Application of array-CGH for the detection of genomic rearrangements responsible for syndromic mental retardation of unknown cause
ABSTRACT: Here we describe an interstitial pure duplication of 19p13.3 that was initially considered as a de novo alteration, in a patient with intellectual disability studied by array-CGH. The finding of the same chromosomal alteration in a first-degree cousin of this patient led us to investigate the presence of insertional translocations. An intrachromosomal insertional translocation was found in at least three generations. Three intellectually disabled patients with the same duplication and multiples abortions among translocation carrier family members were found. A review of other published cases has allowed us to find three other cases with a similar pure duplication and some clinical findings present in all patients as intrauterine growth retardation, microcephaly, motor and speech delay, moderate to severe intellectual disability and dysmorphic features. These findings allow us to suggest the existence of a new microduplication syndrome in chromosomal region 19p13.3. Whole genome array-CGH was performed on Agilent oligo-chip 44K (human genome CGH microarray G4410B from Agilent Technologies, Palo Alto, CA) as recommended. The patients’ DNA samples were tested against a pool of 10 sex-matched normal DNA samples, all of them (patients and normal controls) from our geographical area. Scanned images were quantified using Agilent Feature Extraction Software (v9.0). The results were analyzed using Agilent Genomic Workbench software. Annotations have been obtained from UCSC (http://genome.ucsc.edu) based on human genome build GRCh37/hg19.
Project description:Epilepsy is genetically complex but common brain disorder of the world affecting millions of people with almost of all age groups. Novel Copy number variations (CNVs) are considered as important reason for the numerous neurodevelopmental disorders along with intellectual disability and epilepsy. DNA array based studies contribute to explain a more severe clinical presentation of the disease but interoperation of many detected CNVs are still challenging.In order to study novel CNVs with epilepsy related genes in Saudi family with six affected and two normal individuals with several forms of epileptic seizures, intellectual disability (ID), and minor dysmorphism, we performed the high density whole genome Agilent sure print G3 Hmn CGH 2x 400 K array-CGH chips analysis. Our results showed de novo deletions, duplications and deletion plus duplication on differential chromosomal regions in the affected individuals that were not shown in the normal fathe and normal kids by using Agilent CytoGenomics 18.104.22.168 softwear. Copy number gain were observed in the chromosome 1, 16 and 22 with LCE3C, HPR, GSTT2, GSTTP2, DDT and DDTL genes respectively whereas the deletions observed in the chromosomal regions 8p23-p21 (4303127-4337759) and the potential gene in this region is CSMD1 (OMIM: 612279). Moreover, the array CGH results deletions and duplication were also validated by using primer design of deleted regions utilizing the flanked SNPs using simple PCR and also by using quantitative real time PCR.We found some of the de novo deletions and duplication in our study in Saudi family with intellectual disability and epilepsy. Our results suggest that array-CGH should be used as a first line of genetic test for epilepsy except there is a strong indication for a monogenic syndrome. The advanced high through put array-CGH technique used in this study aim to collect the data base and to identify new mechanisms describing epileptic disorder, may help to improve the clinical management of individual cases in decreasing the burden of epilepsy in Saudi Arabia.
Project description:We present a clinical report of an 11-year-old male patient with an interstitial duplication of 19p13.3 (829?kb in size) at genomic coordinates 3,804,495-4,033,722?bp (hg19) identified by chromosomal microarray analysis and review the literature from nine published reports adding knowledge regarding this chromosomal anomaly and clinical outcomes. The size of the duplication ranged from 0.83 to 8.9 Mb in the nine individuals. The young boy in our report was dysmorphic with microcephaly, abnormal craniofacial features, intellectual disability, aggression, and a heart murmur. All patients were found to have a psychomotor developmental delay and/or intellectual disability with the majority having microcephaly, intrauterine growth retardation, and hypotonia. Common craniofacial findings included a tall, prominent forehead, an elongated face, epicanthal folds, hypertelorism, prominent low-set ears, philtrum anomaly, and a small mouth. Other less common features included abnormal digits, sparse hair, and cardiac defects. Clinical features, chromosome duplication sizes, locations, and the number of genes will be summarized in a tabular form.
Project description:AIM:The aim of our study was to identify chromosomal imbalances by whole-genome microarray-based comparative genomic hybridization (array CGH) in DNA samples of children in which karyotype results cannot be obtained. The present paper describes the first Albanian experience of an array CGH application. MATERIAL AND METHODS:The cohort included seven children with developmental delay or intellectual disability, facial dysmorphism and congenital anomalies according to clinical criteria, suggestive of chromosomal anomalies. The age range was from newborn to five years old. The cytogenetic analysis determined by a standard method of G-banding according to the International System for Human Cytogenetic Nomenclature (ISCN 2005) was performed for all our patients, while array CGH was performed on genomic DNA isolated from the blood of 7 cases. RESULTS:Among the seven patients analysed with array CGH, three patients resulted in duplication and one deletion, one patient with a microdeletion and three patients with duplication. Array CGH facilitated the recognition of submicroscopic deletions and duplications as risk factors for genetic diagnosis in all our patients. CONCLUSIONS:Our case series with congenital chromosomal anomalies confirms the high diagnostic value of the method, as suggested by previous studies. The technique must be available also in less developed countries, to significantly improve the genetic diagnosis of paediatric patients with developmental delay or intellectual disability, congenital anomalies and dysmorphic features. The identification of chromosomal abnormalities in these patients and the genetic counselling will provide family members with an explanation for their child's developmental disability or birth defect, allowing better information about recurrence risks, and permit the anticipation of certain medical problems that require intervention.
Project description:Helsmoortel-van der Aa (SWI/SNF autism-related or ADNP syndrome) is an autosomal dominant monogenic syndrome caused by de novo variants in the last exon of ADNP gene and no deletions have been documented to date. We report the first case of a 3 years and 10 months old boy exhibiting typical features of ADNP syndrome, including intellectual disability, autistic traits, facial dysmorphism, hyperlaxity, mood disorder, behavioral problems, and severe chronic constipation. 60K Agilent array-comparative genomic hybridization (CGH) identified a heterozygous interstitial microdeletion at 20q13.13 chromosome region, encompassing ADNP and DPM1. Taking into account the clinical phenotype of previously reported cases with ADNP single-point variants, genotype-phenotype correlation in the proband was established and the diagnosis of Helsmoortel-van der Aa syndrome was made. Our report thus confirms that ADNP haploinsufficiency is associated with Helsmoortel-van der Aa syndrome as well as highlights the utility of whole-genome array-CGH for detection of unbalanced submicroscopic chromosomal rearrangements in routine clinical setting in patients with unexplained intellectual disability and/or syndromic autism.
Project description:In 65 patients, who had unexplained ocular developmental anomalies (ODAs) with at least one other birth defect and/or intellectual disability, we performed oligonucleotide comparative genome hybridisation-based microarray analysis (array-CGH; 105A or 180K, Agilent Technologies). In four patients, array-CGH identified clinically relevant deletions encompassing a gene known to be involved in ocular development (FOXC1 or OTX2). In four other patients, we found three pathogenic deletions not classically associated with abnormal ocular morphogenesis, namely, del(17)(p13.3p13.3), del(10)(p14p15.3), and del(16)(p11.2p11.2). We also detected copy number variations of uncertain pathogenicity in two other patients. Rearranged segments ranged in size from 0.04 to 5.68 Mb. These results show that array-CGH provides a high diagnostic yield (15%) in patients with syndromal ODAs and can identify previously unknown chromosomal regions associated with these conditions. In addition to their importance for diagnosis and genetic counselling, these data may help identify genes involved in ocular development.
Project description:A novel 19.98-Mb duplication in chromosome Xp22.33p22.12 was detected by array CGH in a 30-year-old man affected by intellectual disability, congenital hypotonia and dysmorphic features. The duplication encompasses more than 100 known genes. Many of these genes (such as neuroligin 4, cyclin-dependent kinase like 5, and others) have already correlated with X-linked intellectual disability and/or neurodevelopmental disorders. Due to the high number of potentially pathogenic genes involved in the reported duplication, we cannot correlate the clinical phenotype to a single gene. Indeed, we suggest that the resulting clinical phenotype may have arisen from the overexpression and consequent perturbation of fine gene dosage.
Project description:Fever-associated syndromic epilepsies ranging from febrile seizures plus (FS+) to Dravet syndrome have a significant genetic component. However, apart from SCN1A mutations in >80% of patients with Dravet syndrome, the genetic underpinnings of these epilepsies remain largely unknown. Therefore, we performed a genome-wide screening for copy number variations (CNVs) in 36 patients with SCN1A-negative fever-associated syndromic epilepsies. Phenotypes included Dravet syndrome (n = 23; 64%), genetic epilepsy with febrile seizures plus (GEFS+) and febrile seizures plus (FS+) (n = 11; 31%) and unclassified fever-associated epilepsies (n = 2; 6%). Array comparative genomic hybridization (CGH) was performed using Agilent 4 × 180K arrays. We identified 13 rare CNVs in 8 (22%) of 36 individuals. These included known pathogenic CNVs in 4 (11%) of 36 patients: a 1q21.1 duplication in a proband with Dravet syndrome, a 14q23.3 deletion in a proband with FS+, and two deletions at 16p11.2 and 1q44 in two individuals with fever-associated epilepsy with concomitant autism and/or intellectual disability. In addition, a 3q13.11 duplication in a patient with FS+ and two de novo duplications at 7p14.2 and 18q12.2 in a patient with atypical Dravet syndrome were classified as likely pathogenic. Six CNVs were of unknown significance. The identified genomic aberrations overlap with known neurodevelopmental disorders, suggesting that fever-associated epilepsy syndromes may be a recurrent clinical presentation of known microdeletion syndromes.
Project description:Interstitial deletion of 6q21-22 has been previously reported in 11 individuals, who presented with intellectual disability, facial dysmorphism, cardiac abnormality, cerebellar hypoplasia and dysplasia of the corpus callosum. Here, we report the first instance of a patient with 6q21-22 deletion presenting with interrupted aortic arch in addition to the previously described clinical signs. Array analysis using Agilent Human genome CGH 180K identified a 13.3-Mb deletion at 6q21-q22.31 (nt. 109885195-123209593).
Project description:Wolf-Hirschhorn syndrome (WHS) is caused by a distal 4p monosomy usually involving the region of the WHSC1 and WHSC2 genes. About 40-45% of WHS patients show an unbalanced translocation leading to both 4p monosomy and partial trisomy of another chromosome arm. In this case report, we describe 2 female cousins (P1 and P2) with a derivative chromosome leading to a 4p16.3pter deletion and 12q24.31qter duplication. Conventional karyotyping and genomic analyses showed that they both had the same rearrangement derived from a balanced parental translocation involving chromosomes 4 and 12, t(4;12)(p16.3;q24.31). The rearrangements occurred between 4p16.3pter and 12q24.31qter detected by array-CGH analysis, with a 2.7-Mb loss at 4p and a large 12.4-Mb gain at 12q. Both affected patients shared global developmental delay and craniofacial dysmorphisms with some distinct phenotypic findings associated with both WHS and 12qter trisomy. P2 was more severely impaired than P1, and she showed severe intellectual disability, seizures, midface hypoplasia, unilateral microtia, and deafness which were absent in P1. Previous studies of distal 4p monosomies have found phenotypic variability in WHS which does not correlate with haploinsufficiency of specific genes. Features of 12q trisomies are diverse with developmental and growth delay, intellectual disability, behavioral problems, and facial abnormalities. Collectively, our analysis of the literature of 3 similar translocations involving 4p and 12q, together with the clinical features of the affected cousins in this familial translocation, permits an evaluation of genes closely linked to WHSC1 and WHSC2 in the context of WHS and the genes involved in 12q trisomy.
Project description:We describe a 32-year-old male patient diagnosed with high-functioning autism spectrum disorder carrying a de novo 196-kb interstitial deletion at chromosome 17q11.2. The deletion was detected by array CGH (180K Agilent) and confirmed by quantitative PCR on genomic DNA. The deleted region spans the entire PSMD11 and CDK5R1 genes and partially the MYO1D gene. The CDK5R1 gene encodes for a regulatory subunit of the cyclin-dependent kinase 5 responsible for its brain-specific activation. This gene has been previously associated with intellectual disability in humans. A reduction in CDK5R1 transcript was detected, consistent with the genomic deletion. Based on the functional role of CDK5R1, this gene appears as the best candidate to explain the clinical phenotype of our patient, whose neuropsychological profile has more resemblance with some of the higher brain function anomalies recently described in the CreER-p35 conditional knockout mouse model than previously described patients with intellectual disability.