Identification of a second <i><scp>HOXA2</scp></i> nonsense mutation in a family with autosomal dominant non‐syndromic microtia and distinctive ear morphology

Piceci, F.; Morlino, Silvia; Castori, Marco; Buffone, Elsa; Luca, Alessandro De; Grammatico, Paola; Guida, Valentina

doi:10.1111/cge.12845

Cited by 25 publications

(15 citation statements)

References 22 publications

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“…Pedigree studies demonstrate both autosomal-dominant and autosomal-recessive patterns of inheritance (Brown et al, 2013;Piceci et al, 2017;Chen et al, 2018;Lupo et al, 2019; FIGURE 2 | Protein-to-protein interactions of candidate genes with known microtia-atresia associated pathways. (A) HOXA4 directly interacts with RARA of the RA pathway, detected in three families (II, III, V); (B) TBX10 interacts directly or indirectly with WINT11 of the Wnt pathway; (C) AMER1 interacts indirectly with WINT3A of the Wnt pathway.…”

Section: Discussionmentioning

confidence: 99%

“…HOX genes encode a set of proteins that have a conserved homeodomain of 60 amino acids, carrying a vital role of building and maintaining the sensorimotor circultry of vertebrates. Both mutations in HOXA1 or HOXA2 have been reported to result in microtia-atresia (Qiao et al, 2015;Piceci et al, 2017). Homeobox protein HOXA4 serves to locate cells on the anterior-posterior axis.…”

Section: Discussionmentioning

confidence: 99%

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Whole-Exome Sequencing of Discordant Monozygotic Twin Families for Identification of Candidate Genes for Microtia-Atresia

et al. 2020

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Objective: We used data from twins and their families to probe the genetic factors contributing to microtia-atresia, in particular, early post-twinning variations that potentially account for the discordant phenotypes of monozygotic twin pairs. Methods: Six families of monozygotic twins discordant for congenital microtia-atresia were recruited for study. The six patients shared a consistent clinical phenotype of unilateral microtia-atresia. Whole-exome sequencing (WES) was performed for all six twin pairs and their parents. Family segregation and multiple bioinformatics methods were applied to identify suspicious mutations in all families. Recurring mutations commonly detected in at least two families were highlighted. All variants were validated via Sanger sequencing. Gene Ontology (GO) analysis was performed to identify candidate gene sets and related pathways. Copy number variation (CNV), linkage analysis, association analysis and machine learning methods were additionally applied to isolate candidate mutations, and comparative genomics and structural modeling tools used to evaluate their potential roles in onset of microtia-atresia. Results: Our analyses revealed 61 genes with suspected mutations associated with microtia-atresia. Five (HOXA4, MUC6, CHST15, TBX10, and AMER1) contained 7 de novo mutations that appeared in at least two families, which have been previously reported as pathogenic for other diseases. Among these, HOXA4 (c.920A>C, p.H307P) was determined as the most likely pathogenic variant for microtia-atresia. GO analysis revealed four gene sets involving 11 pathways potentially related to underlying pathogenesis of the disease. CNVs in three genes (UGT2B17, OVOS, and KATNAL2) were detected in at least two families. Linkage analysis disclosed 13 extra markers for the disease, of which two (FGFR1 and EYA1) were validated via machine learning analysis as plausible candidate genes for the disease.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Whole-Exome Sequencing of Discordant Monozygotic Twin Families for Identification of Candidate Genes for Microtia-Atresia

et al. 2020

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“…A small number of studies have also focused on the HOXA2 gene as a genetic cause of isolated microtia. Identification of pathogenic mutations in HOXA2 was reported in three different isolated bilateral microtia families [ 23 – 25 ], prompting researchers to propose that HOXA2 may be among genes responsible for the pathogenesis of isolated microtia. However, studies that have focused on sporadic microtia patients have found no pathogenic mutations in HOXA2 [ 26 , 27 ].…”

Section: Discussionmentioning

confidence: 99%

Target sequencing of 307 deafness genes identifies candidate genes implicated in microtia

et al. 2017

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Microtia is a congenital malformation of the external ear caused by genetic and/or environmental factors. However, no causal genetic mutations have been identified in isolated microtia patients. In this study, we utilized targeted genomic capturing combined with next-generation sequencing to screen for mutations in 307 deafness genes in 32 microtia patients. Forty-two rare heterozygous mutations in 25 genes, including 22 novel mutations in 24 isolated unilateral microtia cases were identified. Pathway analysis found five pathways especially focal adhesion pathway and ECM-receptor interaction pathway were significantly associated with microtia. The low-frequency variants association study was used and highlighted several strong candidate genes MUC4, MUC6, COL4A4, MYO7A, AKAP12, COL11A1, DSPP, ESPN, GPR98, PCDH15, BSN, CACNA1D, TPRN, and USH1C for microtia (P = 2.51 × 10−4). Among these genes, COL4A4 and COL11A1 may lead to microtia through focal adhesion pathway and ECM-receptor interaction pathway which are connected to the downstream Wnt signaling pathway. The present results indicate that certain genes may affect both external/middle and inner ear development, and demonstrate the benefits of using a capture array in microtia patients.

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“…Genetic studies have made great progress in understanding ear development and function by identifying underlying genetic defects of certain diseases, especially in hearing loss, but less is known about genetic control of external ear morphogenesis. To date, only HOXA2 mutations have been reported as responsible for isolated bilateral microtia with or without hearing loss in humans [5][6][7]. Single-gene defects and chromosomal aberrations have also been reported in different microtia-associated syndromes [3,8].…”

Section: Introductionmentioning

confidence: 99%

Duplications involving the long range HMX1 enhancer are associated with human isolated bilateral concha-type microtia

Meng

et al. 2020

J Transl Med

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Background: Microtia is a congenital anomaly of ear that ranges in severity from mild structural abnormalities to complete absence of the outer ears. Concha-type microtia is considered to be a mild form. The H6 family homeobox 1 transcription factor gene (HMX1) plays an important role in craniofacial structures development. Copy number variations (CNVs) of a downstream evolutionarily conserved enhancer region (ECR) of Hmx1 associated with ear and eye abnormalities have been reported in different animals, but not yet in human. To date, no genetic defects responsible for isolated human microtia has been reported except for mutations in HOXA2. Here we recruited five Chinese families with isolated bilateral concha-type microtia, and attempt to identify the underlying genetic causes. Methods: Single Nucleotide polymorphism (SNP) array was performed to map the disease locus and detect CNVs on a genome scale primarily in the largest family (F1). Whole genome sequencing was performed to screen all SNVs and CNVs in the candidate disease locus. Array comparative genomic hybridization (aCGH) was then performed to detect CNVs in the other four families, F2-F5. Quantitative real-time polymerase chain reaction (qPCR) was used to validate and determine the extent of identified CNVs containing HMX1-ECR region. Precise breakpoints in F1 and F2 were identified by gap-PCR and sanger sequencing. Dual-luciferase assays were used to detect the enhancer function. qPCR assays were also used to detect HMX1-ECR CNVs in 61 patients with other types mictrotia. Results: Linkage and haplotype analysis in F1 mapped the disease locus to a 1.9 Mb interval on 4p16.1 containing HMX1 and its downstream ECR region. Whole genome sequencing detected no potential pathogenic SNVs in coding regions of HMX1 or other genes within the candidate disease locus, but it detected a 94.6 Kb duplication in an intergenic region between HMX1 and CPZ. aCGH and qPCRs also revealed co-segregated duplications in intergenic region downstream of HMX1 in the other four families. The 21.8 Kb minimal overlapping region encompassing the core sequences consensus with mouse ECR of Hmx1. Luciferase assays confirmed the enhancer function in human sequences, and proved that HOXA2 could increase its enhancer activity. No CNVs were detected in HMX1-ECR regions in 61 patients with other type of microtia. Conclusion: Duplications involving long range HMX1 enhancers are associated with human isolated bilateral concha-type microtia. We add to evidences in human that copy number variations in HMX1-ECR associates with ear

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Identification of a second HOXA2 nonsense mutation in a family with autosomal dominant non‐syndromic microtia and distinctive ear morphology

Cited by 25 publications

References 22 publications

Whole-Exome Sequencing of Discordant Monozygotic Twin Families for Identification of Candidate Genes for Microtia-Atresia

Whole-Exome Sequencing of Discordant Monozygotic Twin Families for Identification of Candidate Genes for Microtia-Atresia

Target sequencing of 307 deafness genes identifies candidate genes implicated in microtia

Duplications involving the long range HMX1 enhancer are associated with human isolated bilateral concha-type microtia

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