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.
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 18.104.22.168.
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).
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