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Eur J Hum Genet. 2019 Oct 7. doi: 10.1038/s41431-019-0522-2. [Epub ahead of print]

Fryns type mesomelic dysplasia of the upper limbs caused by inverted duplications of the HOXD gene cluster.

Author information

1
CHU Nantes, Service de Génétique Médicale, Nantes, France. lecaignec.c@chu-toulouse.fr.
2
Universite de Nantes, Nantes, France. lecaignec.c@chu-toulouse.fr.
3
CHU Nantes, Service de Génétique Médicale, Nantes, France.
4
Service de Chirurgie Orthopédique Pédiatrique, CHRU de Tours, Tours, France.
5
Université François-Rabelais de Tours, PRES Centre-Val de Loire Université, Tours, France.
6
INSERM, UMR_S1087, l'institut du thorax, Nantes, France.
7
CNRS, UMR 6291, Nantes, France.
8
Department of Genetics, Lyon University Hospital, Lyon, France.
9
Claude Bernard Lyon I University, Lyon, France.
10
CRNL, CNRS UMR 5292, INSERM U1028, Lyon, France.
11
Bio-informatic Cell, Hospices Civils de Lyon, Lyon, France.
12
Service de Génétique, Hôpital Bretonneau, CHU, Tours, France.
13
UMR 1253, iBrain, Université de Tours, Inserm, Tours, France.
14
University of Geneva and Federal Institute of Technology (EPFL), Lausanne, Switzerland.
15
Institut Jérome Lejeune, Paris, France.

Abstract

The HoxD cluster is critical for vertebrate limb development. Enhancers located in both the telomeric and centromeric gene deserts flanking the cluster regulate the transcription of HoxD genes. In rare patients, duplications, balanced translocations or inversions misregulating HOXD genes are responsible for mesomelic dysplasia of the upper and lower limbs. By aCGH, whole-genome mate-pair sequencing, long-range PCR and fiber fluorescent in situ hybridization, we studied patients from two families displaying mesomelic dysplasia limited to the upper limbs. We identified microduplications including the HOXD cluster and showed that microduplications were in an inverted orientation and inserted between the HOXD cluster and the telomeric enhancers. Our results highlight the existence of an autosomal dominant condition consisting of isolated ulnar dysplasia caused by microduplications inserted between the HOXD cluster and the telomeric enhancers. The duplications likely disconnect the HOXD9 to HOXD11 genes from their regulatory sequences. This presumptive loss-of-function may have contributed to the phenotype. In both cases, however, these rearrangements brought HOXD13 closer to telomeric enhancers, suggesting that the alterations derive from the dominant-negative effect of this digit-specific protein when ectopically expressed during the early development of forearms, through the disruption of topologically associating domain structure at the HOXD locus.

PMID:
31591517
DOI:
10.1038/s41431-019-0522-2

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