RESEARCH ARTICLE
Deletions in 14q24.1q24.3 are Associated With Congenital Heart Defects, Brachydactyly, and Mild Intellectual Disability Barbara Oehl-Jaschkowitz,1 Olivier M. Vanakker,2 Anne De Paepe,2 Bjo¨rn Menten,2 Thomas Martin,1 Georg Weber,1 Alexander Christmann,1 Romain Krier,3 Simone Scheid,3 Susan E. McNerlan,4 Shane McKee,4 and Andreas Tzschach5* 1
Practice of Human Genetics, Homburg (Saar), Germany
2
Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium
3
Practice of Pediatrics, Wittlich, Germany Northern Ireland Regional Genetics Service, Belfast City Hospital, Belfast, UK
4 5
Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen, Germany
Manuscript Received: 29 April 2013; Manuscript Accepted: 14 September 2013
Interstitial deletions of chromosome band 14q24.1q24.3 are apparently very rare. We report on three unrelated patients with overlapping de novo deletions of sizes 5.4, 2.8, and 2.3 Mb in this region. While some clinical problems such as intestinal malrotation, cryptorchidism, and ectopic kidney were only observed in single patients, all three patients had mild intellectual disability, congenital heart defects (truncus arteriosus, pulmonary atresia, atrial septal defect, and/or ventricular septal defect), brachydactyly, hypertelorism, broad nasal bridge, and thin upper lips. Likely haploinsufficiency of one or several of the 19 genes in the common deleted interval (ACTN1, DCAF5, EXD2, GALNTL1, ERH, SLC39A9, PLEKHD1, CCDC177, KIAA0247, LOC100289511, SRSF5, SLC10A1, SMOC1, SLC8A3, ADAM21P1, COX16, SYNJ2BP, SYNJ2BPCOX16, ADAM21) was responsible for these manifestations, but apart from SMOC1, mutations in which cause autosomal recessive Waardenburg anophthalmia syndrome, and ACTN1, mutations in which are associated with congenital macrothrombocytopenia, no disease associations have so far been reported for the other genes. Functional studies and a systematic search for mutations or chromosome aberrations in this region will elucidate the role of individual genes in the clinical manifestations and will provide insight into the underlying biological mechanisms. Ó 2013 Wiley Periodicals, Inc.
How to Cite this Article: Oehl-Jaschkowitz B, Vanakker OM, De Paepe A, Menten B, Martin T, Weber G, Christmann A, Krier R, Scheid S, McNerlan SE, McKee S, Tzschach A. 2014. Deletions in 14q24.1q24.3 are associated with congenital heart defects, brachydactyly, and mild intellectual disability. Am J Med Genet Part A 164A:620–626.
duplications with the accompanying clinical consequences. There are, however, still “white spots” on this map, that is, chromosome regions for which no well-characterized aberrations have been described. One of those regions is chromosome band 14q24.1q24.3. Here, we report on three unrelated patients with mild intellectual disability, congenital heart defects, brachydactyly and additional abnormalities in whom overlapping interstitial de novo deletions were detected in 14q24.1q24.3.
Key words: del14q24.1q24.3; array CGH; intellectual disability; congenital heart disease; brachydactyly; SMOC1; ACTN1; DCAF5
INTRODUCTION The widespread application of array technologies in routine cytogenetic diagnostics in recent years has provided the basis for an ever more detailed correlation of small chromosomal deletions or
Ó 2013 Wiley Periodicals, Inc.
Conflict of interest: none. Grant sponsor: Wellcome Trust. Correspondence to: Andreas Tzschach, M.D., Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Calwerstr. 7, 72076 Tuebingen, Germany. E-mail: [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 19 December 2013 DOI 10.1002/ajmg.a.36321
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CLINICAL REPORTS Patient 1 This boy was born after an uneventful pregnancy at term to healthy and nonconsanguineous German parents. At birth, small hands and a small atrial septal defect (which did not require surgery) were noted, but he had no other malformations (birth measurements: length 48 cm (10–25th centile), weight 2,560 g (
Deletions in 14q24.1q24.3 are Associated With Congenital Heart Defects, Brachydactyly, and Mild Intellectual Disability Barbara Oehl-Jaschkowitz,1 Olivier M. Vanakker,2 Anne De Paepe,2 Bjo¨rn Menten,2 Thomas Martin,1 Georg Weber,1 Alexander Christmann,1 Romain Krier,3 Simone Scheid,3 Susan E. McNerlan,4 Shane McKee,4 and Andreas Tzschach5* 1
Practice of Human Genetics, Homburg (Saar), Germany
2
Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium
3
Practice of Pediatrics, Wittlich, Germany Northern Ireland Regional Genetics Service, Belfast City Hospital, Belfast, UK
4 5
Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen, Germany
Manuscript Received: 29 April 2013; Manuscript Accepted: 14 September 2013
Interstitial deletions of chromosome band 14q24.1q24.3 are apparently very rare. We report on three unrelated patients with overlapping de novo deletions of sizes 5.4, 2.8, and 2.3 Mb in this region. While some clinical problems such as intestinal malrotation, cryptorchidism, and ectopic kidney were only observed in single patients, all three patients had mild intellectual disability, congenital heart defects (truncus arteriosus, pulmonary atresia, atrial septal defect, and/or ventricular septal defect), brachydactyly, hypertelorism, broad nasal bridge, and thin upper lips. Likely haploinsufficiency of one or several of the 19 genes in the common deleted interval (ACTN1, DCAF5, EXD2, GALNTL1, ERH, SLC39A9, PLEKHD1, CCDC177, KIAA0247, LOC100289511, SRSF5, SLC10A1, SMOC1, SLC8A3, ADAM21P1, COX16, SYNJ2BP, SYNJ2BPCOX16, ADAM21) was responsible for these manifestations, but apart from SMOC1, mutations in which cause autosomal recessive Waardenburg anophthalmia syndrome, and ACTN1, mutations in which are associated with congenital macrothrombocytopenia, no disease associations have so far been reported for the other genes. Functional studies and a systematic search for mutations or chromosome aberrations in this region will elucidate the role of individual genes in the clinical manifestations and will provide insight into the underlying biological mechanisms. Ó 2013 Wiley Periodicals, Inc.
How to Cite this Article: Oehl-Jaschkowitz B, Vanakker OM, De Paepe A, Menten B, Martin T, Weber G, Christmann A, Krier R, Scheid S, McNerlan SE, McKee S, Tzschach A. 2014. Deletions in 14q24.1q24.3 are associated with congenital heart defects, brachydactyly, and mild intellectual disability. Am J Med Genet Part A 164A:620–626.
duplications with the accompanying clinical consequences. There are, however, still “white spots” on this map, that is, chromosome regions for which no well-characterized aberrations have been described. One of those regions is chromosome band 14q24.1q24.3. Here, we report on three unrelated patients with mild intellectual disability, congenital heart defects, brachydactyly and additional abnormalities in whom overlapping interstitial de novo deletions were detected in 14q24.1q24.3.
Key words: del14q24.1q24.3; array CGH; intellectual disability; congenital heart disease; brachydactyly; SMOC1; ACTN1; DCAF5
INTRODUCTION The widespread application of array technologies in routine cytogenetic diagnostics in recent years has provided the basis for an ever more detailed correlation of small chromosomal deletions or
Ó 2013 Wiley Periodicals, Inc.
Conflict of interest: none. Grant sponsor: Wellcome Trust. Correspondence to: Andreas Tzschach, M.D., Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Calwerstr. 7, 72076 Tuebingen, Germany. E-mail: [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 19 December 2013 DOI 10.1002/ajmg.a.36321
620
OEHL-JASCHKOWITZ ET AL.
621
CLINICAL REPORTS Patient 1 This boy was born after an uneventful pregnancy at term to healthy and nonconsanguineous German parents. At birth, small hands and a small atrial septal defect (which did not require surgery) were noted, but he had no other malformations (birth measurements: length 48 cm (10–25th centile), weight 2,560 g (
