Whole-Genome Sequencing Identifies Two Novel Rare Mutations in BMP5 and BMP2 in Monozygotic Twins With Microtia

Abstract

Microtia is a rare congenital anomaly of the ear; it is regulated by both genetic and environmental factors. However, the mechanisms underlying its pathogenesis are unknown. In this study, the genomes of 2-year-old twin sisters with right microtia were sequenced using human genome-wide sequencing, an approach useful for identifying mutations in genes responsible for congenital microtia. The phenotypes of the twin sisters included congenital microtia on the right side, abnormal auricle shape in the right external ear, a peanut shape for the residual ear, and complete atresia of the right external auditory canal. In the twin sisters, we identified a previously unknown mutation in BMP5(exon4:c.833-4C>G), as well as a new mutation (exon2:c.G332T:p.S111I) in BMP2, both of which were confirmed using polymerase chain reaction-based amplification of the corresponding genome regions, followed by first-generation sequencing. The exon4:c.833-4C>G mutation in human BMP5 may be the main cause of microtia in the twin sisters. A pathogenic mutation in human BMP2 (exon2:c.G332T:p.S111I) may be responsible for the facial deformity in the twin sisters. Thus, our study demonstrates the potential of genome-wide sequencing for identifying novel mutations associated with microtia on the whole-genome scale and extends the mutation spectrum of BMP5. Additionally, our data suggest that BMP2 is another pathogenic gene associated with microtia.

Changes in the Transcriptome-Associated Co-Expression Profile of Embryonic External Ear Development After the BMP5 Gene Mutation

“…Ten pregnant F2 generation Bmp5 short-eared mice were obtained for the experiments. In this study, the mice were propagated through heterozygous mating, and homozygous and wild-type fetal mice in the same litter were used as experimental and control groups, respectively 3…”

“…The targeting lncRNA of miRNA can be predicted using the miRanda software and psRobot software, respectively. The targeted lncRNA of miRNA in animal samples and plant samples can be predicted 3. The data of target interaction relationship between miRNA and mRNA was differentially expressed, and the data file of target interaction relationship between miRNA and mRNA was directly imported into the Cytoscape software for visual editing 4.…”

“…The targeted lncRNA of miRNA in animal samples and plant samples can be predicted. 3 The data of target interaction relationship between miRNA and mRNA was differentially expressed, and the data file of target interaction relationship between miRNA and mRNA was directly imported into the Cytoscape software for visual editing. 4 miRNAs and circRNAs were screened using Cytoscape software to construct a circRNA and miRNA network based on binding sites (http:// manual.cytoscape.org/en/stable/index.html).…”

Genetics and Epigenetics in the Genesis and Development of Microtia

“…Bmp5 was highly expressed in the proliferative zone chondrocytes of the tibia of mice, and the expression increased with the differentiation of chondrocytes, indicating its importance in chondrocyte differentiation and proliferation 16 . Few reports about BMP5 and its association with nonsyndromic microtia have been reported 17,18 . More studies are needed to confirm this link.…”

BMP Signaling Pathway in Dentin Development and Diseases

“…On PNs, Bmp-5 expression is evident in ameloblasts during amelogenesis and is seen in chondrocytes and osteoblasts [ 48 , 49 , 50 ]. Mutations of BMP-5 gene are associated with short ears in humans and mice [ 51 , 52 ]. Additionally, genetic variants of BMP-5 are associated with susceptibility to osteoarthritis (OA) [ 53 , 54 ].…”