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OTX2 duplication is implicated in hemifacial microsomia.

Zielinski D, Markus B, Sheikh M, Gymrek M, Chu C, Zaks M, Srinivasan B, Hoffman JD, Aizenbud D, Erlich Y - PLoS ONE (2014)

Bottom Line: Whole-exome sequencing results indicated the absence of a pathogenic coding point mutation.All of these approaches implicated OTX2 as the most likely causal gene.Moreover, OTX2 is a known oncogenic driver in medulloblastoma, a condition that was diagnosed in the proband during the course of the study.

View Article: PubMed Central - PubMed

Affiliation: Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, United States of America.

ABSTRACT
Hemifacial microsomia (HFM) is the second most common facial anomaly after cleft lip and palate. The phenotype is highly variable and most cases are sporadic. We investigated the disorder in a large pedigree with five affected individuals spanning eight meioses. Whole-exome sequencing results indicated the absence of a pathogenic coding point mutation. A genome-wide survey of segmental variations identified a 1.3 Mb duplication of chromosome 14q22.3 in all affected individuals that was absent in more than 1000 chromosomes of ethnically matched controls. The duplication was absent in seven additional sporadic HFM cases, which is consistent with the known heterogeneity of the disorder. To find the critical gene in the duplicated region, we analyzed signatures of human craniofacial disease networks, mouse expression data, and predictions of dosage sensitivity. All of these approaches implicated OTX2 as the most likely causal gene. Moreover, OTX2 is a known oncogenic driver in medulloblastoma, a condition that was diagnosed in the proband during the course of the study. Our findings suggest a role for OTX2 dosage sensitivity in human craniofacial development and raise the possibility of a shared etiology between a subtype of hemifacial microsomia and medulloblastoma.

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Prioritization of genes in 14q22.(a) Ranking similarity of the molecular signatures of the genes in the duplicated region to causal genes in CHARGE, VACTERL, and Townes-Brocks using Endeavour and ToppGene. The average rank of both tools is indicated in red. (b) Ranking of expression levels in pharyngeal arches (PA) compared to heart and urogenital epithelium (UG) [37] in E10.5 and expression in the head compared to liver, heart, and lung in E13.5 for genes in the duplicated region. Comparative expression ranked OTX2 highest in the affected tissues in all conditions. (c) Ranking of dosage sensitivity predictions for 3 of the duplicated genes [44].
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pone-0096788-g003: Prioritization of genes in 14q22.(a) Ranking similarity of the molecular signatures of the genes in the duplicated region to causal genes in CHARGE, VACTERL, and Townes-Brocks using Endeavour and ToppGene. The average rank of both tools is indicated in red. (b) Ranking of expression levels in pharyngeal arches (PA) compared to heart and urogenital epithelium (UG) [37] in E10.5 and expression in the head compared to liver, heart, and lung in E13.5 for genes in the duplicated region. Comparative expression ranked OTX2 highest in the affected tissues in all conditions. (c) Ranking of dosage sensitivity predictions for 3 of the duplicated genes [44].

Mentions: First, we prioritized the genes in the duplicated region based on the similarity of their molecular signatures to known etiological genes of other facial malformations. We and others have successfully identified etiological genes using this guilt-by-association approach in previous studies of rare human disorders [34]–[36]. The basis of this technique is that similar phenotypes are caused by genes that reside in close biological modules such as the same pathway, co-expression cluster, and shared regulatory control (Goh et al 2007). To identify a set of disorders similar to HFM in an unbiased manner, we used MimMiner, which ranks clinical conditions in OMIM based on phenotypic resemblance [37]. The top three phenotypes with similar features to HFM were CHARGE syndrome (OMIM: 214800), VACTERL association (OMIM: 314390), and Townes-Brocks syndrome (OMIM: 107480). In fact, HFM and TBS are both characterized by first and second arch defects, including ear, jaw, and kidney malformations [38]. Interestingly, a previous study also cited the commonalities between HFM, CHARGE, and VACTERL [39], adding additional support to the MimMiner prediction. We then compared the biological signatures of all coding genes in the duplicated region to CHD7, ZIC3, and SALL1, the corresponding genes of the three syndromes. To increase the robustness of our analysis, we tested these similarities using two gene prioritization tools: Endeavour [40] and ToppGene [41]. These algorithms utilize different biological datasets and employ distinct prioritization procedures. These two algorithms independently ranked OTX2 as the gene with the closest molecular signature to other facial anomalies (Figure 3a).


OTX2 duplication is implicated in hemifacial microsomia.

Zielinski D, Markus B, Sheikh M, Gymrek M, Chu C, Zaks M, Srinivasan B, Hoffman JD, Aizenbud D, Erlich Y - PLoS ONE (2014)

Prioritization of genes in 14q22.(a) Ranking similarity of the molecular signatures of the genes in the duplicated region to causal genes in CHARGE, VACTERL, and Townes-Brocks using Endeavour and ToppGene. The average rank of both tools is indicated in red. (b) Ranking of expression levels in pharyngeal arches (PA) compared to heart and urogenital epithelium (UG) [37] in E10.5 and expression in the head compared to liver, heart, and lung in E13.5 for genes in the duplicated region. Comparative expression ranked OTX2 highest in the affected tissues in all conditions. (c) Ranking of dosage sensitivity predictions for 3 of the duplicated genes [44].
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4016008&req=5

pone-0096788-g003: Prioritization of genes in 14q22.(a) Ranking similarity of the molecular signatures of the genes in the duplicated region to causal genes in CHARGE, VACTERL, and Townes-Brocks using Endeavour and ToppGene. The average rank of both tools is indicated in red. (b) Ranking of expression levels in pharyngeal arches (PA) compared to heart and urogenital epithelium (UG) [37] in E10.5 and expression in the head compared to liver, heart, and lung in E13.5 for genes in the duplicated region. Comparative expression ranked OTX2 highest in the affected tissues in all conditions. (c) Ranking of dosage sensitivity predictions for 3 of the duplicated genes [44].
Mentions: First, we prioritized the genes in the duplicated region based on the similarity of their molecular signatures to known etiological genes of other facial malformations. We and others have successfully identified etiological genes using this guilt-by-association approach in previous studies of rare human disorders [34]–[36]. The basis of this technique is that similar phenotypes are caused by genes that reside in close biological modules such as the same pathway, co-expression cluster, and shared regulatory control (Goh et al 2007). To identify a set of disorders similar to HFM in an unbiased manner, we used MimMiner, which ranks clinical conditions in OMIM based on phenotypic resemblance [37]. The top three phenotypes with similar features to HFM were CHARGE syndrome (OMIM: 214800), VACTERL association (OMIM: 314390), and Townes-Brocks syndrome (OMIM: 107480). In fact, HFM and TBS are both characterized by first and second arch defects, including ear, jaw, and kidney malformations [38]. Interestingly, a previous study also cited the commonalities between HFM, CHARGE, and VACTERL [39], adding additional support to the MimMiner prediction. We then compared the biological signatures of all coding genes in the duplicated region to CHD7, ZIC3, and SALL1, the corresponding genes of the three syndromes. To increase the robustness of our analysis, we tested these similarities using two gene prioritization tools: Endeavour [40] and ToppGene [41]. These algorithms utilize different biological datasets and employ distinct prioritization procedures. These two algorithms independently ranked OTX2 as the gene with the closest molecular signature to other facial anomalies (Figure 3a).

Bottom Line: Whole-exome sequencing results indicated the absence of a pathogenic coding point mutation.All of these approaches implicated OTX2 as the most likely causal gene.Moreover, OTX2 is a known oncogenic driver in medulloblastoma, a condition that was diagnosed in the proband during the course of the study.

View Article: PubMed Central - PubMed

Affiliation: Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, United States of America.

ABSTRACT
Hemifacial microsomia (HFM) is the second most common facial anomaly after cleft lip and palate. The phenotype is highly variable and most cases are sporadic. We investigated the disorder in a large pedigree with five affected individuals spanning eight meioses. Whole-exome sequencing results indicated the absence of a pathogenic coding point mutation. A genome-wide survey of segmental variations identified a 1.3 Mb duplication of chromosome 14q22.3 in all affected individuals that was absent in more than 1000 chromosomes of ethnically matched controls. The duplication was absent in seven additional sporadic HFM cases, which is consistent with the known heterogeneity of the disorder. To find the critical gene in the duplicated region, we analyzed signatures of human craniofacial disease networks, mouse expression data, and predictions of dosage sensitivity. All of these approaches implicated OTX2 as the most likely causal gene. Moreover, OTX2 is a known oncogenic driver in medulloblastoma, a condition that was diagnosed in the proband during the course of the study. Our findings suggest a role for OTX2 dosage sensitivity in human craniofacial development and raise the possibility of a shared etiology between a subtype of hemifacial microsomia and medulloblastoma.

Show MeSH
Related in: MedlinePlus