Submicroscopic deletion of 12q13 including <i>HOXC</i> gene cluster with skeletal anomalies and global developmental delay

Okamoto, Nobuhiko; Tamura, Daisuke; Nishimura, Gen; Shimojima, Keiko; Yamamoto, Toshiyuki

doi:10.1002/ajmg.a.34324

Cited by 11 publications

(5 citation statements)

References 23 publications

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“…Moreover, heart defects which were seen in some of patients with deletion of the 12q13.13 region were not observed in patients with duplication of the same region. Other skeletal abnormalities, such as scoliosis and cone-shaped epiphyses of distal phalanges, reported in four of the seven patients with a 12q13.13 deletion ([5–7], DECIPHER patient: 250,426), were also seen in our patient who had a duplication in this region.…”

Section: Discussionsupporting

confidence: 70%

“…It is interesting to note that deletions of this region were also reported in seven patients ([5–7], DECIPHER patients: 293,324 and 250,426; dbVar: nssv577386 and nssv577387). A comparison of the location and size of the deletions and duplications are illustrated in the middle panel of Fig.…”

Section: Discussionmentioning

confidence: 99%

“…However, six of seven reported patients with the 12q13.13 deletion involve the HOXC gene cluster, which are thought to be the candidate genes for the development of skeletal anomalies and limb deformities [5–7]. Mutations or deletions involving other HOX genes have been well documented in developmental disorders in both humans and mice, particularly limb anomalies [12].…”

Section: Discussionmentioning

confidence: 99%

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Chromosome 12q13.13q13.13 microduplication and microdeletion: a case report and literature review

Infante

et al. 2017

Mol Cytogenet

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BackgroundDuplications or deletions in the 12q13.13 region are rare. Only scattered cases with duplications and/or deletions in this region have been reported in the literature or in online databases. Owing to the limited number of patients with genomic alteration within this region and lack of systematic analysis of these patients, the common clinical manifestation of these patients has remained elusive.Case presentationHere we report an 802 kb duplication in the 12q13.13q13.13 region in a 14 year-old male who presented with dysmorphic features, developmental delay (DD), mild intellectual disability (ID) and mild deformity of digits. Comparing the phenotype of our patient with those of reported patients, we find that patients with the 12q13.13 duplication or the deletion share similar phenotypes, including dysmorphic facies, abnormal nails, intellectual disability, and deformity of digits or limbs. However, patients with the deletion appear to have more severe deformity of digits or limbs.ConclusionsDeletion and duplication of the 12q13.13 region may represent novel contiguous gene alteration syndromes. All seven reported 12q13.13 deletions and three of four duplications are de novo and vary in size. Therefore, these genomic alterations are not due to non-allelic homologous recombination.

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Section: Discussionsupporting

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Chromosome 12q13.13q13.13 microduplication and microdeletion: a case report and literature review

Infante

et al. 2017

Mol Cytogenet

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“…25 While loss of the entire HOXC gene cluster has been described in three individuals with large chromosome 12 deletions (>1 Mb) and cognitive impairment, the loss of additional genes precludes the assignment of HOXC gene effects. Skeletal abnormalities described previously in these patients include ulnar deviation of hands, flexion deformities of fourth and fifth fingers and contractures of Achilles tendons, 26 severe kyphoscoliosis, ulnar deviation of the hands and finger flexion contractures, 27 and arthrogryposis with valgus ankle position and pectus excavatum. 28 Microdeletions of 5 0 HOXC genes as described here have not been reported by other investigators and none are annotated in the DGV or DECIPHER database.…”

Section: Discussionmentioning

confidence: 64%

Deletions of 5′HOXCgenes are associated with lower extremity malformations, including clubfoot and vertical talus

Alvarado

McCall

Hecht³

et al. 2016

J Med Genet

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Background Deletions of the HoxC gene cluster result in variable phenotypes in mice, but have been rarely described in humans. Here, we report chromosome 12q13.13 microdeletions ranging from 13-175 kb and involving the 5’ HOXC genes in four families segregating congenital lower limb malformations, including clubfoot, vertical talus, and hip dysplasia. Methods Probands (N=253) with clubfoot or vertical talus were screened for point mutations and copy number variants (CNVs) using Multiplexed Direct Genomic Selection (MDiGS), a pooled BAC targeted capture approach. SNP genotyping included 1178 clubfoot or vertical talus probands and 1775 controls. Results The microdeletions share a minimal noncoding region overlap upstream of HOXC13, with variable phenotypes depending upon HOXC13, HOXC12 or the HOTAIR lncRNA inclusion. SNP analysis revealed HOXC11 p.Ser191Phe segregating with clubfoot in a small family and enrichment of HOXC12 p.Asn176Lys in patients with clubfoot or vertical talus (rs189468720, p=0.0057, OR=3.8). Defects in limb morphogenesis include shortened and overlapping toes, as well as peroneus muscle hypoplasia. Finally, HOXC and HOXD gene expression is reduced in fibroblasts from a patient with a 5’ HOXC deletion, consistent with prior studies demonstrating that dosage of lncRNAs alters expression of HOXD genes in trans. Conclusions Because HOXD10 has been implicated in the etiology of congenital vertical talus, variation in its expression may contribute to the lower limb phenotypes occurring with 5’ HOXC microdeletions. Identification of 5’ HOXC microdeletions highlights the importance of transcriptional regulators in the etiology of severe lower limb malformations and will improve their diagnosis and management.

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“…A mutation in Fbxo45 is also associated with schizophrenia [ 138 ]. Interestingly, microdeletions [ 139 – 141 ] and microduplications [ 142 , 143 ] that include Dlk/MAP3K12 , a likely Fbxo45 ubiquitination target, also result in intellectual disability and autism. Splicing of dlk-1 in worms is regulated by DGCR14/ES2 [ 46 ].…”

Section: Introductionmentioning

confidence: 99%

The PHR proteins: intracellular signaling hubs in neuronal development and axon degeneration

2016

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During development, a coordinated and integrated series of events must be accomplished in order to generate functional neural circuits. Axons must navigate toward target cells, build synaptic connections, and terminate outgrowth. The PHR proteins (consisting of mammalian Phr1/MYCBP2, Drosophila Highwire and C. elegans RPM-1) function in each of these events in development. Here, we review PHR function across species, as well as the myriad of signaling pathways PHR proteins regulate. These findings collectively suggest that the PHR proteins are intracellular signaling hubs, a concept we explore in depth. Consistent with prominent developmental functions, genetic links have begun to emerge between PHR signaling networks and neurodevelopmental disorders, such as autism, schizophrenia and intellectual disability. Finally, we discuss the recent and important finding that PHR proteins regulate axon degeneration, which has further heightened interest in this fascinating group of molecules.

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Submicroscopic deletion of 12q13 including HOXC gene cluster with skeletal anomalies and global developmental delay

Cited by 11 publications

References 23 publications

Chromosome 12q13.13q13.13 microduplication and microdeletion: a case report and literature review

Chromosome 12q13.13q13.13 microduplication and microdeletion: a case report and literature review

Deletions of 5′HOXCgenes are associated with lower extremity malformations, including clubfoot and vertical talus

The PHR proteins: intracellular signaling hubs in neuronal development and axon degeneration

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