Proximal Long Arm Of Chromosome Research Articles

Congenital hypopituitarism and multiple midline defects in a newborn with non-familial Cat Eye syndrome

BackgroundCat eye syndrome (CES) is a rare chromosomal disease, with estimated incidence of about 1 in 100,000 live newborns. The classic triad of iris coloboma, anorectal malformations, and auricular abnormalities is present in 40% of patients, and other congenital defects may also be observed. The typical associated cytogenetic anomaly relies on an extra chromosome, derived from an inverted duplication of short arm and proximal long arm of chromosome 22, resulting in partial trisomy or tetrasomy of such regions (inv dup 22pter-22q11.2).Case presentationWe report on a full-term newborn, referred to us soon after birth. Physical examination showed facial dysmorphisms, including hypertelorism, down slanted palpebral fissures, and dysplastic ears with tragus hypoplasia and pre-auricular pit. Ophthalmologic evaluation and heart ultrasound identified left chorioretinal and iris coloboma and ostium secundum type atrial septal defect, respectively. Based on the suspicion of cat eye syndrome, a standard karyotype analysis was performed, and detected an extra small marker chromosome confirming the CES diagnosis. The chromosomal abnormality was then defined by array comparative genome hybridization (a-CGH, performed also in the parents), which identified the size of the rearrangement (3 Mb), and its de novo occurrence. Postnatally, our newborn presented with persistent hypoglycemia and cholestatic jaundice. Endocrine tests revealed congenital hypothyroidism, cortisol and growth hormone (GH) deficiencies, which were treated with replacement therapies (levotiroxine and hydrocortisone). Brain magnetic resonance imaging, later performed, showed aplasia of the anterior pituitary gland, agenesis of the stalk and ectopic neurohypophysis, confirming the congenital hypopituitarism diagnosis. She was discharged at 2 months of age, and included in a multidisciplinary follow-up. She currently is 7 months old and shows a severe global growth failure, and developmental delay. She started GH replacement treatment, and continues oral hydrocortisone, along with ursodeoxycholic acid and levothyroxine, allowing an adequate control of glycemic and thyroid profiles as well as of cholestasis.ConclusionsCES phenotypic spectrum is wide and highly variable. Our report highlights how among the possible associated endocrine disorders, congenital hypopituitarism may occur, leading to persistent hypoglycemia and cholestasis. These patients should be promptly assessed for complete hormonal evaluations, in addition to major malformations and midline anomalies. Early recognition of such defects is necessary to decrease fatal events, as well as short and long-term related adverse outcomes.

41. Clinical significance of comprehensive genetic workup prior to use of assisted reproductive technology: A case study

A 16-month-old female was seen at the genetics clinic due to hypotonia and significant developmental delay. The proband was the product of a twin pregnancy. Chromosome analysis as well as fragile X, Prader Willi and Angelman tests were all normal. Whole-genome microarray analysis revealed a 4.6 Mb interstitial copy number gain involving the distal part of the long arm of chromosome 3q28-q29 (chr3:190800735_195464853). Confirmatory metaphase FISH as well as whole-chromosome paint FISH revealed that the duplicated 3q28-q29 material is not tandem but rather inserted into the proximal long arm of chromosome 9, resulting in 46,XX,ins(9;3)(q21.2;q28q29). In order to determine the origin of this abnormality, FISH was performed on parental specimens. To our surprise, the maternal interphase FISH analysis revealed the loss of the 3q region. However, review of the metaphase FISH and subsequently maternal karyotype indicated that the deleted 3q region was in fact involved in an apparently unbalanced translocation between chromosomes 1 and 3 resulting in 46,XX,der(1)t(1;3)(q25.2;q28),der(3)?del(3)(q29)t(1;3). It is unclear how a maternal unbalanced translocation involving chromosomes 1 and 3 with a net loss of the 3q region, could result in an insertion-duplication involving chromosome 3 and 9. This seemingly unusual finding prompted further investigation which revealed that the pregnancy was achieved via IVF using both the mother's as well as related donor oocytes i.e. the maternal aunt's. Reportedly, three embryos were transferred, only one of which was derived from maternal oocyte. It is therefore plausible that the maternal aunt would be the carrier of a related rearrangement e.g. a balanced insertion. Follow up familial analyses are underway and will be discussed with the audience. This case highlights the significance of comprehensive genetic workup prior to the utilization of assisted reproductive technology, even in the absence of phenotypic anomalies in the parents.

New Human Chromosomal Sites with "Safe Harbor" Potential for Targeted Transgene Insertion.

This study identified 35 new sites for targeted transgene insertion that have the potential to serve as new human genomic "safe harbor" sites (SHS). SHS potential for these 35 sites, located on 16 chromosomes, including both arms of the human X chromosome, and for the existing human SHS AAVS1, hROSA26, and CCR5 was assessed using eight different desirable, widely accepted criteria for SHS verifiable with human genomic data. Three representative newly identified sites on human chromosomes 2 and 4 were then experimentally validated by in vitro and in vivo cleavage-sensitivity tests, and analyzed for population-level and cell line-specific sequence variants that might confound site targeting. The highly ranked site on chromosome 4 (SHS231) was further characterized by targeted homology-dependent and -independent transgene insertion and expression in different human cell lines. The structure and fidelity of transgene insertions at this site were confirmed, together with analyses that demonstrated stable expression and function of transgene-encoded proteins, including fluorescent protein markers, selectable marker cassettes, and Cas9 protein variants. SHS-integrated transgene-encoded Cas9 proteins were shown to be capable of introducing a large (17 kb) gRNA-specified deletion in the PAX3/FOXO1 fusion oncogene in human rhabdomyosarcoma cells and as a Cas9-VPR fusion protein to upregulate expression of the muscle-specific transcription factor MYF5 in human rhabdomyosarcoma cells. An engineering "toolkit" was developed to enable easy use of the most extensively characterized of these new human sites, SHS231, located on the proximal long arm of chromosome 4. The target sites identified here have the potential to serve as additional human SHS to enable basic and clinical gene editing and genome-engineering applications.

A rare 3q13.31 microdeletion including GAP43 and LSAMP genes

BackgroundInterstitial deletions affecting the proximal long arm of chromosome 3 have been rarely reported in the literature. The deleted segments vary in localization and size with different breakpoints making genotype-phenotype correlation very difficult. Until now, a girl with a 1.9-Mb interstitial deletion of 3q13.2q13.31 and 14 novel patients with deletions in 3q11q23 have been reported.ResultsHere we report on a 7-year-old girl with neuropsychiatric disorders and renal, vascular and skeletal anomalies. Array-CGH analysis revealed a small rare inherited 3q13.31 deletion containing only two genes, GAP43 and LSAMP. The mutation analysis of the two genes was negative on the other non-deleted chromosome. GAP43 is considered a crucial component for an effective regenerative response in the nervous system and its mRNA is localized exclusively to nerve tissue where the protein is linked to the synaptosomal membrane. LSAMP is a 64- to 68-kD neuronal surface glycoprotein found in cortical and subcortical regions of the limbic system that acts as an adhesion molecule and guides the development of specific patterns of neuronal connection. The deleted region is adjacent to a “desert gene” region extending 2.099 Mb.ConclusionsWe discuss the effects of GAP43 and LSAMP haploinsufficiency, proposing that their deletion may be responsible for the main phenotype. Further cases with similar microdeletion are expected to be diagnosed and will help to better characterize the clinical spectrum of phenotypes associated with 3q13.31 microdeletion.

Secondary findings from non‐invasive prenatal testing for common fetal aneuploidies by whole genome sequencing as a clinical service

To report secondary or additional findings arising from introduction of non-invasive prenatal testing (NIPT) for aneuploidy by whole genome sequencing as a clinical service. Five cases with secondary findings were reviewed. In Case 1, NIPT revealed a large duplication in chromosome 18p, which was supported by arrayCGH of amniocyte DNA, with final karyotype showing mosaic tetrasomy 18p. In Case 2, a deletion in the proximal long arm of chromosome 18 of maternal origin was suspected and confirmed by arrayCGH of maternal white cell DNA. In Case 3, NIPT was negative for trisomies 21 and 18. In-depth analysis for deletions/duplications was requested when fetal structural anomalies were detected at routine scan. A deletion in the proximal long arm of chromosome 3 was found and confirmed by karyotyping. In Case 4, NIPT correctly predicted confined placental mosaicism with triple trisomy involving chromosomes X, 7 and 21. In Case 5, NIPT correctly detected a previously unknown maternal mosaicism for 45X. Non-invasive prenatal testing is able to detect a wide range of fetal, placental and maternal chromosomal abnormalities. This has important implications on patient counseling when an abnormality is detected by NIPT.

儿童Prader-Willi综合征合并扩张性心肌病一例

Prader-Willi综合征是由于15号染色体长臂特异区基因缺失或母源二倍体所致，其共同的临床表现为新生儿期肌张力低下，儿童期肥胖，智力低下，青春期无性发育，身材矮小。本文报道儿童Prader-Willi 综合征合并扩张性心肌病一例，并探讨Prader-Willi综合征的临床表现及遗传学特征、治疗方案，及与扩张性心肌病之间的关联。 Prader-Willi syndrome (PWS) is a disorder caused by a deletion or disruption of genes in the proximal long arm of chromosome 15 or by maternal disomy in the proximal long arm of chromosome 15. Commonly associated characteristics of this disorder include diminished fetal activity, hypotonia, obesity, mental retardation, short stature, hypogonadism, and small hands and feet. We report a case of Prader-Willi syndrome with dilated cardiomyopathy, and review its Clinical manifestations, genetic characteristics and treatment method, then analysis the relation with the di- lated cardiomyopathy.

A Novel Pseudo-Dicentric Variant of 16p11.2–q11.2 Contains Euchromatin from 16p11.2–p11.1 and Resembles Pathogenic Duplications of Proximal 16q

An unusually large G-light band between 2 G-dark bands in the proximal long arm of chromosome 16 was found in a boy of 5 years of age ascertained with growth retardation, microcephaly, and dysmorphic features. Dual color bacterial artificial chromosome fluorescence in situ hybridization (BAC FISH) and oligonucleotide array comparative genomic hybridization (oaCGH) were used to show that these bands contained a euchromatic duplication of a minimum of 940 kb between base pairs 34,197,413–35,137,025 in 16p11.2–p11.1 as well as a duplication of the centromere and major 16qh/16p11.2 heterochromatic block, covering a minimum of 12.3 Mb. The same pseudo-dicentric chromosome was found in the father who has attention deficit hyperactivity disorder (ADHD). The euchromatic region is not known to be subject to imprinting and overlaps multiple large copy number variations (CNVs) in the Database of Genomic Variants as well as similar CNVs that are benign or of uncertain significance in the International Standards for Cytogenomic Arrays database. We conclude that this family has a novel pseudo-dicentric euchromatic variant of chromosome 16 that is unlikely to be the cause of the variable phenotype in father and son but needs to be distinguished from heterochromatic variants or pathogenic duplications of proximal 16q.

Prader-Willi Syndrome: Clinical Aspects

Prader-Willi Syndrome (PWS) is a complex multisystem genetic disorder that shows great variability, with changing clinical features during a patient's life. The syndrome is due to the loss of expression of several genes encoded on the proximal long arm of chromosome 15 (15q11.2–q13). The complex phenotype is most probably caused by a hypothalamic dysfunction that is responsible for hormonal dysfunctions and for absence of the sense of satiety. For this reason a Prader-Willi (PW) child develops hyperphagia during the initial stage of infancy that can lead to obesity and its complications. During infancy many PW child display a range of behavioural problems that become more noticeable in adolescence and adulthood and interfere mostly with quality of life. Early diagnosis of PWS is important for effective long-term management, and a precocious multidisciplinary approach is fundamental to improve quality of life, prevent complications, and prolong life expectancy.

West syndrome associated with mosaic duplication of FOXG1 in a patient with maternal uniparental disomy of chromosome 14

FOXG1 on chromosome 14 has recently been suggested as a dosage-sensitive gene. Duplication of this gene could cause severe epilepsy and developmental delay, including infantile spasms. Here, we report on a female patient diagnosed with maternal uniparental disomy of chromosome 14 and West syndrome who carried a small supernumerary marker chromosome. A chromosomal analysis revealed mosaicism of 47,XX, + mar[8]/46,XX[18]. Spectral karyotyping multicolor fluorescence in situ hybridization analysis confirmed that the marker chromosome was derived from chromosome 14. A DNA methylation test at MEG3 in 14q32.2 and microsatellite analysis using polymorphic markers on chromosome 14 confirmed that the patient had maternal uniparental disomy 14 as well as a mosaic small marker chromosome of paternal origin containing the proximal long arm of chromosome 14. Microarray-based comparative genomic hybridization analysis conclusively defined the region of the gain of genomic copy numbers at 14q11.2-q12, encompassing FOXG1. The results of the analyses of our patient provide further evidence that not only duplication but also a small increase in the dosage of FOXG1 could cause infantile spasms.

A new case of rare proximal 3q13 interstitial deletion

Abstract We present the case of a 20-year-old man referred to the clinical geneticist because of mental retardation and dysmorphic features because of concerns about hereditability when his older, healthy brother was expecting a child. Deletion of proximal 3q arm was found with standard G-banding, and array comparative genomic hybridisation (array-CGH) was used to further locate the breakpoints. A unique interstitial deletion del 3q13.11q13.33 was confirmed. The first clinical symptoms in the 20-year-old were described at the age of 4 months when the pediatrician reported muscle hypertonia of the lower limbs, which later evolved into hypotonia. Later clinical observations revealed that the patient’s psychomotor development was delayed: he exhibited craniofacial abnormalities, cryptorchidism, thoracic kyphosis, and tapering fingers. Interstitial deletions of the proximal long arm of chromosome 3 have rarely been reported:; there are only 12 previously reported cases. The breakpoints and sizes of described deletions vary greatly, which makes definite genotype-phenotype conclusions impossible at this time. Developmental delay is one of the common features described in the majority of reported cases. The BTB-zinc finger gene ZBTB20 might be a potential candidate gene: it was shown in the mouse hippocampus to be expressed during the important period of neurogenesis of pyramidal neurons. Also, four of patients reported to date had agenesis of the corpus callosum and one, holoprosencephaly. We suggest that the GAP43 gene is involved in the development of structural neurological abnormalities in patients with 3q deletion.

Microdeletion/microduplication of proximal 15q11.2 between BP1 and BP2: a susceptibility region for neurological dysfunction including developmental and language delay

The proximal long arm of chromosome 15 has segmental duplications located at breakpoints BP1-BP5 that mediate the generation of NAHR-related microdeletions and microduplications. The classical Prader-Willi/Angelman syndrome deletion is flanked by either of the proximal BP1 or BP2 breakpoints and the distal BP3 breakpoint. The larger Type I deletions are flanked by BP1 and BP3 in both Prader-Willi and Angelman syndrome subjects. Those with this deletion are reported to have a more severe phenotype than individuals with either Type II deletions (BP2-BP3) or uniparental disomy 15. The BP1-BP2 region spans approximately 500 kb and contains four evolutionarily conserved genes that are not imprinted. Reports of mutations or disturbed expression of these genes appear to impact behavioral and neurological function in affected individuals. Recently, reports of deletions and duplications flanked by BP1 and BP2 suggest an association with speech and motor delays, behavioral problems, seizures, and autism. We present a large cohort of subjects with copy number alteration of BP1 to BP2 with common phenotypic features. These include autism, developmental delay, motor and language delays, and behavioral problems, which were present in both cytogenetic groups. Parental studies demonstrated phenotypically normal carriers in several instances, and mildly affected carriers in others, complicating phenotypic association and/or causality. Possible explanations for these results include reduced penetrance, altered gene dosage on a particular genetic background, or a susceptibility region as reported for other areas of the genome implicated in autism and behavior disturbances.

Familial partial trisomy 15q11-13 presenting as intractable epilepsy in the child and schizophrenia in the mother

Various rearrangements involve the proximal long arm of chromosome 15, including deletions, duplications, translocations, inversions and supernumerary marker chromosome of an inverted duplication. The large marker 15, that contains the Prader-Willi syndrome (PWS)/Angelman syndrome (AS) chromosome region, is usually associated with an abnormal phenotype of moderate to severe mental retardation, seizures, poor motor coordination, early-onset central hypotonia, autism and autistic-like behavior, schizophrenia and mild dysmorphic features. We report a ten year-old girl with normal intelligence prior to the onset of seizures, who developed severe intractable epilepsy at the age of seven years. Family history was significant for a mother with recurrent episodes of acute psychosis. The patient’s and mother’s karyotype revealed 47,XX+m. Array comparative genomic hybridization (A-CGH) identified a gain of 13 BAC clones from 15q11.2 through 15q13.1, which was then confirmed by FISH to be part of the marker chromosome. This duplicated region contains the SNRPN/UBE3A locus. This case demonstrates that a duplication of 15q11-13 can present differently in the same family either as intractable epilepsy or as a psychiatric illness and that intelligence can be preserved. We suggest that CGH microarray should be performed in cases with intractable epilepsy or schizophrenia, with or without mental retardation.

Prader–Willi syndrome and Angelman syndrome

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are two distinct neurogenetic disorders in which imprinted genes on the proximal long arm of chromosome 15 are affected. Although the SNORD116 gene cluster has become a prime candidate for PWS, it cannot be excluded that other paternally expressed genes in the chromosomal region 15q11q13 contribute to the full phenotype. AS is caused by a deficiency of the UBE3A gene, which in the brain is expressed from the maternal allele only. The most frequent genetic lesions in both disorders are a de novo deletion of the chromosomal region 15q11q13, uniparental disomy 15, an imprinting defect or, in the case of AS, a mutation of the UBE3A gene. Microdeletions in a small number of patients with PWS and AS have led to the identification of the chromosome 15 imprinting center (IC). The IC consists of two critical elements, which act in cis to regulate imprinting in the whole chromosome 15q11q13 imprinted domain.

13q13.1–q13.2 deletion in tetralogy of Fallot: Clinical report and a literature review

Recent advances in microarray technology are helping to identify more genetic anomalies associated with tetralogy of Fallot and other congenital heart defects. We report on a 24-year-old woman with a syndromic form of tetralogy of Fallot who was found to have a novel de novo deletion of the proximal long arm of chromosome 13. History of developmental delay and learning difficulties, mild dysmorphic facial features, and anal atresia prompted genetic investigations. A review of the literature on deletions that overlap this region showed that several were associated with major congenital heart defects. The results suggest that the 13q13.1-q13.2 region may harbour a gene or genes important in cardiac development.

Absent Smooth Muscle Actin Immunoreactivity of the Small Bowel Muscularis Propria Circular Layer in Association with Chromosome 15q11 Deletion in Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome

Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS; OMIM%249210) is a rare and severe form of congenital intestinal and urinary dysfunction and malformation. Histologic studies suggest that the predominant intestinal manifestation is smooth muscle myopathy. Molecular observations have linked the disease to the neuronal nicotinic acetylcholine receptor (ηAChR), namely the absence of a functional α3 subunit of the ηAChR in patients with MMIHS. We describe a case of MMIHS in association with a de novo deletion of the proximal long arm of chromosome 15 (15q11.2). Histologic evaluation revealed an appropriate light microscopic appearance of both the circular and longitudinal layers of the small bowel muscularis propria. Immunohistochemical staining for smooth muscle actin, however, was selectively absent in the circular layer, demonstrating isolated absence in a unique and previously undescribed pattern. These observations raise the possibility that the proximal long arm of chromosome 15 (15q11) may be of clinical significance in MMIHS.

Autistic disorder associated with a paternally derived unbalanced translocation leading to duplication of chromosome 15pter-q13.2: a case report

Autism spectrum disorders have been associated with maternally derived duplications that involve the imprinted region on the proximal long arm of chromosome 15. Here we describe a boy with a chromosome 15 duplication arising from a 3:1 segregation error of a paternally derived translocation between chromosome 15q13.2 and chromosome 9q34.12, which led to trisomy of chromosome 15pter-q13.2 and 9q34.12-qter. Using array comparative genome hybridization, we localized the breakpoints on both chromosomes and sequence homology suggests that the translocation arose from non-allelic homologous recombination involving the low copy repeats on chromosome 15. The child manifests many characteristics of the maternally-derived duplication chromosome 15 phenotype including developmental delays with cognitive impairment, autism, hypotonia and facial dysmorphisms with nominal overlap of the most general symptoms found in duplications of chromosome 9q34. This case suggests that biallelically expressed genes on proximal 15q contribute to the idic(15) autism phenotype.

Mechanisms of imprinting of the Prader–Willi/Angelman region

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are two distinct neurodevelopmental disorders, each caused by several genetic and epigenetic mechanisms involving the proximal long arm of chromosome 15. Lack of a functional paternal copy of 15q11-q13 causes PWS; lack of a functional maternal copy of UBE3A, a gene within 15q11-q13, causes AS. This region of chromosome 15 contains a number of imprinted genes that are coordinately regulated by an imprinting center (PWS/AS-IC) that contains two functional elements, the PWS-SRO and the AS-SRO. A chromosome lacking the PWS-SRO has the maternal state of gene activity and epigenetic modification after either maternal or paternal transmission; a chromosome lacking the AS-SRO but containing the PWS-SRO has the paternal state of gene activity and epigenetic modification after either maternal or paternal transmission. The maternal state of chromosome 15q11-q13 is associated with methylation of the PWS-SRO, while the paternal state is associated with lack of methylation of the PWS-SRO. Although most models of PWS/AS region imprinting assume that the PWS-SRO is methylated during oogenesis and that this methylation of the maternal PWS-SRO is maintained after fertilization, several lines of evidence suggest that the maternal PWS-SRO is in fact not methylated until after fertilization. Imprinting defects affecting the PWS/AS region can arise from failure to demethylate the PWS-SRO in the male germ line, from failure to methylate the maternal PWS-SRO, or from failure to maintain PWS-SRO methylation after fertilization.

Delineation of the proximal 3q microdeletion syndrome

Interstitial deletions of the proximal long arm of chromosome 3 are very rare and a defined clinical phenotype is not established yet. We report on the clinical, cytogenetic and molecular findings of a 20-month-old Hispanic male with a 2.5 Mb de novo deletion on q13.11q13.12. Up to now, this is the smallest deletion reported among patients with the proximal 3q microdeletion syndrome. The patient has distinct facial features including brachycephaly, broad and prominent forehead, flat nasal bridge, prominent ears, anteverted nose, tetralogy of Fallot, bilateral cryptorchidism, and peripheral skeletal abnormalities. To further delineate the proximal 3q deletion syndrome, the phenotype of our patient was compared with 10 other patients previously described. We found that ALCAM and CBLB are the only genes deleted in our patient and based on previously published data, we propose that the CBLB gene is responsible for the craniofacial phenotype in patients with deletions of proximal 3q region.

Multiple forms of atypical rearrangements generating supernumerary derivative chromosome 15

BackgroundMaternally-derived duplications that include the imprinted region on the proximal long arm of chromosome 15 underlie a complex neurobehavioral disorder characterized by cognitive impairment, seizures and a substantial risk for autism spectrum disorders[1]. The duplications most often take the form of a supernumerary pseudodicentric derivative chromosome 15 [der(15)] that has been called inverted duplication 15 or isodicentric 15 [idic(15)], although interstitial rearrangements also occur. Similar to the deletions found in most cases of Angelman and Prader Willi syndrome, the duplications appear to be mediated by unequal homologous recombination involving low copy repeats (LCR) that are found clustered in the region. Five recurrent breakpoints have been described in most cases of segmental aneuploidy of chromosome 15q11-q13 and previous studies have shown that most idic(15) chromosomes arise through BP3:BP3 or BP4:BP5 recombination events.ResultsHere we describe four duplication chromosomes that show evidence of atypical recombination events that involve regions outside the common breakpoints. Additionally, in one patient with a mosaic complex der(15), we examined homologous pairing of chromosome 15q11-q13 alleles by FISH in a region of frontal cortex, which identified mosaicism in this tissue and also demonstrated pairing of the signals from the der(15) and the normal homologues.ConclusionInvolvement of atypical BP in the generation of idic(15) chromosomes can lead to considerable structural heterogeneity.

22q11.2 Distal Deletion: A Recurrent Genomic Disorder Distinct from DiGeorge Syndrome and Velocardiofacial Syndrome

Microdeletions within chromosome 22q11.2 cause a variable phenotype, including DiGeorge syndrome (DGS) and velocardiofacial syndrome (VCFS). About 97% of patients with DGS/VCFS have either a common recurrent approximately 3 Mb deletion or a smaller, less common, approximately 1.5 Mb nested deletion. Both deletions apparently occur as a result of homologous recombination between nonallelic flanking low-copy repeat (LCR) sequences located in 22q11.2. Interestingly, although eight different LCRs are located in proximal 22q, only a few cases of atypical deletions utilizing alternative LCRs have been described. Using array-based comparative genomic hybridization (CGH) analysis, we have detected six unrelated cases of deletions that are within 22q11.2 and are located distal to the approximately 3 Mb common deletion region. Further analyses revealed that the rearrangements had clustered breakpoints and either a approximately 1.4 Mb or approximately 2.1 Mb recurrent deletion flanked proximally by LCR22-4 and distally by either LCR22-5 or LCR22-6, respectively. Parental fluorescence in situ hybridization (FISH) analyses revealed that none of the available parents (11 out of 12 were available) had the deletion, indicating de novo events. All patients presented with characteristic facial dysmorphic features. A history of prematurity, prenatal and postnatal growth delay, developmental delay, and mild skeletal abnormalities was prevalent among the patients. Two patients were found to have a cardiovascular malformation, one had truncus arteriosus, and another had a bicuspid aortic valve. A single patient had a cleft palate. We conclude that distal deletions of chromosome 22q11.2 between LCR22-4 and LCR22-6, although they share some characteristic features with DGS/VCFS, represent a novel genomic disorder distinct genomically and clinically from the well-known DGS/VCF deletion syndromes.