Paternal deletion 6q24.3: a new congenital anomaly syndrome associated with intrauterine growth failure, early developmental delay and characteristic facial appearance

Deletions of the long arm of chromosome 6 are relatively uncommon and to date minimal genotype-phenotype correlations have been observed. We report on three unrelated patients with de novo paternal interstitial deletions of 6q24.3. FISH mapping was used to delineate the minimal region of overlap between these three patients. Although all three patients had different size deletions and different breakpoints, two of the patients shared a 2.5 Mb region of overlap and strikingly similar facial features including a triangular face, frontal bossing with metopic prominence, short and upward-slanting palpebral fissures, asymmetry of upper eyelids, hooded eyelids, shallow orbits, prominent inferior orbital crease, wide mouth, and long and flat philtrum. They also had redundant skin, joint laxity, a small thorax, and early developmental delay. The smallest region of overlap between all three patients was a region of deletion less than 1 Mb; all had a history of IUGR and postnatal short stature without overt radiologic skeletal anomalies. The dysmorphic features, early developmental and growth delay may be due to the hemizygous state for one of the genes in the deleted region of two of the patients or to a long range effect of the deletion on expression of other genes. In addition, since imprinted genes have been reported in this region, paternal deletion of an imprinted gene in all three patients may contribute to the growth phenotype. We propose that this is a new congenital malformation syndrome associated with a paternal deletion of 6q24.3.     

High resolution mapping of interstitial long arm deletions of chromosome 16: relationship to phenotype.

The breakpoints of seven interstitial deletions of the long arm of chromosome 16 and two ring chromosomes of this chromosome were mapped by in situ hybridisation or by analysis of mouse/human somatic cell hybrids containing the deleted chromosome 16. Use of a high resolution cytogenetic based physical map of chromosome 16 enabled breakpoints to be assigned to an average resolution of at least 1.6 Mb. In general, interstitial deletions involving q12 or q22.1 have broadly similar phenotypes though there are differences in specific abnormalities. Deletions involving regions more distal, from 16q22.1 to 16q24.1, were associated with relatively mild dysmorphism. One region of the long arm, q24.2 to q24.3, was not involved in any deletion, either in this study or in any previous report. Presumably, monosomy for this region is lethal. In contrast, patients with deletions of 16q21 have a normal phenotype. These results are consistent with the proposed distribution of genes, frequent in telomeric Giesma light band regions but infrequent in G positive bands.     

Atypical 22q11.2 deletion in a patient with DGS/VCFS spectrum

Deletions in region 22q11.2 usually occur between two low copy repeat regions (LCRs), which are preferred chromosome sites for rearrangements. Most of the deletions encompass the same 3 or 1.5 Mb region, with breakpoints at LCR A and D or at LCR A and B, respectively. We report on a patient with clinical features of the 22q deletion syndrome who presents a novel, atypical deletion, smaller than 1.5 Mb, with distal breakpoint in LCR B and proximal breakpoint within no known LCR site.     

Multigeneration family with short stature,developmental delay,and dysmorphic features due to 4q27-q28.1 microdeletion

Deletions of the long arm of chromosome 4 are rare but have been previously reported to be associated with craniofacial anomalies, digital anomalies, developmental delay, growth failure, and cardiovascular anomalies [1], [2], [3], [4], [5], [6]. Strehle et al. [1] previously presented 20 patients with 4q deletions and began to construct a phenotype–genotype map for chromosome 4q. This report follows up on that work by providing clinical and molecular cytogenetic data on a three generation pedigree including seven patients with short stature, dysmorphic features, and developmental delay identified to have a 4q27-q28.1 microdeletion of approximately 5.68 Mb by oligonucleotide chromosomal microarray. This family represents a rare report of an inherited interstitial deletion of the long arm of chromosome 4. To our knowledge, only two cases have been previously reported [7], [8]. The contribution of candidate genes in the region is discussed.     

Novel deletions of 14q11.2 associated with developmental delay, cognitive impairment and similar minor anomalies in three children

METHODS AND RESULTS: We identified de novo submicroscopic chromosome 14q11.2 deletions in two children with idiopathic developmental delay and cognitive impairment. Vancouver patient 5566 has a approximately 200 kb deletion and Vancouver patient 8326 has a approximately 1.6 Mb deletion. The Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources (DECIPHER) revealed a third patient with idiopathic developmental delay and cognitive impairment, DECIPHER patient 126, who has a approximately 1.1 Mb deletion of 14q11.2. The deletion of patient 5566 overlaps that of patient 126 and both of these deletions lie entirely within that of patient 8326. All three children have similar dysmorphic features, including widely-spaced eyes, short nose with flat nasal bridge, long philtrum, prominent Cupid's bow of the upper lip, full lower lip and similar auricular anomalies. CONCLUSION: The minimal common deletion region on chromosome 14q11.2 is only approximately 35 kb (from 20.897 to 20.932, University of California at Santa Cruz (UCSC) Genome Browser; build hg18, March 2006) and includes only two genes, SUPT16H and CHD8, which are good candidate genes for the phenotypes. The non-recurrent breakpoints of these patients, the presence of normal copy number variants in the region and the local genomic structure support the notion that this region has reduced stability.     

Pure proximal deletion of chromosome 21 and kyphosis

We report on two unrelated patients with a proximal deletion of the long arm of chromosome 21. The deletion encompassed 14.5 Mb of DNA. Molecular studies showed that the two telomeric breakpoints were within the same DNA clone (BAC RP11-56D12). The centromeric breakpoints, however, were separated by only 250 kb of DNA (BAC RP11-645E14 and RP11-324B9). The phenotype observed in the two patients was very different, as patient 2, who had the largest deletion, had severe kyphosis not observed in patient 1. Previous studies have identified a 6 Mb region of chromosome 21 associated with severe kyphosis. Interestingly, this region overlaps the 250 kb segment deleted in patient 2. We suggest that one gene (NT011512.4) located in this small overlapping region might be responsible for severe kyphosis.     

Complex craniosynostosis is associated with the 2p15p16.1 microdeletion syndrome

In a screening project of patients with (complex) craniosynostosis using genomic arrays, we identified two patients with craniosynostosis and microcephaly with a deletion in the 2p15p16.1 chromosomal region. This region has been associated with a new microdeletion syndrome, for which patients have various features in common, including microcephaly and intellectual disability. Deletions were identified using Affymetrix 250K SNP array and further characterized by fluorescence in situ hybridization (FISH) analysis and qPCR. The deletions in our two patients overlapped within the 2p15p16.1 microdeletion syndrome area and were 6.8 and 6.9 Mb in size, respectively. FISH and qPCR confirmed the presence of only one copy in this region. Finemapping of the breakpoints indicated precise borders in our patients and were further finemapped in two other previously reported patients. Clinical features of patients with deletions in the 2p15p16.1 region vary. Including data from our patients, now eight out of nine reported patients have microcephaly, one of the major features, and all had intellectual disability. The current reported two patients add different forms of craniosynostosis to the clinical spectrum of this recently recognized microdeletion syndrome. © 2013 Wiley Periodicals, Inc.     

Characterization of chromosome arm 20q abnormalities in myeloid malignancies using genome‐wide single nucleotide polymorphism array analysis

Deletion of the long arm of chromosome 20 is a common abnormality associated with myeloid malignancies. We characterized abnormalities of chromosome 20 as defined by metaphase cytogenetics (MC) in patients with myeloid neoplasms to define commonly deleted regions (CDR) and commonly retained regions (CRR) using genome‐wide, high resolution single nucleotide polymorphism array (SNP‐A) analysis. We reviewed the MC results of a cohort of 1,162 patients with myeloid malignancies, including myelodysplastic syndromes (MDS), MDS/myeloproliferative neoplasia (MDS/MPN), and acute myeloid leukemia (AML). We further analyzed a subcohort of 532 patients by SNP‐A using the Affymetrix Genome‐Wide Human SNP Array 6.0 and GeneChip Human Mapping 250K Nsp arrays. By MC, 5% (54/1,162) harbored a deletion of 20q; in 30% (16/54), del(20q) was the sole cytogenetic abnormality. By SNP‐A analysis, we identified del(20q) in 23 patients, 3 not detected by MC. In four cases, monosomy 20 with a marker chromosome by MC was proven to be an interstitial deletion of 20q by SNP‐A. We defined 2 CDR and 2 CRR on chromosome arm 20q: CDR1 spanned 2.5 Mb between bands 20q11.23 and 20q12, while CDR2 encompassed 1.8 Mb within 20q13.12. CRR1 spanned 1.9 Mb within 20q11.21 and CRR2 encompassed 2.5 Mb within 20q13.33. In contrast to other chromosomes frequently affected by deletions, no somatic copy neutral loss of heterozygosity (CN‐LOH) was detected. Our data suggest that SNP‐A is useful for the detection of cryptic aberrations of chromosome 20q and allows for a more precise characterization of complex karyotypes. Furthermore, SNP‐A allowed definition of a CDR on 20q. © 2010 Wiley‐Liss, Inc.     

A 3-cM commonly deleted region in 6q21 in leukemias and lymphomas delineated by fluorescence in situ hybridization

Deletions of the long arm of chromosome 6 (6q) are frequent chromosome aberrations in non-Hodgkin lymphomas (NHLs) and acute lymphoblastic leukemias (ALLs). It is presumed that one or more tumor suppressor genes are localized on 6q. By means of fluorescence in situ hybridization (FISH), we attempted to detect and delineate deletions of 6q in leukemias and lymphomas. We performed FISH on 148 cases of lymphoma and acute leukemia using a panel of 36 YAC probes distributed from 6q12 to 6q27 and a centromeric probe of chromosome 6 as internal control. Deletions of 6q that included a 7-cM commonly deleted region in 6q21 were detected in 59 patients who had B- and T-cell low-grade and high-grade NHL and ALL. FISH with two YAC probes flanking this region was performed on an additional 97 cases of NHL and leukemia. Deletions in 6q21 were detected in an additional 21 cases. In five cases of high-grade B- and T-cell NHL and ALL, the deletion breakpoints were located within the commonly deleted region. To define the deletion breakpoints exactly and to narrow this region further, FISH was performed with six additional YAC probes that have been physically localized within this region. A 3-cM (4-5 Mb) commonly deleted region in 6q21 was delineated. Our study suggests that this commonly deleted region harbors a putative tumor suppressor gene involved in the pathogenesis of both low-grade and high-grade NHL and ALL. Genes Chromosomes Cancer 27:52-58, 2000.     

Extended runs of homozygosity at 17q11.2: an association with type‐2 NF1 deletions?

Large deletions in the NF1 gene region at 17q11.2 are caused by nonallelic homologous recombination (NAHR). The recurrent type‐2 NF1 deletions span 1.2 Mb, with breakpoints in the SUZ12 gene and SUZ12P. Type‐2 NF1 deletions occur preferentially during mitosis and are associated with somatic mosaicism. A panel of 16 type‐2 NF1 deletions was used as a model system in which to investigate whether extended homozygosity across 17q11.2 might be associated with somatic deletion. Using SNP arrays, a 3.2 Mb interval encompassing the NF1 deletion region was found to harbor runs of homozygosity (ROHs) in different human populations. However, ROHs ≥500 kb directly flanking the NF1 deletion region on both sides were not found to occur disproportionately in NF1 patients harboring type‐2 deletions compared to controls. Although low allelic diversity in 17q11.2 is unlikely to be a key factor in promoting NAHR‐mediated somatic type‐2 deletions, a specific ROH of 588 kb (roh1), located some 525 kb proximal to the deletion interval, was found to occur more frequently (P=0.012) in the type‐2 deletion patients compared with controls. We postulate that roh1 may act remotely, via an as yet unknown mechanism, to increase the frequency of somatic recombination between the distally duplicated SUZ12 sequences. Hum Mutat 30:1–10, 2010. © 2010 Wiley‐Liss, Inc.     

Molecular cytogenetic analysis of five 2q37 deletions: refining the brachydactyly candidate region

Deletions of the 2q37 region are associated with a recognizable pattern of MCA/MR so-called the AHO-like syndrome. Brachydactyly is a variable but characteristic feature of this clinical entity. Here we report on five cases of cytogenetically visible de novo deletions of this 2q37 chromosome region. Using FISH, we characterized at the molecular level the breakpoints of these deletions using a set of 15 BACs, PACs and YACs. In four patients, terminal deletions of variable size ranged between 6.2 and 10 Mb. The fifth patient had an interstitial deletion with an AHO-like phenotype including brachydactyly. These findings when compared to previous observations allowed us to narrow down the brachydactyly critical region between BACs RP11-585E12 and RP11-351E10. It contains HDAC4 and STK25 candidate genes loci.     

Molecular heterogeneity at the breakpoints of smaller 20q deletions

Deletions of the long arm of chromosome 20 [del(20q)] are recurring abnormalities in patients with myeloid disorders. Although variable in size, these deletions are usually interstitial. With the object of defining a commonly deleted region for smaller 20q deletions, we used quantitative Southern blot analysis complemented by restriction fragment length polymorphism (RFLP) analysis to determine the copy number at 15 loci spanning 20q. The proximal breakpoints of three such deletions were found to separate HCK and the growth hormone releasing factor (GHRF) locus near the centromeric boundary of band 20q 11.2. The distal breakpoints were localized to the vicinity of the D20S22 locus in band q13.1.A candidate tumor suppressor gene, RBL2, and the SRC oncogene were both located within the commonly deleted region. Six loci in terminal region q13.2-q13.3 were conserved on these del(20q) chromosomes, thereby confirming that the deletions were interstitial. Molecular heterogeneity at one and possibly both deletion breakpoints rules out the pathological involvement of loci at these sites. Instead, loss of a tumor suppressor locus from within the commonly deleted region may contribute to deregulated hemopoiesis.     

Molecular cytogenetic characterization of 2p23.2p23.3 deletion in a child with developmental delay,hypotonia and cryptorchism

Deletions of the short arm of chromosome 2 are exceedingly rare and only nine cases involving regions from 2p23 to 2pter have been reported to date. Most of these deletions had only been analysed by GTG banding. Here, we report an interstitial de novo deletion resulting in a microdeletion of 3.9 Mb involving 2p23.2-p23.3 segment, detected by SNP-array analysis, in a 5 year-old boy showing hypotonia, overweight, dysmorphic facial features and cryptorchidism. We compared the clinical features of the present case to previously described patients with deletions within this chromosomal region. Our case adds new information to the deletion of the distal part of chromosome 2p improving the knowledge on this rearrangement.     

A novel interstitial deletion of 10q24.2q24.32 in a patient with renal coloboma syndrome

Renal coloboma syndrome (RCS) is considered to be a rare autosomal dominant inherited disorder characterized by renal malformations and optic disc coloboma. Ocular anomalies range from asymptomatic abnormalities in retinal blood vessel patterning to large excavations of the optic nerve associated with reduced visual acuity. Commonly observed manifestations of the kidney are renal hypoplasia and vesicoureteric reflux leading to end-stage renal disease. Mutations in the PAX2 gene on chromosome 10 have been identified in patients with RCS. Up to date, nucleotide substitutions, insertions, small deletions, one de novo translocation, and one 240 kb deletion of the coding region of the PAX2 gene have been described to be responsible for RCS.We report here a new case of a patient with RCS due to a deletion of 3.8 Mb on chromosome 10q. Deletions on the long arm of chromosome 10 harboring the PAX2 gene seem to be a rare cause for RCS. Nevertheless, array-CGH testing should represent an important and valuable addition to PAX2 gene sequencing in diagnostic of RCS.     

Detailed characterization of,and clinical correlations in, 10 patients with distal deletions of chromosome 9p

PurposeDeletions of distal 9p are associated with trigonocephaly, mental retardation, dysmorphic facial features, cardiac anomalies, and abnormal genitalia. Previous studies identified a proposed critical region for the consensus phenotype in band 9p23, between 11.8 Mb and 16 Mb from the 9p telomere. Here we report 10 new patients with 9p deletions; 9 patients have clinical features consistent with 9p− syndrome, but possess terminal deletions smaller than most reported cases, whereas one individual lacks the 9p− phenotype and shows a 140-kb interstitial telomeric deletion inherited from his mother.MethodsWe combined fluorescence in situ hybridization and microarray analyses to delineate the size of each deletion.ResultsThe deletion sizes vary from 800 kb to 12.4 Mb in our patients with clinically relevant phenotypes. Clinical evaluation and comparison showed little difference in physical features with regard to the deletion sizes. Severe speech and language impairment were observed in all patients with clinically relevant phenotypes.ConclusionThe smallest deleted region common to our patients who demonstrate a phenotype consistent with 9p− is <2 Mb of 9pter, which contains six known genes. These genes may contribute to some of the cardinal features of 9p deletion syndrome.     

Delineation of a critical region on chromosome 18 for the del(18)(q12.2q21.1) syndrome

Deletions involving the long arm of chromosome 18 have been reported in many patients. Most of these deletions are localized in the distal half of the long arm (18q21.1 --> qter) and are detectable by standard cytogenetic analysis. However, smaller interstitial deletions leading to a recognizable phenotype and residing in the region around chromosome band 18q12.3 (bands q12-q21) are less common. Here we report on an interstitial deletion of less than 1.8 Mb within chromosomal band 18q12.3. The phenotypic features of the propositus correspond well with those observed in patients with larger cytogenetically detectable deletions encompassing chromosome band 18q12.3. The deletion enabled us to define a critical region for the following features of the del(18)(q12.2q21.1) syndrome: hypotonia, expressive language delay, short stature, and behavioral problems.     

SALL4 and NFATC2: Two major actors of interstitial 20q13.2 duplication

Interstitial duplication within the long arm of chromosome 20 is an uncommon chromosome structural abnormality. We report here the clinical and molecular characterization associated with pure 20q13.2 duplication in three unrelated patients. The most frequent clinical features were developmental delay, facial dysmorphism, cardiac malformation and skeletal anomalies. All DNA gains occurred de novo, ranging from 1.1 Mb to 11.5 Mb. Compared with previously reported conventional cytogenetic analyses, oligonucleotides array CGH allowed us to refine breakpoints and determine the genes of interest in the region. Involvement of SALL4 in cardiac malformations and NFATC2 gene disruption in both cardiac and skeletal anomalies are discussed.     

Chromosome 9p deletion syndrome and sex reversal: Novel findings and redefinition of the critically deleted regions

Deletions of the short arm of chromosome 9 are associated with two distinct clinical entities. Small telomeric 9p24.3 deletions cause genital anomalies in male subjects, ranging from disorder of gonadal sex to genital differentiation anomalies, while large terminal or interstitial deletions result in 9p-malformation syndrome phenotype. The critical region for non-syndromic 46,XY sex reversal was assigned to a 1?Mb interval of chromosome 9p, extending from the telomere to the DMRT genes cluster. The 9p-syndrome was assigned to bands 9p22.3p24.1, but a phenotypic map has not been established for this condition, probably because of the lack of detailed molecular and/or phenotypic characterization, as well as frequent involvement of additional chromosome rearrangements. Here, we describe a unique patient with a small isolated 9p terminal deletion, characterized by array-CGH and FISH, who shows a complex phenotype with multiple physical anomalies, resembling the 9p-syndrome, disorder of sex development with gonadoblastoma, congenital heart defect and epilepsy. The observed deletion includes the 46,XY sex-reversal critical region, excluding the region so far associated with the 9p-syndrome. Genotype-phenotype correlations are tentatively established comparing our patient to seven other previously reported males with isolated terminal 9p deletions, finely defined at a molecular level. Our observations expand the 9p deletion clinical spectrum, and add significantly to the definition of a 9p-syndrome critical region. ? 2012 Wiley Periodicals, Inc.