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Phenotypic subregions within the split-hand/foot malformation 1 locus

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Abstract

Split-hand/foot malformation 1 (SHFM1) is caused by chromosomal aberrations involving the region 7q21.3, DLX5 mutation, and dysregulation of DLX5/DLX6 expression by long-range position effects. SHFM1 can be isolated or syndromic with incomplete penetrance and a highly variable clinical expression, possibly influenced by sex and imprinting. We report on a new family with five affected individuals with syndromic SHFM1 that includes split-hand/foot malformations, hearing loss, and craniofacial anomalies, and an inv(7)(q21.3q35) present both in the proband and her affected son. The proximal inversion breakpoint, identified by next generation mate-pair sequencing, truncates the SHFM1 locus within the regulatory region of DLX5/6 expression. Through genotype-phenotype correlations of 100 patients with molecularly characterized chromosomal aberrations from 32 SHFM1 families, our findings suggest three phenotypic subregions within the SHFM1 locus associated with (1) isolated SHFM, (2) SHFM and hearing loss, and (3) SHFM, hearing loss, and craniofacial anomalies, respectively (ranked for increasing proximity to DLX5/6), and encompassing previously reported tissue-specific enhancers for DLX5/6. This uniquely well-characterized cohort of SHFM1 patients allowed us to systematically analyze the recently suggested hypothesis of skewed transmission and to confirm a higher penetrance in males vs. females in a subgroup of patients with isolated SHFM.

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Acknowledgments

We thank the patients who participated in the study. The project was hosted by Wilhelm Johannsen Centre for Functional Genome Research.

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Authors and Affiliations

  1. Department of Cellular and Molecular Medicine, The Panum Institute, University of Copenhagen, Copenhagen, Denmark

    Malene B. Rasmussen, Mads Bak, Yuan Mang, Marianne Lodahl, Esben Budtz-Jørgensen, Niels Tommerup, Lisbeth Tranebjærg & Nanna D. Rendtorff

  2. Departments of Paediatric Dentistry and Clinical Genetics, School of Dentistry, The Panum Institute, University of Copenhagen, Copenhagen, Denmark

    Sven Kreiborg

  3. Mental Health Centre Ballerup, Capital Region Mental Health, University of Copenhagen, Copenhagen, Denmark

    Per Jensen

  4. Department of ORL, H & N Surgery and Audiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

    Lisbeth Tranebjærg & Nanna D. Rendtorff

  5. Clinical Genetic Clinic, Kennedy Center, Rigshospitalet, University of Copenhagen, 2600, Glostrup, Denmark

    Lisbeth Tranebjærg & Nanna D. Rendtorff

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  1. Malene B. Rasmussen
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Correspondence to Nanna D. Rendtorff.

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The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Funding

This study was funded by the Oticon Foundation, and Widex AS, to LT, The Danish Medical Association Research Fund (2011-3271/480853-62), The Lundbeck Foundation (2013-14290), the UCPH Programme for Interdisciplinary Research (Global Genes, Local Concerns) and The Danish Council for Independent Research - Medical Sciences (4183-00482B) to NT.

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Informed consent was obtained from all individual participants included in the study. Additional informed consent was obtained from all individual participants for whom identifying information is included in this article.

Electronic supplementary material

Below is the link to the electronic supplementary material.

439_2016_1635_MOESM1_ESM.pdf

Supplementary Clinical data: Detailed clinical description of individual III:2 and IV:1 in the present family, including audiogram for both individuals. (PDF 103 kb)

439_2016_1635_MOESM2_ESM.pdf

Supplementary Fig. S1 Inversion breakpoint-junctions in the present family Sequences of inversion breakpoint junctions at 7q21.3 and 7q35, respectively, compared with reference sequence. a) 7q21.3 breakpoint spanning sequences from III:2 (middle line). b) 7q35 breakpoint spanning sequences from III:2 (middle line). Microhomology regions at the junctions are boxed. The position of a SNP (rs12673393) present in III:2 is underlined. (PDF 73 kb)

439_2016_1635_MOESM3_ESM.pdf

Supplementary Table S1 Genotype–phenotype data on a total of 36 SHFM1 families with molecularly characterized chromosomal aberrations and point mutations Genotype–phenotype data on the present family and 35 previously reported SHFM1 families with molecularly characterized chromosomal aberrations and point mutations presented chronologically. (PDF 101 kb)

439_2016_1635_MOESM4_ESM.xlsx

Supplementary Table S2 Data on sex and transmission pattern in 100 patients from 32 SHFM1 families with molecularly characterized chromosomal aberrations (XLSX 120 kb)

439_2016_1635_MOESM5_ESM.xlsx

Supplementary Table S3 Enhancers and DNA Markers within the SHFM1 locus S3a) Previously reported tissue-specific enhancers within the SHFM1 locus including: Human genomic position of the enhancers (hg19); Nature of functional study; Tissue-specific expression; Additional functional studies including proximity mapping; References. S3b) DNA Markers used for mapping of breakpoints on chromosome 7q21.3 in SHFM1 patients. (XLSX 128 kb)

439_2016_1635_MOESM6_ESM.pdf

Supplementary Fig. S2 Schematic illustration of physical interactions between previously identified regulatory elements and genes at the SHFM1 locus on chromosome 7q21.3 Previously reported tissue-specific enhancers are shown in the same color as in Fig. 3b. Above the line: Black arrows indicate physical interaction between enhancers and genes, or between enhancers, identified by three-dimensional proximity-mapping such as chromatin conformation capture (3C) or DNA fluorescent in situ hybridization (FISH). The red P illustrates the promotor region of DLX5 and DLX6. Below the line: Gray arrows indicate genetic interaction as described by Verzi et al. (Verzi et al. 2007) including a feed-forward transcriptional circuit between MEF2C and Dlx5/6, and the synergistically activation of the Mef2-BA enhancer by MEF2C and Dlx5. (PDF 329 kb)

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Rasmussen, M.B., Kreiborg, S., Jensen, P. et al. Phenotypic subregions within the split-hand/foot malformation 1 locus. Hum Genet 135, 345–357 (2016). https://doi.org/10.1007/s00439-016-1635-0

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