Check this box if you wish to receive a copy of your message. Disease definition A rare partial deletion of the long arm of chromosome 6 characterized by a variable clinical phenotype that includes a characteristic craniofacial dysmorphism including microcephaly, broad nose with prominent nasal root and bulbous nasal tip, large ears that may be malformed and low-set, characteristic downturned mouth, and short neck , global development delay, intellectual disability, and variable, non-specific, congenital malformations.
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Birth weight was g 3rd centile , length 48 cm 21st centile and head circumference The Apgar score was eight at 1 min and nine at 5 min. The patient did not experience seizures, but his motor and language development was delayed. He started walking when he was 18 months old, and he pronounced the first words only around 3 years old.
When he was 4 years old, the neuropsychological assessment showed developmental disorders of speech and language, hyperkinetic disorder, and global developmental delay.
At the age of 6 years, the patient was referred to a clinical geneticist for evaluation of developmental delay and dysmorphic features. His physical examination showed microcephaly head circumference, He was clumsy in movements. Weight was 23 kg 72nd centile and height was cm 63rd centile. A The patient and his facies showing mild dysmorphological features. B Patient brain MRI is showing slight enlargement of the occipital horns with normal morphology.
C Positive and negative views of the patient GTC-banded chromosomes six at bands resolution with the arrows pointing to the deleted region. D High-resolution chromosome microarray analysis CMA in the patient. Deviations of probe Log2 ratios from zero of the SNP probes on chromosome 6qq27 cytoband indicate the deleted region identified in the genomic profile of the patient.
MRI of the brain detected slight enlargement of the ventricular system mainly in occipital horns with normal morphology Figure 1B. Cardiac examination with echocardiogram was normal as well-ophthalmological and audiological evaluation. Ultrasound of kidneys and urinary tract shows the absence of anomalies. His medical history also included surgery to remove a thyroglossal duct cyst and frequent episodes of wetting and encopresis.
Chromosomes were obtained from cultured peripheral lymphocytes using Synchroset kit Euroclone, Milano, Italy. The conventional technique of G banding analysis was used.
The CytoScan HD array contains more than 2. Of these markers, 1,, are unique, non-polymorphic oligonucleotide probes, and , are SNP probes used for genotyping. The average marker spacing is one probe per 1. Briefly: total genomic DNA was digested with a restriction enzyme NspI , ligated to an appropriate adapter for the enzyme, and subjected to PCR amplification using a single primer.
After digestion, with DNase I, the PCR products were labeled with a biotinylated nucleotide analog, using terminal deoxynucleotidyl transferase and hybridized to the microarray. Hybridization was carried out in the Hybridization Oven while subsequent washing and staining were performed using the Fluidics Station The array was then scanned with the Scanner 7G and both quality control step and copy number analysis were performed using the Chromosome Analysis Suite Software version 3.
Twenty metaphases of the patient and the parents were analyzed after GTG banding at chromosome band resolution. Karyotype showed a small deletion in the terminal region of the long arm of chromosome 6 in all the analyzed metaphases. This rearrangement was not detected in the parents. To map deletion breakpoint more accurately high-resolution CMA was made. Results of SNP array analysis of the patient displayed a copy number loss in chromosome bands 6qq27 of about 7, Mb ranging from nucleotide ,, to ,, Figure 1D.
The haploinsufficiency of some genes must be implicated in the clinical phenotype of this patient with the telomeric deletion of 6qq According to the International System for Human Cytogenetic Nomenclature [ISCN, ], the molecular karyotype of the patient showing both the minimum and maximum extent of the deletion was defined as follows: arr[GRCh37] 6qq27 ,,,, x1 dn. The PARK2 gene maps in 6q26 deletion breakpoint. Sequencing did not show any other mutation. This condition is a rare cytogenetic disorder characterized by extended variation in the size of the deleted region that can go from cytogenetically visible to small submicroscopic deletions, ranging from 0.
Only molecular cytogenetic techniques as fluorescent in situ hybridization FISH and comparative genomic hybridization CGH can precisely recognize and define the smaller terminal deletions Erdel et al.
Patients with distal deletion of chromosome 6q show also variable phenotypic features with only a few common symptoms that include, besides intellectual disability and developmental delay Bertini et al. Craniofacial anomalies Hopkin et al. Also, heart defects Nair et al. Several authors have tried to correlate the distal deletion of chromosome 6q to a distinct clinical phenotype Stevenson et al. Others have sought to identify the minimum deleted interval containing the critical genes responsible for the major clinical problems Eash et al.
However, it is still very problematic to identify clinically patients carrying such deletion and to correlate deleted genes with a clinical phenotype Rigon et al. Here, we report the clinical and genomic characterization of a patient with an intellectual disability, delayed language developmental and dyspraxia and minor dysmorphic features due to a non-recurrent 6qqter deletion identified using high-resolution CMA in a screening of patients with non-syndromic intellectual disability.
In this patient haplodeficiency of chromosome 6q subtelomeric region is the result of a de novo event and it is not due to familiar unbalanced translocation. It is well-known that FRA6E is a genomic hotspot that predisposes to chromosomal deletion and it is considered the third most mutation-prone fragile site of the human genome Palumbo et al.
In the center of this genomic site is located the PARK2 gene that is a huge gene implicated in the autosomal recessive early-onset type of Parkinson disease. We believe that PARK2 haploinsufficiency may have a role in the etiology of intellectual disability of this patient since we can exclude mutations in the other PARK2 allele.
In mouse, Park2 knock out does not reproduce any sign of the Parkinson disease Perez and Palmiter, Illustrative metaphase FISH images.
The derivative chromosome is indicated with an arrow. Hybridization with a chromosome 15 specific WCP probe and a centromere 15 CEP15 specific probe indicating that the derivative chromosome was entirely composed of chromosome material and that it was dicentric. WCP15 cross-hybridizes with the p-arms of all acrocentric chromosomes seen as green spots.
Hybridization with a probe specific for the nucleolus organizing regions NOR of the acrocentric chromosomes and a control probe 15q14 showing the presence of p-arm material in duplicate on the derivative chromosome. Hybridization with BAC probes specific for the 15q The array CGH analysis confirmed the distal deletion of 15q resulting from the dic 15 that was initially detected by the G-banding analysis.
In concordance with the subsequent FISH findings the deletion breakpoint was revised to 15q The array CGH analysis mapped the terminal deletion to encompass a 6. Known genes in the region are summarized in Table 2. No additional aberrations were detected. Constitutional deletions involving chromosome band 15q26 seem to be rather rare unbalanced aberrations which seldom are diagnosed and characterized at the cytogenetic level.
However with subtelomeric FISH becoming standard clinical practice and array CGH being more commonly implicated as a powerful tool to characterize cases with submicroscopic aberrations it is likely to assume that patients harboring distal 15q-deletions might be more frequently discovered in the future.
In this study we used array CGH to delineate the breakpoint to position This approach of using tiling BACs to cover the whole genome in a single hybridization gives a resolution standard of — kb, applying the exclusion criteria that three contiguous clones must display abnormal log2 ratios to be considered to signal an aberration. This study, characterizing in detail a constitutional 15qdeletion, is one of the first ones using molecular cytogenetic characterization with submegabase resolution on a syndrome related to this chromosomal region.
Klaassens et al. The platform used was a 1-Mb Human BAC array, giving resolution standards tenfold smaller than 32 k arrays [ 11 ]. However, a later study used array techniques with submegabase resolution on a similar patient [ 22 ].
In addition Slavotinek et al. The origin of the dicentric chromosome in the present case remains unknown since both parents displayed normal karyotypes and directed microsatellite analysis was not performed. However, it has been demonstrated that a de novo 15q-deletion can be of both paternal and maternal origin [ 4 , 6 ].
Studies on terminal chromosomal deletions have suggested that de novo telomere addition, by telomerase activity or recombinant mechanisms, work to stabilize the affected chromosome [ 23 ].
It could be speculated that the latter event might explain the formation of the dic 15 in the present case, but involving centromeres rather than telomeres.
It is noteworthy that no duplication of near-centromeric q-arm material could be detected on the log2 ratio plot of chromosome 15 Figure 4. The preceding FISH analysis had confirmed that the duplication included the centromeric region, as well as p-arm material, both being located in regions not covered by the array. The vast majority of patients with deletions of distal 15q have displayed pre- and postnatal growth retardation, cardiac defects, developmental delay, ear abnormalities, and clinodactyly.
Although high resolution cytogenetic mapping for all reported cases are lacking this wide range of phenotypic manifestations probably reflect size heterogeneity of distal 15q-deletions. More precise data on 15q-breakpoints might enable an elucidation of different candidate regions for different phenotypic manifestations. For instance, patients suffering from CDH in association with 15qdeletion have been extensively studied and a critical region associated with CDH was assessed to a region ranging from distal 15q The 15q-breakpoint in the present case mapped outside of the suggested critical region and in accordance did not suffer from CDH.
Deletions of 15q26 have also been reported in association with Russel-Silver syndrome, which share many of the clinical features displayed in patients with deletions of distal 15q and it is possible that these cases should be categorized as an subgroup of the latter syndrome [ 24 , 25 ].
Considering all the reported cases with deletion of 15q26, the salient finding must be that the majority report loss of IGFR1 , a gene that contributes to a wide range of developmental processes [ 26 ]. The relation between IGFR1 and pre- and postnatal growth in association with distal 15q-deletions has been studied without conclusive results [ 5 , 8 ].
In relation to the developmental delay commonly seen in patients with distal 15q-deletions, the IGF1 receptor gene plays an important function in the development of the central nervous system, which could partly explain this feature [ 27 ].
Studies on the effect of IGFR1 on the cardiovascular system indicate that it is an important player in heart development [ 24 ]. Monozygosity of this gene could therefore partly contribute to the complex cardiac defects so often seen in patients with this deletion.
Obviously, all suggested clinical features postulated to relate to loss of one copy of the IGFR gene remains to be elucidated, preferentially by further gene expression studies on diagnostic material. MEF2A have been suggested as a candidate gene for the cardiac defects [ 11 ] included in the phenotype of 15qdeletions since the gene encode for DNA-binding regulatory protein that enhances the differentiation of mesodermal precursor cells to myoblast and therefore is key player in cardiac myocyte development [ 28 ].
The MEF2-family is an ancient mediator of signal-dependant transcription and diverse developmental programs and MEF2A was quite recently demonstrated to be involved in morphogenesis of postsynaptic neurons [ 29 ] which implicate that it could also contribute to the developmental delay seen in the patient. Another gene in the deleted segment that could be directly implicated due to its protein function is CHSY1 that encodes chondroitin sulfate [ 30 ], a glycosaminoglycan expressed on the surface of most cells and in extracellular matrices.
Glycosaminoglycan chains are covalently linked to a wide range of core protein families and regulate many biologic processes, including cell proliferation and recognition, extracellular matrix deposition, and morphogenesis. Furthermore, TM2D3 , located in the deleted region, synthesizes a protein that have a structural module related to that of the seven transmembrane domain G protein-coupled receptor superfamily and may have regulatory roles in cell death or proliferation signal cascades [ 31 ].
We present a case with a dic 15;15 q11;q The dicentric chromosome harbor a terminal deletion involving 15q MEF2A has previously been suggested as a candidate gene for the cardiac defects seen in investigated patients. In addition CHSY1 is involved in cell proliferation and morphogenesis and TM2D3 may have regulatory roles in cell death or proliferation signal cascades. Previous studies have demonstrated that terminal 15q-deletions frequently results in loss of one allele of the IGF1R gene, a finding also observed in our patient.
IGF1R contributes to a wide range of developmental processes such as development of the central nervous and cardiovascular systems, and monozygosity for this gene could contribute to the developmental delay and complex cardiac defects seen in our patient. However, all suggested clinical features postulated to relate to IGF1R deletions remains to be elucidated, preferentially by gene expression studies on patients harboring similar 15q-aberrations.
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