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


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.

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We are grateful to the patients and their families who participated in this study. We are most grateful to the Genomics platform of Nantes (Biogenouest Genomics) core facility for its technical support. DNA panels from the NINDS Human Genetics Resource Center DNA and Cell Line Repository ( were used in this study.

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Authors’ roles: Study design: CLC, OP, and AT. Study conduct: CLC, OP, and AT. BdC, CB, AM, and AT clinically characterized the patients and collected blood samples. Array CGH analysis and interpretation of the data: CLC, AB, OP, and MSC. Whole-genome sequencing and data interpretation: OP, PL, RR, CSB, and DS. Fiber FISH experiments and data interpretation: OP, MSC. Drafting manuscript: CLC, OP, DD, and AT. Revising manuscript content: CLC, OP, DD, MLV, AM, and AT. Approving final version of manuscript: CLC, OP, AB, BdC, CB, DD, MLV, PL, RR, CSB, MSC, DS, DD, AM, and AT. CLC and AT take responsibility for the integrity of the data analysis.

Correspondence to Cédric Le Caignec.

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Le Caignec, C., Pichon, O., Briand, A. et al. Fryns type mesomelic dysplasia of the upper limbs caused by inverted duplications of the HOXD gene cluster. Eur J Hum Genet 28, 324–332 (2020).

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