Characterization of the complex 7q21.3 rearrangement in a patient with bilateral split‐foot malformation and hearing loss

Saitsu, Hirotomo; Kurosawa, Kenji; Kawara, Hiroki; Eguchi, M; Mizuguchi, Takeshi; Harada, Naoki; Kaname, Tadashi; Kano, Hiroki; Miyake, Noriko; Toda, Tatsushi; Matsumoto, Naomichi

doi:10.1002/ajmg.a.32877

Cited by 16 publications

(22 citation statements)

References 26 publications

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“…In addition, disruption of both Dlx5 and Dlx6 also resulted in limb malformations that phenocopied Split hand/foot and mouth syndrome (SHFM) in humans (Robledo et al, 2002). The Dlx5 and 6 genes are located in the SHFM type 1 locus on human 7q21, and approximately 35% of those with SHFM1 also have sensorineural, or mixed hearing loss (Elliott and Evans, 2006; Saitsu et al, 2009). …”

Section: Resultsmentioning

confidence: 99%

Identification of differentially expressed genes in early inner ear development

Paxton

Bleyl

Chapman

et al. 2010

Gene Expression Patterns

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To understand the etiology of congenital hearing loss, a comprehensive understanding of the molecular genetic mechanisms underlying normal ear development is required. We are identifying genes involved in otogenesis, with the longer term goal of studying their mechanisms of action, leading to inner ear induction and patterning. Using Agilent microarrays, we compared the differential expression of a test domain (which consisted of the pre-otic placodal ectoderm with the adjacent hindbrain ectoderm and the underlying mesendodermal tissues) with a rostral control domain (which included tissue that is competent, but not specified, to express inner ear markers in explant assays). We identified 1,261 transcripts differentially expressed between the two domains at a 2-fold or greater change: 463 were upregulated and 798 were downregulated in the test domain. We validated the differential expression of several signaling molecules and transcription factors identified in this array using in situ hybridization. Furthermore, the expression patterns of the validated group of genes from the test domain were explored in detail to determine how the timing of their expression relates to specific events of otic induction and development. In conclusion, we identified a number of novel candidate genes for otic placode induction. KeywordsOtic induction; inner ear; Wnt; Fgf; Notch; Hox; otic placode; microarray; gene expression screen RESULTS AND DISCUSSIONCongenital hearing loss is among the most common birth defects, affecting approximately 3 out of every 1000 infants born each year in the United States. Genetic causes account for about 50% of all congenital hearing loss, but the roles of only a small number of genes directly linked to hearing loss are known. To better understand the mechanisms underlying congenital hearing Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptGene Expr Patterns. Author manuscript; available in PMC 2011 January 1. Through candidate gene approaches and subsequent gene mis-expression experiments, a small number of secreted proteins have been identified in the initiation and early patterning of the otic placode and vesicle, such that a rudimentary signaling network is beginning to be established. The signaling proteins thus far identified in this cascade belong mainly to the FGF, WNT, SHH, and Notch protein families (Ladher et al., 2000(Ladher et al., , 2005Vendrell et al., 2000;Adamska et al., 2001;Phillips et al., 2001Phillips et al., , 2004Leger and Brand, 2002;Maroon et al., 2002;Liu et al., 2002Liu et al., , 2003Riccoma...

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Section: Resultsmentioning

confidence: 99%

Identification of differentially expressed genes in early inner ear development

Paxton

Bleyl

Chapman

et al. 2010

Gene Expression Patterns

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“…This model is in agreement with recent reports on genomic aberrations in 7q21 that were associated with SHFM1. In one report, a human breakpoint located at 38 kb telomeric to DSS1 and at 258 kb centromeric to DLX6 is associated with SHFM and hearing loss phenotype (Figure S5) [82]. This breakpoint leaves the SHFM1-BS1 association with DSS1 intact, but disconnects it from DLX5 and DLX6 .…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide Profiling of p63 DNA–Binding Sites Identifies an Element that Regulates Gene Expression during Limb Development in the 7q21 SHFM1 Locus

et al. 2010

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Heterozygous mutations in p63 are associated with split hand/foot malformations (SHFM), orofacial clefting, and ectodermal abnormalities. Elucidation of the p63 gene network that includes target genes and regulatory elements may reveal new genes for other malformation disorders. We performed genome-wide DNA–binding profiling by chromatin immunoprecipitation (ChIP), followed by deep sequencing (ChIP–seq) in primary human keratinocytes, and identified potential target genes and regulatory elements controlled by p63. We show that p63 binds to an enhancer element in the SHFM1 locus on chromosome 7q and that this element controls expression of DLX6 and possibly DLX5, both of which are important for limb development. A unique micro-deletion including this enhancer element, but not the DLX5/DLX6 genes, was identified in a patient with SHFM. Our study strongly indicates disruption of a non-coding cis-regulatory element located more than 250 kb from the DLX5/DLX6 genes as a novel disease mechanism in SHFM1. These data provide a proof-of-concept that the catalogue of p63 binding sites identified in this study may be of relevance to the studies of SHFM and other congenital malformations that resemble the p63-associated phenotypes.

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“…All had hearing loss due to abnormalities of the inner ear but none showed limb abnormalities. Saitsu et al (2009) reported a complex rearrangement in a patient with bilateral split-foot malformation and hearing loss. This well-characterized rearrangement detected a chromosomal 7q21.3 break, mapped to 258 and 272 kb centromeric to the DLX6 and DLX5, respectively, in addition to a microdeletion of 806 kb located 750 kb telomeric to the 7q21.3 breakpoint.…”

Section: Discussionmentioning

confidence: 99%

“…Besides TP63 located on chromosome 3q27, five other loci have been considered in relation to syndromic and non-syndromic SHFM: SHFM1 on chromosome 7q21, SHFM2 on Xq26, SHFM3 on 10q24, SHFM5 on 2q31 and SHFM6 on 12q13 (for review see Saitsu et al, 2009). SHFM1 is associated with deletions of variable extent on chromosome 7q21, minimally including the DSS1 gene and the distallessrelated homeogenes DLX5 and DLX6 (Crackower et al, 1996;Scherer et al, 1994aScherer et al, , 1994b.…”

Section: Introductionmentioning

confidence: 99%