Phenotypic and genetic characterization of a patient with a de novo interstitial 14q24.1q24.3 deletion
© Tassano et al.; licensee BioMed Central Ltd. 2014
Received: 22 April 2014
Accepted: 30 June 2014
Published: 21 July 2014
Interstitial deletions of chromosome bands 14q24.1q24.3 are very rare with only three reported cases.
We describe a 7-year-old boy with a 5.345 Mb de novo interstitial deletion at 14q24.1q24.3 band detected by array-CGH who had a complex phenotype characterized by seizures, congenital heart defects, dysmorphisms, psychomotor delay, and bronchopulmonary, skeletal, and brain anomalies.
The deleted region contains numerous genes, but we focused our attention on three of them (C14orf169, NUMB, and PSEN1), which could account, at least partially, for the phenotype of the boy. We therefore discuss the involvement of these genes and the observed phenotype compared to that of previously described patients.
KeywordsInterstitial 14q24.1q24.3 deletion De novo Array-CGH Genotype-phenotype correlation
Interstitial deletions involving chromosome band 14q24.1q24.3 are very rare. The use of array-CGH in routine cytogenetic diagnostics allowed the detection of pathogenic copy number variants (CNVs), which contribute to the delineation of new genomic disorders. However, there are chromosome regions in which no well-characterized aberrations were found, such as 14q24.1q24.3. Recently, Oehl-Jaschkowitz et al., described the first three unrelated patients with overlapping de novo interstitial 14q23.1q24.3 deletion characterized by array-CGH. All three patients had mild intellectual disability, congenital heart defect, brachydactyly, hypertelorism, broad nasal bridge and thin upper lip.
Here, we report on a de novo 14q24.1q24.3 deletion in a boy with complex phenotype characterized by seizures, congenital heart defects, dysmorphisms, psychomotor delay, and bronchopulmonary, skeletal, and brain anomalies. We compare the phenotype of our patient with that of previously reported patients and discuss the role of the deleted genes in order to investigate the possibility of a genotype-phenotype correlation.
Clinical Features of the patients with 14q24.1q24.3 deletion
Patient 1 Oehl-Jaschkowitz et al., 
Patient 2 Oehl-Jaschkowitz et al., 
Patient 3 Oehl-Jaschkowitz et al., 
Position of 14q24 deletion (hg19)
Size of 14q24 deletion
Respiratory insufficiency. Bronchial hyperactivity
Congenital heart disease
Atrial septal defect
Atrial septal defect
Pulmonary atresia with a ventricular septal defect, anteriorly-set aorta and severe stenosis of the pulmonary arterial confluence
Broad and sparse eyebrows, convergent strabismus, broad nasal bridge and hypertelorism, nose with columella and naris broad, ears with prominent helix and antihelix and large lobe, long philtrum, thin upper lip, short neck, low set posterior hairline
Hypertelorism, high nasal bridge, long and flat philtrum, thin upper lip.
Hypertelorism, small nose, thin upper lip, downslanting palpebral fissures.
Hypertelorism, mild synophrys, epicanthic folds and downslanting palpebral fissures, midface hypoplasia, thin lips
Hand and foot anomalies
Short fingers and nails of feet and hands, broad toes and thumbs, valgus -flat feet
Bilateral hypoplastic thumbs, short and tapering fingers and cutaneous syndactyly of the fingers.
Very small hands that were narrow across the metacarpophalangeal joints and proximally-set thumbs. The feet were small with minimal 2-3 toe syndactyly and an over-curved 4th toenail bilaterally.
Attention deficiency and hyperactivity
Pectus excavatum, joint hyperlaxity of lower limbs, valgus-flat feet
Limited extension and supination of elbows
Short arms, limited elbow extension with bilateral dislocation of the radial heads
Hyperlaxity of the fingers and elbows
Mild symmetrical enlargement of supratentorial ventricular cavities and enlargement of fronto-insular periencephalic spaces
Given the large number of deleted genes comprised in the deletion, the comparison of our patient with a second case could contribute to the identification of candidate genes responsible for the phenotypic features of patients with 14q24.1q24.3 deletion.
The clinical features shared by the three patients reported by Oehl-Jaschkowitz et al. were congenital heart defects, brachydactyly, mild intellectual disability, and facial dysmorphic signs. These authors suggested a possible causative role of SMOC1 and DCAF5 genes in the phenotypic features of their patients.
It is interesting to note that both patients 2 and 3, carrying a smaller deletion, had more severe heart defects and patient 2 had anomalies of hands and feet. This could be due to the haploinsufficiency of more genes or to their different expressivity. However, we can hypothesize that other genes or genetic factors could modify the phenotype in each particular case.
In addition to the above-mentioned genes, we considered C14orf169 (NO66), NUMB, and PSEN1 as possible causative genes for the phenotype of our patient and for patient 1 reported by Oehl-Jaschkowitz et al..
The gene product of NO66 (C14orf169) is a jumonji C-containing protein identified as Osterix-interacting polypeptides expressed in bone that exhibits an in vitro demethylase activity with dual specificity for lysines 4 and 36 of histone H3. According to Sinha et al., interactions of NO66 demethylase with Osterix should be considered physiologically significant in regulating osteoblast differentiation through modulation of Osterix activity. The authors concluded that NO66 helps gene repression through histone demethylation and/or formation of a repressor complex, which results in multilayered control of chromatin architecture of specific osteoblast genes.
In ACD, a dividing mother cell segregates cell fate determinants asymmetrically into only one of the two daughter cells, and this process is indeed crucial for balancing self-renewal, cell differentiation, and correct spatial and temporal specification of cell lineages during development[7–9].
In the lung, ACD plays an essential role in mediating the balance between lung epithelial stem/progenitor cell maintenance and differentiation of cell populations at distal epithelial tips during lung development[10, 11].
Lethal defects of gas diffusion capacity such as the common congenital forms of lung hypoplasia and bronchopulmonary dysplasia as well as the limited capacity of the lung to recover from these defects could be explained by a significant deficiency of stem/progenitor cells[11, 12]. Therefore, proper balance between self-renewal and differentiation of lung-specific progenitors, which is mediated by ACD, is essential for normal morphogenesis and regeneration of the lung.
Moreover, loss of epithelial cell polarity is also involved in lung epithelial cancers and chronic obstructive pulmonary disease, which are likewise related to disruption of lung epithelial differentiation and cellular function.
As regards neurogenesis, it has been reported that Numb and Numblike (Numbl) are functionally related proteins that critically regulate progenitor differentiation and neuroepithelial integrity during embryonic neurogenesis[14–17]. They function during neural precursor ACD to antagonize Notch function in one of the daughter cells. In mouse, the loss of Numb and Numbl causes premature progenitor cell depletion and, consequently, a highly specific malformation of the neocortex and hippocampus.
Recently, Zhao et al. studied NUMB functions in cardiac progenitor cell differentiation and cardiac morphogenesis. Heart development is a spatiotemporal multistep morphogenetic process that depends on the addition of progenitor cells from four different sources, including cells from the first heart field and the second heart field (FHF and SHF), cells derived from cardiac neural crest cells, and cells derived from the pro-epicardial organ[20–24].
Perturbations in different cardiac cell populations determine a spectrum of congenital heart defects. The posterior SHF contributes to create chambre septation. Abnormal differentiation and development of the cells of this area were found associated with atrial septal defect and atrioventricular septal defect[25, 26]. In fact, as demonstrated in knockout mice, the deletion of NUMB and NUMBL in SHF-derived cells resulted in atrioventricular septation defects, which indicates their role in cardiac morphogenesis.
Finally, another deleted gene in our patient, PSEN1 (Presenilin 1), is the catalytic component of the γ-secretase complex, a membrane-embedded aspartyl protease that plays a central role in biology and in the pathogenesis of Alzheimer's disease.
Mutations in the PSEN1 gene are the most common cause of autosomal dominant Alzheimer's disease (AD), with around 180 mutations described to date. PSEN1 AD has a broad clinical phenotype, encompassing not only dementia but also a variety of other neurological features that may include epileptic seizures. Recently, in a transgenic mouse model, it has been shown that altered expression of Numb isoforms in vulnerable neurons occurs during AD pathogenesis, which suggests a role for Numb in the disease process.
The other genes in this interval with known disease associations are DNAL1, COQ6, ALDH6A1, CHX10, and ABCD4. Their mutations cause autosomal recessive syndromes and no abnormalities have been reported in heterozygous carriers.
Therefore, in our opinion NUMB and PSEN1 could be suggestive of cardiac, neurological, and respiratory phenotypes. Moreover, NO66 deletion could play a role in the skeletal anomalies of our patient.
In conclusion, we identified a new very rare case of a 14q24.1q24.3 deletion in a boy affected by cardiac, neurological, bronchopulmonary, and skeletal anomalies. This region encompasses about 50 RefSeq genes. We suggest that NUMB, PSEN1, and NO66 genes, in addition to those reported by Oehl-Jaschkowitz et al., may play a role in the phenotypic features of our patient. Furthermore, the patient 1 and our patient are the first human cases of a deletion of the NUMB gene, which are consistent with its importance for the cardiac, neurologic and lung normal development. On the other hand, we cannot exclude some influence of the many other genes included in the deleted region.
Standard GTG banding was performed at a resolution of 400-550 bands on metaphase chromosomes from peripheral blood lymphocytes of the patient and his parents. Molecular karyotyping was performed on the proband and his parents using Human Genome CGH Microarray Kit G3 180 (Agilent Technologies, Palo Alto, USA) with ~13 Kb overall median probe spacing. Labelling and hybridization were performed following the protocols provided by the manufacturers. A graphical overview was obtained using the Agilent Genomic Workbench Lite Edition Software 22.214.171.124.
Written informed consent was obtained from the patient’s parents for publication of this paper and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
We thank the patient’s parents for their kind participation and support. We are grateful to Marco Bertorello and Corrado Torello for their technical assistance. This work was supported by “Cinque per mille dell’IRPEF- Finanziamento della ricerca sanitaria” and “Finanziamento Ricerca Corrente, Ministero Salute (contributo per la ricerca intramurale).
- 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: Deletions in 14q24.1q24.3 are associated with congenital heart defects, brachydactyly, and mild intellectual disability. Am J Med Genet A 2014, 164: 620–626. 10.1002/ajmg.a.36321View ArticleGoogle Scholar
- Sinha KM, Yasuda H, Coombes MM, Dent SY, de Crombrugghe B: Regulation of the osteoblast-specific transcription factor Osterix by NO66, a Jumonji family histone demethylase. EMBO J 2010, 29: 68–79. 10.1038/emboj.2009.332PubMed CentralView ArticlePubMedGoogle Scholar
- Sinha KM, Yasuda H, Zhou X, Decrombrugghe B: Osterix and NO66 histone demethylase control the chromatin of osterix target genes during osteoblast differentiation. J Bone Miner Res 2014, 29: 855–865. 10.1002/jbmr.2103PubMed CentralView ArticlePubMedGoogle Scholar
- Knoblich JA: Asymmetric cell division during animal development. Nat Rev Mol Cell Biol 2001, 2: 11–20. 10.1038/35048085View ArticlePubMedGoogle Scholar
- Knoblich JA: Asymmetric cell division: recent developments and their implications for tumour biology. Nat Rev Mol Cell Biol 2010, 11: 849–860. 10.1038/nrm3010PubMed CentralView ArticlePubMedGoogle Scholar
- El-Hashash AH, Warburton D: Numb expression and asymmetric versus symmetric cell division in distal embryonic lung epithelium. J Histochem Cytochem 2012, 60: 675–682. 10.1369/0022155412451582PubMed CentralView ArticlePubMedGoogle Scholar
- Knoblich JA: Mechanisms of asymmetric stem cell division. Cell 2008, 132: 583–597. 10.1016/j.cell.2008.02.007View ArticlePubMedGoogle Scholar
- Zhong W, Chia W: Neurogenesis and asymmetric cell division. Curr Opin Neurobiol 2008, 18: 4–11. 10.1016/j.conb.2008.05.002View ArticlePubMedGoogle Scholar
- Siller KH, Doe CQ: Spindle orientation during asymmetric cell division. Nat Cell Biol 2009, 11: 365–374. 10.1038/ncb0409-365View ArticlePubMedGoogle Scholar
- Warburton D, Schwarz M, Tefft D, Flores-Delgado G, Anderson KD, Cardoso WV: The molecular basis of lung morphogenesis. Mech Dev 2000, 92: 55–81. 10.1016/S0925-4773(99)00325-1View ArticlePubMedGoogle Scholar
- Warburton D, Perin L, Defilippo R, Bellusci S, Shi W, Driscoll B: Stem/progenitor cells in lung development, injury repair, and regeneration. Proc Am Thorac Soc 2008, 5: 703–706. 10.1513/pats.200801-012AWPubMed CentralView ArticlePubMedGoogle Scholar
- Shi W, Xu J, Warburton D: Development, repair and fibrosis: what is common and why it matters. Respirology 2009, 14: 656–665. 10.1111/j.1440-1843.2009.01565.xPubMed CentralView ArticlePubMedGoogle Scholar
- Xu J, Tian J, Grumelli S, Haley K, Shapiro SD: Stage-specific effects of cAMP signaling during distal lung epithelial development. J Biol Chem 2006, 281: 38894–38904. 10.1074/jbc.M609339200View ArticlePubMedGoogle Scholar
- Petersen PH, Zou K, Hwang JK, Jan YN, Zhong W: Progenitor cell maintenance requires numb and numblike during mouse neurogenesis. Nature 2002, 419: 929–934. 10.1038/nature01124View ArticlePubMedGoogle Scholar
- Shen Q, Zhong W, Jan YN, Temple S: Asymmetric Numb distribution is critical for asymmetric cell division of mouse cerebral cortical stem cells and neuroblasts. Development 2002, 129: 4843–4853.PubMedGoogle Scholar
- Li HS, Wang D, Shen Q, Schonemann MD, Gorski JA, Jones KR, Temple S, Jan LY, Jan YN: Inactivation of Numb and Numblike in embryonic dorsal forebrain impairs neurogenesis and disrupts cortical morphogenesis. Neuron 2003, 40: 1105–1118. 10.1016/S0896-6273(03)00755-4View ArticlePubMedGoogle Scholar
- Petersen PH, Zou K, Krauss S, Zhong W: Continuing role for mouse Numb and Numbl in maintaining progenitor cells during cortical neurogenesis. Nat Neurosci 2004, 7: 803–811. 10.1038/nn1289View ArticlePubMedGoogle Scholar
- Roegiers F, Jan YN: Asymmetric cell division. Curr Opin Cell Biol 2004, 16: 195–205. 10.1016/j.ceb.2004.02.010View ArticlePubMedGoogle Scholar
- Zhao C, Guo H, Li J, Myint T, Pittman W, Yang L, Zhong W, Schwartz RJ, Schwarz JJ, Singer HA, Tallquist MD, Wu M: Numb family proteins are essential for cardiac morphogenesis and progenitor differentiation. Development 2014, 141: 281–295. 10.1242/dev.093690PubMed CentralView ArticlePubMedGoogle Scholar
- Kelly RG, Brown NA, Buckingham ME: The arterial pole of the mouse heart forms from Fgf10-expressing cells in pharyngeal mesoderm. Dev Cell 2001, 1: 435–440. 10.1016/S1534-5807(01)00040-5View ArticlePubMedGoogle Scholar
- Mjaatvedt CH, Nakaoka T, Moreno-Rodriguez R, Norris RA, Kern MJ, Eisenberg CA, Turner D, Markwald RR: The outflow tract of the heart is recruited from a novel heart-forming field. Dev Biol 2001, 238: 97–109. 10.1006/dbio.2001.0409View ArticlePubMedGoogle Scholar
- Waldo KL, Kumiski DH, Wallis KT, Stadt HA, Hutson MR, Platt DH, Kirby ML: Conotruncal myocardium arises from a secondary heart field. Development 2001, 128: 3179–3188.PubMedGoogle Scholar
- Verzi MP, McCulley DJ, De Val S, Dodou E, Black BL: The right ventricle, outflow tract, and ventricular septum comprise a restricted expression domain within the secondary/anterior heart field. Dev Biol 2005, 287: 134–145. 10.1016/j.ydbio.2005.08.041View ArticlePubMedGoogle Scholar
- Vincent SD, Buckingham ME: How to make a heart: the origin and regulation of cardiac progenitor cells. Curr Top Dev Biol 2010, 90: 1–41.View ArticlePubMedGoogle Scholar
- Snarr BS, O'Neal JL, Chintalapudi MR, Wirrig EE, Phelps AL, Kubalak SW, Wessels A: Isl1 expression at the venous pole identifies a novel role for the second heart field in cardiac development. Circ Res 2007, 101: 971–974. 10.1161/CIRCRESAHA.107.162206View ArticlePubMedGoogle Scholar
- Briggs LE, Kakarla J, Wessels A: The pathogenesis of atrial and atrioventricular septal defects with special emphasis on the role of the dorsal mesenchymal protrusion. Differentiation 2012, 84: 117–130. 10.1016/j.diff.2012.05.006PubMed CentralView ArticlePubMedGoogle Scholar
- Larner AJ: Presenilin-1 mutation Alzheimer's disease: a genetic epilepsy syndrome? Epilepsy Behav 2011, 21: 20–22. 10.1016/j.yebeh.2011.03.022View ArticlePubMedGoogle Scholar
- Chigurupati S, Madan M, Okun E, Wei Z, Pattisapu JV, Mughal MR, Mattson MP, Chan SL: Evidence for altered Numb isoform levels in Alzheimer's disease patients and a triple transgenic mouse model. J Alzheimers Dis 2011, 24: 349–361.PubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.