title: Phenotypic subregions within the split-hand/foot malformation 1 locus.
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.
authors.affiliation: Department of Cellular and Molecular Medicine, The Panum Institute, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Malene B
authors.initials: MB
authors.lastname: Rasmussen
authors.affiliation: Departments of Paediatric Dentistry and Clinical Genetics, School of Dentistry, The Panum Institute, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Sven
authors.initials: S
authors.lastname: Kreiborg
authors.affiliation: Mental Health Centre Ballerup, Capital Region Mental Health, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Per
authors.initials: P
authors.lastname: Jensen
authors.affiliation: Department of Cellular and Molecular Medicine, The Panum Institute, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Mads
authors.initials: M
authors.lastname: Bak
authors.affiliation: Department of Cellular and Molecular Medicine, The Panum Institute, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Mang
authors.affiliation: Department of Cellular and Molecular Medicine, The Panum Institute, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Marianne
authors.initials: M
authors.lastname: Lodahl
authors.affiliation: Department of Cellular and Molecular Medicine, The Panum Institute, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Esben
authors.initials: E
authors.lastname: Budtz-Jørgensen
authors.affiliation: Department of Cellular and Molecular Medicine, The Panum Institute, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Tommerup
authors.affiliation: Department of Cellular and Molecular Medicine, The Panum Institute, University of Copenhagen, Copenhagen, Denmark.|Department of ORL, H & N Surgery and Audiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.|Clinical Genetic Clinic, Kennedy Center, Rigshospitalet, University of Copenhagen, 2600, Glostrup, Denmark.
authors.forename: Lisbeth
authors.initials: L
authors.lastname: Tranebjærg
authors.affiliation: Department of Cellular and Molecular Medicine, The Panum Institute, University of Copenhagen, Copenhagen, Denmark. nanna.dahl.rendtorff@regionh.dk.|Department of ORL, H & N Surgery and Audiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. nanna.dahl.rendtorff@regionh.dk.|Clinical Genetic Clinic, Kennedy Center, Rigshospitalet, University of Copenhagen, 2600, Glostrup, Denmark. nanna.dahl.rendtorff@regionh.dk.
authors.forename: Nanna D
authors.initials: ND
authors.lastname: Rendtorff
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D007446:Chromosome Inversion / Q000235:genetics; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics; D019465:Craniofacial Abnormalities / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation; D056726:Genetic Association Studies; D056426:Genetic Loci; D034381:Hearing Loss / Q000235:genetics; D059014:High-Throughput Nucleotide Sequencing; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D017880:Limb Deformities, Congenital / Q000175:diagnosis / Q000235:genetics*; D016015:Logistic Models; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D046988:Proteasome Endopeptidase Complex / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics; D055815:Young Adult
chemical_list: C100596:DLX5 protein, human; C491014:DLX6 protein, human; D018398:Homeodomain Proteins; C484606:SEM1 protein, human; D014157:Transcription Factors; D046988:Proteasome Endopeptidase Complex
references.citation: Genes Dev. 2002 May 1;16(9):1089-101
references.pmid: 12000792
references.citation: Orphanet J Rare Dis. 2014 Jul 29;9:108
references.pmid: 25231166
references.citation: Hum Mol Genet. 1996 May;5(5):571-9
references.pmid: 8733122
references.citation: BMC Med Genet. 2011 Aug 09;12:106
references.pmid: 21827697
references.citation: Genesis. 2002 Jun;33(2):97-101
references.pmid: 12112878
references.citation: Hum Mol Genet. 2003 Apr 1;12 Spec No 1:R51-60
references.pmid: 12668597
references.citation: Development. 1999 Sep;126(17):3795-809
references.pmid: 10433909
references.citation: Hum Mol Genet. 1994 Aug;3(8):1345-54
references.pmid: 7987313
references.citation: J Med Genet. 2014 Apr;51(4):264-7
references.pmid: 24459211
references.citation: Am J Med Genet A. 2006 Jul 1;140(13):1419-27
references.pmid: 16688749
references.citation: Eur J Hum Genet. 2014 Feb;22(2):171-8
references.pmid: 23714751
references.citation: Am J Med Genet. 1993 Jun 15;46(5):492-3
references.pmid: 8322806
references.citation: Hum Mol Genet. 2012 Nov 15;21(22):4930-8
references.pmid: 22914741
references.citation: Dev Cell. 2007 Apr;12(4):645-52
references.pmid: 17420000
references.citation: Genome Res. 2012 Jun;22(6):1059-68
references.pmid: 22442009
references.citation: Am J Med Genet. 1991 Jun 15;39(4):413-4
references.pmid: 1877619
references.citation: Nucleic Acids Res. 2001 Jan 1;29(1):275-6
references.pmid: 11125110
references.citation: J Med Genet. 2001 Jun;38(6):405-9
references.pmid: 11424924
references.citation: Am J Med Genet A. 2013 Nov;161A(11):2860-72
references.pmid: 24115638
references.citation: J Cell Mol Med. 2010 Aug;14(8):2078-84
references.pmid: 20597996
references.citation: J Appl Genet. 2014 Feb;55(1):105-15
references.pmid: 24163146
references.citation: Nature. 2006 Nov 23;444(7118):499-502
references.pmid: 17086198
references.citation: Am J Med Genet A. 2007 Feb 15;143(4):333-7
references.pmid: 17230488
references.citation: Am J Hum Genet. 1994 Jul;55(1):12-20
references.pmid: 8023840
references.citation: Am J Med Genet A. 2009 Jun;149A(6):1224-30
references.pmid: 19449426
references.citation: Gene. 2012 Apr 15;497(2):292-7
references.pmid: 22342398
references.citation: Neuron. 2015 Mar 18;85(6):1332-43
references.pmid: 25754826
references.citation: Cell. 2015 May 21;161(5):1012-1025
references.pmid: 25959774
references.citation: Nat Genet. 2015 May;47(5):544-9
references.pmid: 25848752
references.citation: J Med Genet. 2014 Dec;51(12 ):817-23
references.pmid: 25332435
references.citation: Birth Defects Res A Clin Mol Teratol. 2014 Oct;100(10):764-71
references.pmid: 25196357
references.citation: J Neurosci. 2000 Jan 15;20(2):709-21
references.pmid: 10632600
references.citation: Am J Med Genet A. 2012 Dec;158A(12):3201-6
references.pmid: 23169702
references.citation: Eur J Hum Genet. 2007 Jun;15(6):711-3
references.pmid: 17392702
references.citation: PLoS Genet. 2010 Aug 19;6(8):e1001065
references.pmid: 20808887
references.citation: Clin Genet. 1995 Feb;47(2):90-5
references.pmid: 7606850
references.citation: Clin Genet. 1991 Sep;40(3):202-6
references.pmid: 1773535
references.citation: Eur J Hum Genet. 2014 Mar;22(3):338-43
references.pmid: 23860044
references.citation: J Med Genet. 2012 Jan;49(1):16-20
references.pmid: 22121204
references.citation: Genome Res. 2003 Apr;13(4):533-43
references.pmid: 12670995
references.citation: Eur J Hum Genet. 2009 Nov;17(11):1432-8
references.pmid: 19401716
references.citation: Clin Genet. 2001 Jan;59(1):28-36
references.pmid: 11168022
references.citation: Mol Cytogenet. 2015 Jun 13;8:37
references.pmid: 26075025
references.citation: J Med Genet. 2004 May;41(5):e54
references.pmid: 15121782
references.citation: Am J Hum Genet. 1994 Oct;55(4):710-3
references.pmid: 7942849
references.citation: BMC Med Genet. 2013 May 07;14:50
references.pmid: 23648064
references.citation: Development. 2008 Apr;135(7):1377-88
references.pmid: 18326838
references.citation: Genome Res. 2015 Jul;25(7):927-36
references.pmid: 25953952
references.citation: Eur J Hum Genet. 2014 Sep;22(9):1105-10
references.pmid: 24496061
references.citation: Am J Med Genet. 1993 Nov 1;47(6):823-31
references.pmid: 8279479
references.citation: Hum Genet. 2010 Jan;127(1):19-31
references.pmid: 19707792
references.citation: J Med Genet. 1995 May;32(5):375-8
references.pmid: 7616545
references.citation: Am J Med Genet A. 2008 Jan 15;146A(2):238-44
references.pmid: 18080328