202His, Asn658Lys, and Leu1136Arg, and (C) two PARD3B mutations, Pro630fs and Arg773Gln.
FIGURE 3
FIGURE 3
Analysis of rare, potentially causative mutations identified in the analyzed hemifacial microsomia (HFM) patient cohort. (A) List of genes found to harbor variants in >2 patients, ranked by mutation frequency. (B) Details of mutations (p.Ala141Thr, p.Lys154Arg, p.Cys19Gly, p.Asn1011Ser, p.Val120Ile, p.Gln535His, p.Pro2223Leu, and p.Gly2217Val.) in PDE4DIP that exhibited the greatest number of mutations and was the most frequently mutated gene among the analyzed patients.
FIGURE 4
FIGURE 4
Results of the ConsensusPathDB enrichment analysis of genes found to be mutated in >2 patients with hemifacial microsomia (HFM).
FIGURE 5
FIGURE 5
Results of the pathway enrichment analysis of genes found to be mutated in the analyzed hemifacial microsomia (HFM) patient cohort. The “laminin-interaction” pathway was predicted to be most significantly affected by the identified mutations (most often in ITGB4, LAMA5, or NID2) and was likely disrupted in 17 (32.69%) of the analyzed patients.
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