- Case report
- Open Access
A new case of de novo 19p13.2p13.12 deletion in a girl with overgrowth and severe developmental delay
© Natiq et al.; licensee BioMed Central Ltd. 2014
- Received: 26 March 2014
- Accepted: 21 May 2014
- Published: 5 June 2014
We report clinical and molecular cytogenetic characterization of a 2 year-old girl with 19p13.2p13.12 microdeletion and compare her clinical features with those of three other patients reported before.
Array comparative genomic hybridization (aCGH) revealed in the present patient a de novo microdeletion of 1.45 Mb within 19p13.2p13.12. The deletion includes seven OMIM genes: MAN2B1, RNASEH2A, KLF1, GCDH, NFIX, CACNA1A and CC2D1A.
The present case and three other patients with partially overlapping 19p13 microdeletion share the following features: psychomotor and language delay, intellectual disability, seizures, hypotonia, skeletal anomalies and facial dysmorphism. The smallest region of overlapping between all four reported patients is around 300 kb and spans only two genes: NFIX and CACNA1A. Their haploinsufficincy could be the base for the phenotype -genotype correlation.
- Psychomotor delay
- 19p13.2p13.12 deletion
- Array comparative genomic hybridization
Array comparative genomic hybridization (aCGH) has allowed for identification of the underlying molecular bases for numerous patients with multiple congenital anomalies. De novo microdeletion 19p13 detected by aCGH is rarely reported [1–4]. However, all yet known patients had intellectual disability and multiple congenital anomalies.
We report clinical and molecular cytogenetic characterization of a 2 year-old girl with a 19p13.2 to 19p13.12 microdeletion and compare her clinical features with those of three other patients [1, 2, 4]. The phenotype is mainly characterized by psychomotor and language delay, intellectual disability, seizures, hypotonia, skeletal anomalies and facial dysmorphism. The shortest region of overlap (SRO) extending for about 300 Kb between the four cases contains candidate genes responsible for their common phenotype (severe developmental delay, seizures, and skeletal anomalies). This microdeletion encompasses seven OMIM genes, among which two (NFIX and CACNA1A) could be the candidate genes for the genotype-phenotype relationship.
At 2 years and 3 months her length was 97 cm (>95th centile), weight 15 kg (95th centile), and head circumference 52 cm (>95th centile). She was still hypotonic, unable to hold her head or to sit down, and with absent speech. The cerebral MRI showed bilateral frontal cortical atrophy. The EEG showed epileptiform focal abnormalities disorganized background rythm of slow (2-3 Hz) waves.
Peripheral blood was collected from the patient and her parents. Informed consent was obtained from the patient’s parents prior to implementation of the genetic studies.
Cytogenetics studies were performed on metaphase chromosome preparations obtained from phytohemagglutinin stimulated lymphocyte cultures according to standard procedures. Chromosome analysis was carried applying RHG banding at a 400-band level as previously reported and according to the International System for Human Cytogenetic: Nomenclature ISCN 2013 [5, 6].
DNA was extracted from whole blood using the QIAmp DNA Kit (QIAGEN) according to the manufacturer’s instructions.
Methyl PCR was performed with Epitect Bisulfite Kit and EpiTect MSP kit according to the manufacturer’s instructions (QIAGEN).
Array-based comparative genomic hybridization
aCGH was carried out using 180 K-oligonucleotide array (Agilent, San Clara, CA) with an average resolution of about 25 kb, the procedure for DNA digestion and hybridization were performed according to the manufacturer’s instruction. For analysis of the result two databases were used respectively for the chromosomal localization: UCSC genome browser (http://genome.UCSC.edu) and for polymorphism control: database of genomic variants (http://dgv.tcag.ca/).
Fluorescent in-situ hybridization (FISH) analysis
FISH was performed on PHA-stimulated peripheral blood lymphocytes obtained from patient and both parents. BAC RP11-782D11 (located in 19p13.2p13.13) and CTD-2265021 (19q subtelomeric) probes obtained from CHORI (Oakland, CA) were used according standard protocols.
Summary of clinical features and cytogenetic characteristics of the reported patients with 19p13 deletion overlapping with our patient
Bonaglia et al.  Patient 3
Auvin et al. 
Lysy et al. 
Deletion size Mb
At last evaluation
Bilateral threshold 60 dB
Advanced bone age
Advanced bone age
Craniocynostosis with left spleno-orbital dysplasia
ClinodactylyV right hand, left I and II toes overlapping bracydactyly
In addition through this case report, we want to focus on the importance of a (aCGH) as a first-tier diagnostic step for patients with developmental disabilities and/or multiples congenital anomalies as reported by several scientific papers [15–18].
This report gives more information for the recently identified 19p13 deletion syndrome and clarifies the clinical implication of genes in the involved chromosomal region. Also, our paper may contribute to a better understanding of the genotype-phenotype correlation in cases with deletion in 19p13 and particularly in the involvement of NFIX and CACNA1A genes in overgrowth, epilepsies and developmental delay.
Written informed consent was obtained from the patient’s parents for publication and accompanying images of this case report. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
The authors would like to gratefully acknowledge the patient and her parents for their collaboration.
- Lysy PA, Ravoet M, Wustefeld S, Bernard P, Nassogne MC, Wyns E, Sibille C: A new case of syndromic craniosynostosis with cryptic 19p13.2-p13.13 deletion. Am J Med Genet A 2009,149A(11):2564–2568. 10.1002/ajmg.a.33056View ArticlePubMedGoogle Scholar
- Auvin S, Holder-Espinasse M, Lamblin MD, Andrieux J: Array-CGH detection of a de novo 0.7-Mb deletion in 19p13.13 including CACNA1A associated with mental retardation and epilepsy with infantile spasms. Epilepsia 2009,50(11):2501–2503. 10.1111/j.1528-1167.2009.02189.xView ArticlePubMedGoogle Scholar
- Jensen DR, Martin DM, Gebarski S, Sahoo T, Brundage EK, Chinault AC, Otto EA, Chaki M, Hildebrandt F, Cheung SW, Lesperance MM: A novel chromosome 19p13.12 deletion in a child with multiple congenital anomalies. Am J Med Genet A 2009,149A(3):396–402. 10.1002/ajmg.a.32691PubMed CentralView ArticlePubMedGoogle Scholar
- Bonaglia MC, Marelli S, Novara F, Commodaro S, Borgatti R, Minardo G, Memo L, Mangold E, Beri S, Zucca C, Brambilla D, Molteni M, Giorda R, Weber RG, Zuffardi O: Genotype-phenotype relationship in three cases with overlapping 19p13.12 microdeletions. Eur J Hum Genet 2010,18(12):1302–1309. 10.1038/ejhg.2010.115PubMed CentralView ArticlePubMedGoogle Scholar
- Simons A, Shaffer LG, Hastings RJ: Cytogenetic nomenclature: changes in the ISCN 2013 compared to the 2009 edition. Cytogenet Genome Res 2013, 141: 1–6. 10.1159/000353118View ArticlePubMedGoogle Scholar
- Aboussair N, Jaouad IC, Dequaqui SC, Sbiti A, Elkerch F, Yahya B, Natiq A, Sefiani A: Cytogenetic analysis of 5572 patients referred for suspected chromosomal abnormalities in Morocco. Genet Test Mol Biomarkers 2012,16(6):569–573. 10.1089/gtmb.2011.0265View ArticlePubMedGoogle Scholar
- Driller K, Pagenstecher A, Uhl M, Omran H, Berlis A, Grunder A, Sippel AE: Nuclear factor I X deficiency causes brain malformation and severe skeletal defects. Mol Cell Biol 2007,27(10):3855–3867. 10.1128/MCB.02293-06PubMed CentralView ArticlePubMedGoogle Scholar
- Malan V, Rajan D, Thomas S, Shaw AC, Louis Dit Picard H, Layet V, Till M, van Haeringen A, Mortier G, Nampoothiri S, Puseljić S, Legeai-Mallet L, Carter NP, Vekemans M, Munnich A, Hennekam RC, Colleaux L, Cormier-Daire V: Distinct effects of allelic NFIX mutations on nonsense-mediated mRNA decay engender either a Sotos-like or a Marshall-Smith syndrome. Am J Hum Genet 2010,87(2):189–198. 10.1016/j.ajhg.2010.07.001PubMed CentralView ArticlePubMedGoogle Scholar
- Yoneda Y, Saitsu H, Touyama M, Makita Y, Miyamoto A, Hamada K, Kurotaki N, Tomita H, Nishiyama K, Tsurusaki Y, Doi H, Miyake N, Ogata K, Naritomi K, Matsumoto N: Missense mutations in the DNA-binding/dimerization domain of NFIX cause Sotos-like features. J Hum Genet 2012,57(3):207–211. HYPERLINK " http://www.ncbi.nlm.nih.gov/pubmed?term=Matsumoto%20N%5BAuthor%5D&cauthor=true&cauthor_uid=22301465 10.1038/jhg.2012.7View ArticlePubMedGoogle Scholar
- Beauvais K, Cave-Riant F, De Barace C, Tardieu M, Tournier-Lasserve E, Furby A: New CACNA1A gene mutation in a case of familial hemiplegic migraine with status epilepticus. Eur Neurol 2004,52(1):58–61. 10.1159/000079546View ArticlePubMedGoogle Scholar
- Kors EE, Melberg A, Vanmolkot KR, Kumlien E, Haan J, Raininko R, Flink R, Ginjaar HB, Frants RR, van den Ferrari MD, Maagdenberg AM: Childhood epilepsy, familial hemiplegic migraine, cerebellar ataxia, and a new CACNA1A mutation. Neurology 2004,63(6):1136–1137. HYPERLINK " " HYPERLINK " http://www.ncbi.nlm.nih.gov/pubmed?term=van%20den%20Maagdenberg%20AM%5BAuthor%5D&cauthor=true&cauthor_uid=15452324 10.1212/01.WNL.0000138571.48593.FCView ArticlePubMedGoogle Scholar
- Marangi G, Orteschi D, Vigevano F, Felie J, Walsh CA, Manzini MC, Neri G: Expanding the spectrum of rearrangements involving chromosome 19: a mild phenotype associated with a 19p13.12-p13.13 deletion. Am J Med Genet A 2012,158A(4):888–893. 10.1002/ajmg.a.35254PubMed CentralView ArticlePubMedGoogle Scholar
- Vahedi K, Denier C, Ducros A, Bousson V, Levy C, Chabriat H, Haguenau M, Tournier-Lasserve E, Bousser MG: CACNA1A gene de novo mutation causing hemiplegic migraine, coma, and cerebellar atrophy. Neurology 2000,55(7):1040–1042. 10.1212/WNL.55.7.1040View ArticlePubMedGoogle Scholar
- Guerin AA, Feigenbaum A, Donner EJ, Yoon G: Stepwise developmental regression associated with novel CACNA1A mutation. Pediatr Neurol 2008,39(5):363–364. 10.1016/j.pediatrneurol.2008.07.030View ArticlePubMedGoogle Scholar
- Miller DT, Adam MP, Aradhya S, Biesecker LG, Brothman AR, Carter NP, Church DM, Crolla JA, Eichler EE, Epstein CJ, Faucett WA, Feuk L, Friedman JM, Hamosh A, Jackson L, Kaminsky EB, Kok K, Krantz ID, Kuhn RM, Lee C, Ostell JM, Rosenberg C, Scherer SW, Spinner NB, Stavropoulos DJ, Tepperberg JH, Thorland EC, Vermeesch JR, Waggoner DJ, Watson MS, Martin CL, Ledbetter DH: Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet 2010,86(5):749–764. HYPERLINK " http://www.ncbi.nlm.nih.gov/pubmed?term=Vermeesch%20JR%5BAuthor%5D&cauthor=true&cauthor_uid=20466091 10.1016/j.ajhg.2010.04.006PubMed CentralView ArticlePubMedGoogle Scholar
- Regier DA, Friedman JM, Marra CA: Value for money? Array genomic hybridization for diagnostic testing for genetic causes of intellectual disability. Am J Hum Genet 2010,86(5):765–772. 10.1016/j.ajhg.2010.03.009PubMed CentralView ArticlePubMedGoogle Scholar
- Yu S, Bittel DC, Kibiryeva N, Zwick DL, Cooley LD: Validation of the Agilent 244K oligonucleotide array-based comparative genomic hybridization platform for clinical cytogenetic diagnosis. Am J Clin Pathol 2009,132(3):349–360. 10.1309/AJCP1BOUTWF6ERYSView ArticlePubMedGoogle Scholar
- Xiang B, Zhu H, Shen Y, Miller DT, Lu K, Hu X, Andersson HC, Narumanchi TM, Wang Y, Wu BL, Li P, Li MM, Chen TJ, Fan YS: Genomewide oligonucleotide array comparative genomic hybridization for etiological diagnosis of mental retardation: a multicenter experience of 1499 clinical cases. J Mol Diagn 2010,12(2):204–212. 10.2353/jmoldx.2010.090115PubMed CentralView ArticlePubMedGoogle 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.