Array-CGH detection of a de novo 0.8 Mb deletion in 19q13.32 associated with mental retardation, cardiac malformation, cleft lip and palate, hearing loss and multiple dysmorphic features

doi:10.1016/j.ejmg.2008.09.007

European Journal of Medical Genetics

Volume 52, Issue 1, January–February 2009, Pages 62-66

https://doi.org/10.1016/j.ejmg.2008.09.007 Get rights and content

Abstract

We report on a 28-year old woman carrying a 0.8 Mb de novo interstitial deletion in 19q13.32 detected by high-resolution array-CGH. She has severe mental retardation, tetralogy of Fallot, cleft lip and palate, deafness, megacolon and other dysmorphic features. Only a few cases of constitutional deletions located at the long arm of chromosome 19 have been previously described and this is the first report involving 19q13.32. The deleted region encompasses 15 genes, among which 3 candidate genes for genotype–phenotype correlation could be delineated. Since SLC8A2 is broadly expressed in brain and plays a potential role during embryonic development, its haploinsufficiency could possibly be related to mental retardation; as it is also expressed in aortic and intestinal smooth muscles, SLC8A2 could be related to the aortic defect of the complex cardiac malformation and to the megacolon. SAE1, a SUMO-1 activating enzyme subunit, may be related to cleft lip and palate. KPTN coding region may be a candidate gene for hearing loss. Further experimental studies on either in vivo models or diagnostic materials are needed to elucidate the role of these potential candidate genes for the phenotypic abnormalities observed in the investigated patient.

Section snippets

Methods of detection

High molecular weight genomic DNA was extracted from the patient's peripheral blood lymphocytes using the QIAamp DNA Blood Midi kit (Qiagen, Valencia, CA) according to the manufacturer's instructions. DNA concentration was determined with NanoDrop ND-1000 spectrophotometer and software (NanoDrop Technologies, Berlin, Germany). Detection of gene copy number was performed by array-Comparative Genomic Hybridization (CGH) experiments following standard and manufacturer's recommendations (Agilent™,

Chromosomal anomaly

Cytogenetic investigations, performed early after the patient's birth by conventional standard (400) or high-resolution (800) R-banding pattern on 30 metaphases or prometaphases from peripheral lymphocytes cultured under phytohemagglutinin-stimulation, revealed a normal 46,XX karyotype. Fluorescence in situ hybridization (FISH) experiments performed on prometaphase preparations by using a set of 41 subtelomeric probes (Chromoprobe Multiprobe T system, Cytocell, Cambridge, UK) did not detect any

Method of confirmation

FISH experiments were performed using a BAC clone on metaphase cells. The deletion was confirmed by using a CTC-483I11 probe whose genomic position, extending from 52 341 333 to 52 496 454 bp, is located inside the deletion interval (Fig. 1B). The DNA probe was labeled by nick translation procedure with spectrum green-dUTP using a commercial kit (Vysis, Downers Grove, IL). Chromosomes were counterstained with 4′-6-diamino-2-phenyl-indole (DAPI). Hybridized cells were analyzed with a Zeiss

Causative of the phenotype

Analysis of the parents' peripheral lymphocyte methaphases did not reveal any chromosome deletion by FISH analyses while using the same fluorescent BAC clone. This finding indicates that the deletion found in the patient was de novo.

Clinical description

The Caucasian patient is the second child of healthy nonconsanguineous 31 years old G3P2 mother and 32 years old father. Her older brother is healthy. The patient was born at term (39 weeks) after an uncomplicated pregnancy, except for a threatening miscarriage at 10 weeks. At birth, the patient's weight, length and head circumference were 3250 g (50th centile), 51 cm (75th centile), 35 cm (75th centile) respectively; Apgar was 8/8 (1/5 min). Immediately after birth, the child was referred to the

Discussion

Deletion of chromosome 19 is quite uncommon and, for the best of our knowledge, only four cases of interstitial deletion involving 19q have been reported [1], [2]. Three cases of cryptic deletion at 19q13.2 have been identified by a Swedish group by means of microsatellite or FISH analyses in children with Diamond-Blackfan anemia, a constitutive red blood cell hypoplasia (for review see Gustavsson et al., 1998 [1]). A new microdeletion syndrome has then been suggested [1]. An additional

Acknowledgements

We thank Delphine Ceraso, Alexis Leurent, Caroline Thuilliez for their excellent technical assistance.

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These authors defined a new 19q13.32 microdeletion syndrome and suggested that the phenotypic severity depends on the size and gene content of the CNV. In fact, Patient 1 and the patient reported by Leal et al. (2009), both with large de novo deletions, shared a recurrent syndromic phenotype, including ID, facial asymmetry, oculomotor paralysis, ptosis, cleft lip and palate, micrognathia, kyphoscoliosis and congenital cardiac and intestinal defects; however, their Patients 2 and 3 did not present most of the distinctive features, probably because they carried shorter deletions, not including the entire critical region for this syndrome. They also suggested that the haploinsufficiency of some of the genes deleted in their patients could explain their phenotypes; specifically, they highlighted NPAS1, NAPA, ARHGAP35, SLC8A2, DHX34, MEIS3 and ZNF541, due to their expression in the brain parenchyma, glia, heart, gastrointestinal tract and musculoskeletal system (Castillo et al. 2014).
Intellectual disability (ID) is a complex and phenotypically heterogeneous neurodevelopmental disorder characterized by significant deficits in cognitive and adaptive skills, debuting during the developmental period. In the last decade, microarray-based copy number variation (CNV) analysis has been proved as a strategy particularly useful in the discovery of loci and candidate genes associated with these phenotypes and is widely used in the clinics with a diagnostic purpose. In this study, we evaluated the usefulness of two genome-wide high density SNP microarrays -Cytogenetics Whole-Genome 2.7 M SNP array (n = 126 patients; Group 1) and CytoScan High-Density SNP array (n = 447 patients; Group 2)- in the detection of clinically relevant CNVs in a cohort of ID patients from Galicia (NW Spain). In 159 (27.7%) patients, we detected 186 rare exonic chromosomal imbalances, that were grouped into the following classes: Clinically relevant (67/186; 36.0%), of unknown clinical significance (93/186; 50.0%) and benign (26/186; 14.0%). The 67 pathogenic CNVs were identified in 64 patients, which means an overall diagnostic yield of 11.2%. Overall, we confirmed that ID is a genetically heterogeneous condition and emphasized the importance of using genome-wide high density SNP microarrays in the detection of its genetic causes. Additionally, we provided clinical and molecular data of patients with pathogenic or likely pathogenic CNVs and discussed the potential implication in neurodevelopmental disorders of genes located within these variants.
19q13.32 microdeletion syndrome: Three new cases
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In conclusion, we present and compare three unrelated patients (Fig. 2 and Table 1) with a deletion involving chromosome 19q13.32, whose phenotypic severity depends on the size and content of the deletion. A recognizable deletion syndrome is defined by the shared phenotypic features in the patient reported by Leal et al. [2009] and our Patient 1. They both share a deleted region (minimally, 52,035,320–52,758,151; maximally 51,970,589–52,878,649), where the commonly deleted 20–23 candidate genes are expressed in the brain parenchyma, glia, heart, gastrointestinal tract and musculoskeletal system and likely play a fundamental role in the expression of this phenotype.
A previous report described a unique phenotype associated with an apparently de novo 732 kb 19q13.32 microdeletion, consisting of intellectual disability, facial asymmetry, ptosis, oculomotor abnormalities, orofacial clefts, cardiac defects, scoliosis and chronic constipation. We report three unrelated patients with developmental delay and dysmorphic features, who were all found to have interstitial 19q13.32 microdeletions of varying sizes. Both the previously reported patient and our Patient 1 with a larger, 1.3-Mb deletion have distinctive dysmorphic features and medical problems, allowing us to define a recognizable 19q13.32 microdeletion syndrome. Patient 1 was hypotonic and dysmorphic at birth, with aplasia of the posterior corpus callosum, bilateral ptosis, oculomotor paralysis, down-slanting palpebral fissures, facial asymmetry, submucosal cleft palate, micrognathia, wide-spaced nipples, right-sided aortic arch, hypospadias, bilateral inguinal hernias, double toenail of the left second toe, partial 2–3 toe syndactyly, kyphoscoliosis and colonic atony. Therefore, the common features of the 19q13.32 microdeletion syndrome include facial asymmetry, ptosis, oculomotor paralysis, orofacial clefting, micrognathia, kyphoscoliosis, aortic defects and colonic atony. These findings are probably related to a deletion of some combination of the 20–23 genes in common between these two patients, especially NPAS1, NAPA, ARHGAP35, SLC8A2, DHX34, MEIS3, and ZNF541. These candidate genes are expressed in the brain parenchyma, glia, heart, gastrointestinal tract and musculoskeletal system and likely play a fundamental role in the expression of this phenotype. This report delineates the phenotypic spectrum associated with the haploinsufficiency of genes found in 19q13.32.
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Chromosomal imbalance letterArray-CGH detection of a de novo 0.8 Mb deletion in 19q13.32 associated with mental retardation, cardiac malformation, cleft lip and palate, hearing loss and multiple dysmorphic features

Abstract

Section snippets

Methods of detection

Chromosomal anomaly

Method of confirmation

Causative of the phenotype

Clinical description

Discussion

Acknowledgements

Am. J. Hum. Genet.

J. Biol. Chem.

Identification of microdeletions spanning the Diamond-Blackfan anaemia locus on 19q13 and evidence for genetic heterogeneity

J. Med. Genet.

Constitutional del(19) (q12q13.1) in a three-year-old girl with severe phenotypic abnormalities affecting multiple organ systems

Am. J.M. Med. Genet.

Global variation in copy number in the human genome

Nature

Chromosomal imbalance letter
Array-CGH detection of a de novo 0.8 Mb deletion in 19q13.32 associated with mental retardation, cardiac malformation, cleft lip and palate, hearing loss and multiple dysmorphic features