Microarray-based comparative genomic hybridization analysis of Wolf-Hirschhorn syndrome in a fetus with deletion of 4p15.3 to 4pter

BACKGROUND: Wolf-Hirschhorn syndrome (WHS), caused by the deletion of a segment in chromosome 4, is characterized by mental and developmental defects. Clinical manifestations of WHS include intrauterine growth restriction, failure to thrive in the neonatal period that is present simultaneously with hypotonia, typical "Greek helmet" facial appearance, cleft lip and palate, mental deficiency, and seizures. CASE: We present a case of WHS with prenatal conventional cytogenetics of 46,XY,der(4)t(4;13)(p15.3;p11.2)pat. High-resolution mapping using microarray-based comparative genomic hybridization (array-CGH), including Affymetrix 10K arrays and cDNA microarrays, confirmed the loss of genes in the deleted region. CONCLUSIONS: The correlation between these candidate genes and the phenotypes of WHS may expand our understanding of the defective development caused by 4p deletion.     

Interstitial deletion of the long arm of chromosome 2 in a polymalformed newborn-karyotype: 46,XX,del(2)(q21;q24)

Summary This report describes a polymalformed female newborn presenting an interstitial deletion of the long arms of chromosome 2. Karyotype: 46,XX,del(2)(q21 q24).     

Arcyptera fusca and Arcyptera tornosi repetitive DNA families: whole-comparative genomic hybridization (W-CGH) as a novel approach to the study of satellite DNA libraries

Whole-comparative genomic hybridization (W-CGH) has been used to exemplify a simple methodology which allows identifying and mapping whole genome differences for highly repetitive DNA sequences between two related species of unknown genomic background. The use of this technique to the species binomy Arcyptera fusca/Arcyptera tornosi has allowed the identification of different DNA families mainly concentrated within the para-/peri-centromeric and distal heterochromatic regions of different chromosomes, which are differentially expanded in both genomes. Additionally, W-CGH allowed chromosome mapping of particular euchromatic regions immersed in the chromosome arms which have been affected by processes of DNA amplification and losses. A molecular approach was also conducted to analyse satellite DNA families in these species. We have found three different families showing an unequal representation in both species. Two of these families showed a centromeric location (EcoRV-390CEN and Sau3A-419CEN), whereas the last one was located at distal heterochromatic regions (Sau3A-197TEL). As A. fusca is a widely distributed species represented in most European high mountains, whereas A. tornosi is an endemic species represented in the Iberian Peninsula, the differences and resemblances reported here offer a good basis to support a close evolutionary relationship between both of the actually isolated species. Finally, W-CGH allowed identification of an asynchronic pattern of heterochromatin condensation through early prophase (characteristic in both species) which is uncommon or probably has been poorly analysed within classical early condensing chromosome domains through meiosis. The congruence of the obtained cytological and molecular results is analysed in light of the ancestral genome relationship between both species.     

A novel de novo deletion of chromosome 7 [46,XX,del(7)(p14.2 p15.1)] in a child with feeding problems

The phenotype and severity of symptoms associated with deletions on chromosome 7 are directly proportional to the size of the deleted segment. Distal and interstitial deletions have been described in 40 cases. In this report the authors aim to report a child with a novel de novo interstitial deletion on chromosome 7, with the following karyotype: 46,XX,del(7)(p14.2 p15.1). We described a female, born at 38 weeks with intrauterine growth restriction and feeding problems with episodes of cyanosis after feedings and failure to thrive. Physical examination showed low implantation of ears, hypertelorism, oblique palpebral fissures, retrognathia, and palate ogived, with insertion anomalies of the toes, poor facial expression and mild axial hypotonia. Transfontanelar ultrasound, magnetic resonance imaging, bronchofibroscopy and metabolic studies were normal. She was hospitalized until the 32nd day of life. She started speech therapy and presented improvements in swallowing. The percutaneous endoscopic gastrostomy was removed at 36 months. She had recurrent urinary tract infection with normal dimercaptosuccinic acid but with a vesicoureteral reflux (grade III). Imagiological studies revealed a bilateral osteonecrosis of femoral epiphysis (Legg-Calvé-Perthes disease). Currently (6years-old), she is being normally fed (body mass index=15.8kg/m(2)). Her weight is 16.4kg (3rd centile) and length is 105cm (3rd to 5th centiles). She has a mild delay of psychomotor development impairment and some speech problems. This is the first case report of a patient with this de novo small interstitial deletion on chromosome 7. This rare chromosomal abnormality was associated with severe feeding problems in the first years of life.     

Chromosome 22q11.2 deletion syndrome: prenatal diagnosis,array comparative genomic hybridization characterization using uncultured amniocytes and literature review

We present prenatal diagnosis of de novo 22q11.2 microdeletion syndrome using uncultured amniocytes in a pregnancy with conotruncal heart malformations in the fetus. We discuss the genotype–phenotype correlation and the consequence of haploinsufficiency of TBX1, COMT, UFD1L, GNB1L and MED15 in the deleted region. We review the literature of chromosomal loci and genes responsible for conotruncal heart malformations and tetralogy of Fallot.     

Combined deletion 18q22.2 and duplication/triplication 18q22.1 causes microcephaly,mental retardation and leukencephalopathy

Chromosome 18 abnormalities rank among the most common autosomal anomalies with 18q being the most frequently affected. A deletion of 18q has been attributed to microcephaly, mental retardation, short stature, facial dysmorphism, myelination disorders, limb and genitourinary malformations and congenital aural atresia. On the other hand, duplications of 18q have been associated with the phenotype of Edwards syndrome. Critical chromosomal regions for both phenotypes are contentious. In this report, we describe the first case of an 11-year old male with a combined interstitial duplication 18q22.1, triplication 18q22.1q22.2 and terminal deletion 18q22.2q23 with phenotypic features of isolated 18q deletion syndrome and absence of phenotypic features characteristic of Edwards syndrome despite duplication of the suggested critical region. This report allows for reevaluation of proposed critical intervals for the phenotypes in deletion 18q syndrome and Edwards syndrome.     

Two cases of the Langer-Giedion syndrome with the same interstitial deletion of the long arm of chromosome 8: 46,XY or XX,del(8)(q23.3q24.13)

Summary Two cases of the Langer-Giedion syndrome (LGS) are reported. Chromosome analysis by high-resolution banding with 850 bands revealed the same abnormal karyotype, 46,XY or XX,del(8)(q23.3q24.13), which was the smallest deletion among those of LGS patients with 8q deletion. The deleted segments found in three patients with LGS analyzed by high-resolution banding have a part of 8q23.3 and 8q24.11 in common.     

Siblings with opposite chromosome constitutions,dup(2q)/del(7q) and del(2q)/dup(7q)

Chromosome 7q36 microdeletion syndrome is a rare genomic disorder characterized by underdevelopment of the brain, microcephaly, anomalies of the sex organs, and language problems. Developmental delay, intellectual disability, autistic spectrum disorders, BDMR syndrome, and unusual facial morphology are the key features of the chromosome 2q37 microdeletion syndrome. A genetic screening for two brothers with global developmental delay using high-resolution chromosomal analysis and subtelomeric multiplex ligation-dependent probe amplification revealed subtelomeric rearrangements on the same sites of 2q37.2 and 7q35, with reversed deletion and duplication. Both of them showed dysmorphic facial features, severe disability of physical and intellectual development, and abnormal genitalia with differential abnormalities in their phenotypes. The family did not have abnormal genetic phenotypes. According to the genetic analysis of their parents, adjacent-1 segregation from their mother's was suggested as a mechanism of their gene mutation. By comparing the phenotypes of our patients with previous reports on similar patients, we tried to obtain the information of related genes and their chromosomal locations.     

Prenatal diagnosis and molecular cytogenetic characterization of a de novo interstitial deletion of 7q (7q22.1 → q31.1)

We present prenatal diagnosis and molecular cytogenetic characterization of de novo interstitial deletion of 7q (7q22.1 → q31.1) by aCGH, FISH and QF-PCR in a fetus with an abnormal maternal serum screening result and ultrasound findings of facial cleft and hypogenitalism. We discuss the genotype–phenotype correlation and the consequence of haploinsufficiency of ZKSCAN5, ARPC1A, CYP3A43, RELN, LAMB1, IMMP2L and DOCK4 in this case.     

Novel chromosomal translocation (17;22)(q12;q12) in a case of myelodisplastic syndrome characterized with signs of hemolytic anemia at presentation

Myelodysplastic syndromes (MDS) are clonal stem cell diseases that can result in cytopenias, dysplasia in one or more cell lineages, infective hematopoiesis, and increase the risk of progression to acute myeloid leukemia (AML). MDSs are characterized by several recurrent cytogenetic defects, which can affect diagnosis, prognosis, and treatment. Some of that chromosomal alterations are associated with very poor prognosis. Conventional cytogenetics cannot accurately define the rearranged karyotype. Instead, molecular cytogenetics analyses can provide important diagnostic and prognostic information for patients affected by MDS, allowing the characterization of the whole mutational spectrum and, mainly, novel chromosomal lesions.In this paper, we report a MDS case with a novel chromosomal translocation [t(17;22)(q12;q22)], described for the first time here. Following Giemsa-banding karyotyping, fluorescent in situ hybridization analyses, by using chromosome-specific probes, displayed the breakpoint regions at chromosomes 17 and 22, within which intra and inter-chromosomal segmental duplications (SD) are present. Because of the occurrence of SDs in breakpoint region, it was not possible to finely define the genomic regions where breaks fell. Further investigations could be required to better understand the molecular basis of the novel translocation t(17;22)(q12;q12) acting in MDS context and to explain if SDs could contribute to the pathogenesis of MDS.     

Novel chromosomal translocation t(11;9)(p15;p23) involving deletion and duplication of 9p in a girl associated with autism and mental retardation

We describe a 5-year-old girl presented with autism and mental retardation features. Conventional karyotyping revealed a novel unidirectional translocation t(11;9)(p15;p23). HumanCytoSNP-12 Chip analysis identified a 13 Mb deletion from 9p24.3 to 9p23 and a 12.5Mb duplication from 9p23 to 9p21.2. The karyotype was described as 45,XX,psu dic(11; 9)(p15;p23), which was reported for the first time here. The deleted region, extending from 9p24.3 to 9p23, overlaps with the candidate region for monosomy 9p syndrome and contains a potential autism spectrum disorders (ASD) locus. The duplication region extending from 9p23 to 9p21.2 was previously identified as a critical region for the 9p duplication syndrome. These results suggested that the apparently balanced de novo translocations could produce cryptic deletions or duplications, and the precise mapping of the abnormal area may improve clinical management.     

Array CGH analysis of a cohort of Russian patients with intellectual disability

The use of array comparative genomic hybridization (array CGH) as a diagnostic tool in molecular genetics has facilitated the identification of many new microdeletion/microduplication syndromes (MMSs). Furthermore, this method has allowed for the identification of copy number variations (CNVs) whose pathogenic role has yet to be uncovered. Here, we report on our application of array CGH for the identification of pathogenic CNVs in 79 Russian children with intellectual disability (ID). Twenty-six pathogenic or likely pathogenic changes in copy number were detected in 22 patients (28%): 8 CNVs corresponded to known MMSs, and 17 were not associated with previously described syndromes. In this report, we describe our findings and comment on genes potentially associated with ID that are located within the CNV regions.