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The Capital Region of Denmark - a part of Copenhagen University Hospital
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Phenotypic subregions within the split-hand/foot malformation 1 locus

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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.

Original languageEnglish
JournalHuman Genetics
Volume135
Issue number3
Pages (from-to)345-57
Number of pages13
ISSN0340-6717
DOIs
Publication statusPublished - Mar 2016

    Research areas

  • Adult, Amino Acid Sequence, Chromosome Inversion, Chromosomes, Human, Pair 7, Craniofacial Abnormalities, Female, Gene Expression Regulation, Genetic Association Studies, Genetic Loci, Hearing Loss, High-Throughput Nucleotide Sequencing, Homeodomain Proteins, Humans, Limb Deformities, Congenital, Logistic Models, Male, Molecular Sequence Data, Mutation, Pedigree, Phenotype, Proteasome Endopeptidase Complex, Transcription Factors, Young Adult, Journal Article, Research Support, Non-U.S. Gov't

ID: 49588770