Proximal 15q Research Articles

15q Duplication associated with autism in a multiplex family with a familial cryptic translocation t(14;15)(q11.2;q13.3) detected using array‐CGH

Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders with a strong genetic aetiology. In approximately 1% of cases, duplication of the 15q11-13 region has been reported. We report the clinical, array-comparative genomic hybridization (CGH) and cytogenetic evaluation of two individuals from a multiplex family demonstrating autism due to a maternally inherited gain of 15q11-13. Our findings indicate that unlike most 15q11-13 gains, which are caused by interstitial duplication of this region or supernumerary marker chromosomes deriving from proximal 15q, the 15q gain in this family is the result of abnormal segregation of a cryptic familial translocation with breakpoints at 14q11.2 and 15q13.3. The affected members of this family were found to have a normal karyotype at >550 band resolution. This translocation was identified using the 1-Mb resolution whole genome array (Spectral Genomics). The affected individuals have a gain of seven clones from proximal 15q, a loss of two clones from proximal 14q and a gain of two clones from 6q. Fluorescent in situ hybridization (FISH) analysis with clones from chromosomes 14 and 15, combined with DAPI reverse banding, showed an abnormal karyotype with one normal chromosome 15 and the der(15) t(14;15)(q11.2.;q13.3), resulting in the gain of proximal 15q and the loss of proximal 14q in affected individuals. The duplication of two clones from 6q in the affected subjects was also found in unaffected members of the family. Our findings suggest that the gain of 15q in autism may in some cases be due to cryptic translocations with breakpoints in the pericentromic regions of chromosome 15 and a different acrocentric chromosome. Variation in the size of pericentromic regions of any acrocentric chromosome may justify karyotype and FISH studies of autistic probands and their parents using probes from the 15q proximal region to determine recurrence risk for autism in some families.

Detection of an unexpected subtelomeric 15q26.2 → qter deletion in a little girl: Clinical and cytogenetic studies

Unlike the small proximal 15q deletions causing Prader-Willi and/or Angelman syndrome, distal deletions of the terminal long arm of chromosome 15 have rarely been described. To the best of our knowledge, only four patients with a pure terminal 15q deletion have been documented in the literature. We report here on an unexpected abnormal hybridization pattern for the 15q specific subtelomeric control probe (clone 154P1) of the commercial SNRPN probe in a girl referred for suspicion of Angelman syndrome. Investigation by fluorescent in situ hybridization (FISH) using bacterial artificial chromosome (BAC) clones defined a partial monosomy 15q26.2 --> 15qter for a minimal critical region of approximately 5.7 Mb, which is the most distal de novo 15qter deletion reported to date. All the de novo 15qter deletion cases, including ours, presented with pre- and post-natal growth retardation related to the loss of one copy of the IGF1R gene. Based on the comparaison with the previous published cases and owing to the clinical phenotype of our patient, we define a new subtelomeric 15qter syndrome which would be characterized by intrauterine growth retardation and global post-natal growth failure, variable mental retardation, facial anomalies including relative micrognathia and triangular facies and minor malformations of the extremities including proximally placed thumbs, cubitus valgus, and brachydactyly with tappering of the digits.

Haploinsufficiency of novel FOXG1B variants in a patient with severe mental retardation, brain malformations and microcephaly

We have investigated the chromosome abnormalities in a female patient exhibiting a severe cognitive disability associated with complete agenesis of the corpus callosum and microcephaly. The patient carries a balanced de novo translocation t(2;14)(p22;q12), together with a neighbouring 720 kb inversion in chromosome 14q12. By combined fluorescence in situ hybridisation and Southern hybridisation, the distal inversion breakpoint on chromosome 14 was mapped to a region harbouring genes and ESTs derived predominantly from brain tissue. RT-PCR studies indicated that these transcripts comprise the 3' ends of novel splice variants of the winged helix transcription factor FOXG1B (also referred to in previous studies as FOXG1A and FOXG1C, as well as Brain Factor 1), the mouse orthologue of which is essential for normal development of the telencephalon. Analysis of these novel FOXG1B transcripts indicated that they are all disrupted by the breakpoint in the patient. Moreover, we have identified novel orthologous Foxg1 transcripts in the mouse and other vertebrates, which validates the functional importance of these variants and provides a direct genetic link between the patient phenotype and that of the heterozygous Foxg1 knockout mice. These results, together with previously published studies on patients with similar disorders and proximal 14q deletions, strongly suggest that several disorders associated with malformations of the human brain may be directly caused by mutations or alterations in the FOXG1B gene.

Mosaicism of proximal 15q duplication/deletion resulting in Prader–Willi syndrome with normal methylation

American Journal of Medical Genetics Part AVolume 138A, Issue 2 p. 181-184 Research Letter Mosaicism of proximal 15q duplication/deletion resulting in Prader–Willi syndrome with normal methylation Luke Boyd, Luke Boyd Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OregonSearch for more papers by this authorMichael G. Brown, Michael G. Brown University Hospitals, Oregon Health & Science University, Portland, OregonSearch for more papers by this authorStephen Kelson, Stephen Kelson University Hospitals, Oregon Health & Science University, Portland, OregonSearch for more papers by this authorHelen Lawce, Helen Lawce University Hospitals, Oregon Health & Science University, Portland, OregonSearch for more papers by this authorSarah Shuttleworth, Sarah Shuttleworth University Hospitals, Oregon Health & Science University, Portland, OregonSearch for more papers by this authorNancy Unsworth, Nancy Unsworth University Hospitals, Oregon Health & Science University, Portland, OregonSearch for more papers by this authorR. Ellen Magenis, Corresponding Author R. Ellen Magenis magenise@ohsu.edu Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, Oregon Child Development Rehabilitation Center, Oregon Health & Science University, Portland, OregonOregon Health & Science University, Cytogenetics Laboratory, 3181 Sam Jackson Park Road, MP350 Portland, OR 97239.Search for more papers by this author Luke Boyd, Luke Boyd Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OregonSearch for more papers by this authorMichael G. Brown, Michael G. Brown University Hospitals, Oregon Health & Science University, Portland, OregonSearch for more papers by this authorStephen Kelson, Stephen Kelson University Hospitals, Oregon Health & Science University, Portland, OregonSearch for more papers by this authorHelen Lawce, Helen Lawce University Hospitals, Oregon Health & Science University, Portland, OregonSearch for more papers by this authorSarah Shuttleworth, Sarah Shuttleworth University Hospitals, Oregon Health & Science University, Portland, OregonSearch for more papers by this authorNancy Unsworth, Nancy Unsworth University Hospitals, Oregon Health & Science University, Portland, OregonSearch for more papers by this authorR. Ellen Magenis, Corresponding Author R. Ellen Magenis magenise@ohsu.edu Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, Oregon Child Development Rehabilitation Center, Oregon Health & Science University, Portland, OregonOregon Health & Science University, Cytogenetics Laboratory, 3181 Sam Jackson Park Road, MP350 Portland, OR 97239.Search for more papers by this author First published: 12 August 2005 https://doi.org/10.1002/ajmg.a.30819Citations: 3Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume138A, Issue21 October 2005Pages 181-184 RelatedInformation

A new case of 2q duplication supports either a locus for orofacial clefting between markers D2S1897 and D2S2023 or a locus for cleft palate only on chromosome 2q13‐q21

We report on a pure duplication of the proximal chromosome 2q in a 6.5-year-old boy with V-shaped midline cleft palate and bifid uvula, posteriorly located tongue, and micrognathia (Pierre Robin sequence), celiac disease, failure to thrive, and developmental delay. Cytogenetic and FISH analysis indicated a duplication of chromosome 2q13-q22. In general, pure proximal duplication or triplication of 2q is rare. The clinical features and chromosomal breakpoints of the 10 previously reported patients varied, and no common phenotype or proximal duplication/triplication 2q syndrome could be defined to date. However, based on four previous patients with different orofacial clefts and our case, a locus for orofacial clefting may be located at proximal 2q. The duplication/triplication comprised chromosome 2q13 in all five affected individuals including our patient. Our patient and three previous cases (two with cleft palate only (CPO) and one with cleft lip/palate (CL/P)) showed a cytogenetic breakpoint at 2q13, which could support the presence of a critical dominant gene disrupted by a common breakpoint, however, the fifth case with CPO showed different breakpoints, advocating against the disruption of a critical dominant gene and supporting that the overexpression of a gene(s) on chromosome 2q13-q21 may cause cleft palate only (CPO) and Pierre Robin sequence. Hence, our findings support either the presence of one locus for orofacial clefting (CL/P, CPO, and Pierre Robin sequence) between markers D2S1897 (chromosome 2q12.2) and D2S2023 (chromosome 2q14.2), or alternatively the presence of a locus for CPO and Pierre Robin sequence on chromosome 2q13-q21.

The consequences of chromosome imbalance

Review of the clinical cytogenetic literature provides compelling evidence for a specific relationship between imbalance of particular chromosomes or chromosomal regions and the appearance of defined patterns of phenotypic abnormalities. In many instances, detailed phenotypic mapping has made it possible to assign portions of a phenotype to relatively small chromosome segments, which are sometimes referred to as "critical regions." However, since these regions are usually defined by a subset of the phenotypic manifestations of an aneuploidy syndrome--generally those anomalies that are regarded as most characteristic or readily observable--it is important not to fall into the trap of thinking that it is imbalance of only these regions that has deleterious effects on development and function. Thus, in Down syndrome, the presence of an extra copy of the proximal part of 21q22.3 appears to result in the typical physical phenotype--as defined principally in terms of the characteristic facial and hand anomalies and congenital heart defect--in addition to mental retardation. But, duplication of proximal 21q also affects mental development, and the regions responsible for many other aspects of the Down syndrome phenotype, including Alzheimer disease, have not been defined at all. Therefore, it remains likely that loci present on many parts of the long arm of chromosome 21 play a role in the development of the overall phenotype of Down syndrome. The immediate effect at the molecular level of an aneuploidy-caused alteration in gene dose appears to be a non-compensated commensurate change in the production of gene products.(ABSTRACT TRUNCATED AT 250 WORDS)

Defining a holoprosencephaly locus on human chromosome 14q13 and characterization of potential candidate genes

Holoprosencephaly (HPE) is the most common developmental field defect in patterning of the human prosencephalon and associated craniofacial structures. The genetics is complex, with 12 loci defined on 11 chromosomes. We defined a locus for HPE (HPE8) on human chromosome 14q13 between markers D14S49 and AFM205XG5, by mapping deletion intervals of affected subjects with proximal chromosome 14q interstitial cytogenetic deletions. A 35-BAC contig was built by chromosome walking. By annotation of the 2.82-Mb minimal critical region, we identified 28 possible genes. Seven genes were expressed in human fetal brain: NPAS3, SNX6, C14ORF11, C14ORF10, PAX9, NKX2.1, and C14ORF19, the last an apparent gene fragment. Molecular embryology, animal modeling, and human mutation studies were reported elsewhere for PAX9 and NKX2.1. We focused on three genes, SNX6, NPAS3, and C14ORF11, as potential candidates for HPE. Genomic structure, human expression patterns, protein cellular localization, and embryonic expression patterns of orthologous murine genes were determined, showing that the three genes have properties similar to those of known HPE genes.

Mosaic tetrasomy 14pter‐q13 due to a supernumerary isodicentric derivate of proximal chromosome 14q

Tetrasomy of proximal 14q is an extremely rare condition and has never been reported to be associated with survival. We here report on the first case of mosaic tetrasomy of 14pter-q13 due to a de-novo supernumerary pseudoisodicentric chromosome in a 2-year-old boy with multiple dysmorphisms and malformations. The marker was detectable in nearly 25% of lymphocytes as well as in cells from buccal mucosa. Detailed fluorescence in situ hybridization (FISH) analyses allowed the characterization of the marker to entirely consist of proximal 14q material and to be symmetric. The pattern of clinical features in our patient only slightly correspond to that of patients with trisomy of proximal 14q, but further cases are needed to define whether tetrasomy of proximal 14q is a separate entity.

Recurrent adjacent‐2 segregation of a familial t(14;21)(q11.2;q11.2): Phenotypic comparison of two brothers and a paternal aunt inheriting the der(14)

A 14-year-old boy was referred for a genetics evaluation after high-resolution chromosome analysis showed a small amount of extra material in the proximal long arm of chromosome 21. Five years prior, his karyotype analysis was interpreted as normal with a variant chromosome 21. The patient has short palpebral fissures, strabismus, flat antihelices of the ears, long thumbs with bilaterally absent interphalangeal creases, proximal bilateral 3/4 syndactyly, small testes, hypotonia, mental retardation, and speech problems. He has significant depression and behavioral problems including hyperactivity, aggression, and impulsivity. His 8-year-old brother has more severe behavioral disturbances and depression, but less significant mental retardation. A paternal aunt has mental retardation, is unusually docile, and appears similar to our patient. Chromosome analysis and fluorescence in situ hybridization (FISH) whole chromosome paint of chromosome 21 showed that the patient's father carries a "cryptic" balanced translocation, 46,XY, t(14;21)(q11.2;q11.2), as does the patient's paternal grandmother. Uniparental disomy studies using seven informative polymorphic nucleotide repeat markers from 14q and 21q confirmed biparental inheritance of the number 14 and 21 chromosomes for each brother, and indicate that they and the paternal aunt, all of whom inherited the der(14), are monosomic for proximal 21q and trisomic for proximal 14q. These karyotypes arose through an adjacent-2 segregation in the father on two occasions, and from the paternal grandmother on one occasion. This family is an example of recurrent malsegregation with translocations involving the acrocentrics.

High-Resolution Molecular Characterization of 15q11-q13 Rearrangements by Array Comparative Genomic Hybridization (Array CGH) with Detection of Gene Dosage

Maternally derived duplication of the imprinted region of chromosome 15q11-q14 leads to a complex neurobehavioral phenotype that often includes autism, cognitive deficits, and seizures. Multiple repeat elements within the region mediate a variety of rearrangements, including interstitial duplications, interstitial triplications, and supernumerary isodicentric marker chromosomes, as well as the deletions that cause Prader-Willi and Angelman syndromes. To elucidate the molecular structure of these duplication chromosomes, we designed a high-resolution array comparative genomic hybridization (array CGH) platform. The array contains 79 clones that form a gapped contig across the critical region on chromosome 15q11-q14 and 21 control clones from other autosomes and the sex chromosomes. We used this array to examine a set of 48 samples from patients with segmental aneuploidy of chromosome 15q. Using the array, we were able to determine accurately the dosage, which ranged from 1 to 6 copies, and also to detect atypical and asymmetric rearrangements. In addition, the increased resolution of the array allowed us to position two previously reported breakpoints within the contig. These results indicate that array CGH is a powerful technique to study rearrangements of proximal chromosome 15q.

Recurrent proximal 18p monosomy and 18q trisomy in a family with a maternal pericentric inversion of chromosome 18

We report a recurrent partial monosomy of 18p10→11.2 and proximal partial trisomy of 18q10→21.3 caused by a maternal pericentric inversion of chromosome 18, involving breakpoints p11.2 and q21q21.3 Based on cytogenetics and FISH analysis, we speculate that the recurrent chromosome abnormality in the proband and in the fetus was the result of a translocation, possibly in a germ cell or germ cell precursor, between the maternal normal 18 and her inverted 18, resulting in maternal germinal mosaicism, i.e. 46,XX,inv(18)/46,XX,t[18;inv(18)][q10;q10]. The unbalanced karyotype of the proband and the fetus is 46,XY,+18,der[18;inv(18)][q10;q10]. To the best of our knowledge, there are no reports of this combination of proximal 18p monosomy and proximal 18q trisomy. The other interesting observation was association of Hirschsprung’s disease in the proband.

Necdin-related MAGE Proteins Differentially Interact with the E2F1 Transcription Factor and the p75 Neurotrophin Receptor

Necdin is a growth suppressor expressed predominantly in postmitotic neurons and implicated in their terminal differentiation. Necdin shows a moderate homology to the MAGE family proteins, the functional roles of which are largely unknown. Human genes encoding necdin, MAGEL2 (necdin-like 1), and MAGE-G1 (necdin-like 2) are located in proximal chromosome 15q, a region associated with neurodevelopmental disorders such as Prader-Willi syndrome, Angelman syndrome, and autistic disorder. The necdin and MAGEL2 genes are subjected to genomic imprinting and suggested to be involved in the etiology of Prader-Willi syndrome. In this study, we compared biochemical and functional characteristics of murine orthologs of these necdin-related MAGE proteins. The colony formation and bromodeoxyuridine incorporation analyses revealed that necdin and MAGE-G1, but not MAGEL2, induced growth arrest. Necdin and MAGE-G1 interacted with the transcription factor E2F1 via its transactivation domain, repressed E2F1-dependent transcription, and antagonized E2F1-induced apoptosis of N1E-115 neuroblastoma cells. In addition, necdin and MAGE-G1 interacted with the p75 neurotrophin receptor via its distinct intracellular domains. In contrast, MAGEL2 failed to bind to these necdin interactors, suggesting that MAGEL2 has no necdin-like function in developing brain. Overexpression of p75 translocated necdin and MAGE-G1 in the proximity of the plasma membrane and reduced their association with E2F1 to facilitate E2F1-induced death of neuroblastoma cells. These results suggest that necdin and MAGE-G1 target both E2F1 and p75 to regulate cell viability during brain development.

Recombination across the centromere of disjoined and non-disjoined chromosome 21.

Meiotic recombination is generally suppressed across the centromere of eukaryotic chromosomes. In human, megabase-long satellite sequences and contiguous segmental duplications hamper both physical and fine scale genetic mapping in regions flanking centromeric DNA. We have developed polymorphic microsatellite markers embedded within the duplicated most proximal sequences of the long arm and of the short arm of chromosome 21 by using paralogous specific bases as anchor points for their specific detection. Segregation analysis in CEPH reference pedigrees shows that recombination is repressed significantly across the centromere of chromosome 21 both in male and in female but not in the most proximal 21q region in female. Extreme size variations of the alpha-satellite I blocks transmitted in these families and deduced from quantitative FISH analysis are not correlated with the inter-individual variations of recombination activity observed in the peri-centromeric region. Finally, none of 28 families with a trisomy 21 child previously associated with a nullitransitional meiosis I non-disjunction event presents a recombination exchange across the centromere. This confirms that, for this group of errors, the lack of recombination is the primary susceptibility factor, not abnormal recombination in the centromeric region.

Results of a genome-wide linkage scan for stuttering.

We performed a linkage study of stuttering using 392 markers distributed across the genome in a series of 68 families identified in the general outbred population of North America and Europe. Standardized diagnosis was performed using recorded samples of both conversation and reading, in which stuttering dysfluencies were scored as percentage of dysfluent words and syllables. Analysis was first performed using non-parametric methods implemented in GENEHUNTER, where we obtained maximum statistical support for markers of chromosome 18, with a maximum NPL (Sall) of 1.51 at D18S976. The single largest pedigree within our sample (pedigree 0006) alone gave an NPL of 4.72 at D18S976. For fine mapping, we analyzed 18 markers on chromosome 18 across all families using ALLEGRO. Overall NPL (Srobdom) scores >5 were obtained with markers on 18p, and Z(lr) scores >/=2.5 on 18p and proximal 18q. Furthermore, pedigree 0006 alone gave an NPL (Srobdom) of 5.35. Overall our results suggest chromosome 18 may harbor a predisposing locus for this disorder, and additional genes may exist.

Dense linkage disequilibrium mapping in the 15q11-q13 maternal expression domain yields evidence for association in autism.

Autism [MIM 209850] is a neurodevelopmental disorder exhibiting a complex genetic etiology with clinical and locus heterogeneity. Chromosome 15q11-q13 has been proposed to harbor a gene for autism susceptibility based on (1) maternal-specific chromosomal duplications seen in autism and (2) positive evidence for linkage disequilibrium (LD) at 15q markers in chromosomally normal autism families. To investigate and localize a potential susceptibility variant, we developed a dense single nucleotide polymorphism (SNP) map of the maternal expression domain in proximal 15q. We analyzed 29 SNPs spanning the two known imprinted, maternally expressed genes in the interval (UBE3A and ATP10C) and putative imprinting control regions. With a marker coverage of 1/10 kb in coding regions and 1/15 kb in large 5' introns, this map was employed to thoroughly dissect LD in autism families. Two SNPs within ATP10C demonstrated evidence for preferential allelic transmission to affected offspring. The signal detected at these SNPs was stronger in singleton families, and an adjacent SNP demonstrated transmission distortion in this subset. All SNPs showing allelic association lie within islands of sequence homology between human and mouse genomes that may be part of an ancestral haplotype containing a functional susceptibility allele. The region was further explored for recombination hot spots and haplotype blocks to evaluate haplotype transmission. Five haplotype blocks were defined within this region. One haplotype within ATP10C displayed suggestive evidence for preferential transmission. Interpretation of these data will require replication across data sets, evaluation of potential functional effects of associated alleles, and a thorough assessment of haplotype transmission within ATP10C and neighboring genes. Nevertheless, these findings are consistent with the presence of an autism susceptibility locus in 15q11-q13.

Deletion of chromosomal region 6q14-16 in prostate cancer.

A detailed analysis of chromosome 6 in DNAs from prostate cancers was performed, to define a region for subsequent search for cancer genes. DNA from 4 prostate cancer cell lines and 11 xenografts was used for CGH and whole-chromosome allelotyping with polymorphic microsatellite markers. Loss of proximal 6q was studied in more detail by high-density allelotyping of xenografts, cell lines and 19 prostate tumour specimens from TURP. Seven of 15 xenografts and cell lines showed deletion of proximal 6q by CGH. Gain of 6q was found in 2 samples. Six samples showed 6p gain, and 1 had 6p loss. Allelotyping results were consistent with CGH data in 11 of 15 DNAs. In LNCaP and DU145 cells, CGH showed 6p loss and 6q loss, respectively, but 2 allelic bands were detected for many polymorphic markers on these chromosome arms. These apparent discrepancies might be explained by aneuploidy. In cell line TSU, allelotyping demonstrated chromosome 6 deletion, which was not clearly detected by CGH, indicating loss of 1 copy of chromosome 6 followed by gain of the retained copy during progressive tumour growth. Loss of heterozygosity was detected in 9 of 19 TURP specimens. Combining all data, we found a common minimal region of loss at 6q14-16 with a length of 8.6 Mbp flanked by markers D6S1609 and D6S417. One hundred and twenty-three STSs, ESTs, genes and candidate genes mapping in this interval were used to screen xenografts and cell lines for HDs, but none was detected. In summary, chromosome region 6q14-16 was deleted in approximately 50% of the prostate cancer specimens analysed. The high percentage of loss underscores the importance of genes within this region in prostate cancer growth.

Small familial supernumerary ring chromosome 2: FISH characterization and genotype-phenotype correlation.

A child and his mother were found to be mosaic for a small supernumerary marker chromosome (SMC) that was identified and characterized by means of fluorescent in situ hybridization. The marker chromosome was derived from the pericentromeric region of chromosome 2; the involvement of proximal 2q was determined by YAC probes. The proband was referred because of psychotic illness and mild mental retardation, whereas his mother presented only minor dysmorphisms. There are only a few published reports concerning SMC(2) or proximal 2q trisomy. We reviewed the previously reported cases in an attempt to establish genotype-phenotype correlations, which are particularly important when SMCs are identified in prenatal diagnosis.

Organisation of the pericentromeric region of chromosome 15: at least four partial gene copies are amplified in patients with a proximal duplication of 15q

Clinical cytogenetic laboratories frequently identify an apparent duplication of proximal 15q that does not involve probes within the PWS/AS critical region and is not associated with any consistent phenotype. Previous...

Novel evidence of a role for chromosome 1 pericentric heterochromatin in the pathogenesis of B-cell lymphoma and multiple myeloma.

1q rearrangement is a remarkably frequent secondary chromosomal change in both non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM), where it is associated with tumor progression. To gain insight into 1q rearrangement-associated disease mechanisms, we used fluorescence in situ hybridization (FISH) to search for recurring 1q breaks in 35 lymphoma samples (31 NHL patients and 4 lymphoma-derived cell lines) as well as 22 MM patients with cytogenetically determined 1q abnormalities. Strikingly, dual-color FISH analysis with chromosome 1 centromere and 1q12-specific probes identified constitutive heterochromatin band 1q12 as the single most frequent breakpoint site in both NHL and MM (39% and 89% of 1q breaks, respectively). These rearrangements consistently generated aberrant heterochromatin/euchromatin junctions and gain of 1q12 material. A further 30% of NHL 1q breaks specifically involved two other novel, closely spaced sites (clusters I and II) within a 2.5 Mb region of proximal 1q21 (D1S3620 to D1S3623). A possible association between these sites and NHL subtype was evident; the cluster I rearrangement was frequent in follicular and diffuse large cell lymphoma, whereas the cluster II rearrangement was more frequently observed in diffuse small-cell lymphoma (2/2 marginal zone lymphomas, 1/2 atypical chronic lymphocytic leukemias, and 1 lymphoplasmacytic lymphoma in this series). Candidate oncogenes bordering this interval (BCL9 and AF1Q) were not rearranged in any patient except one (AF1Q). This study provides the first evidence of involvement of 1q12 constitutive heterochromatin in the pathogenesis of NHL and MM and indicates proximal 1q21 to be of specific pathological significance in NHL.

A necdin/MAGE-like gene in the chromosome 15 autism susceptibility region: expression, imprinting, and mapping of the human and mouse orthologues

BackgroundProximal chromosome 15q is implicated in neurodevelopmental disorders including Prader-Willi and Angelman syndromes, autistic disorder and developmental abnormalities resulting from chromosomal deletions or duplications. A subset of genes in this region are subject to genomic imprinting, the expression of the gene from only one parental allele.ResultsWe have now identified the NDNL2 (also known as MAGE-G) gene within the 15q autistic disorder susceptibility region and have mapped its murine homolog to the region of conserved synteny near necdin (Ndn) on mouse Chr 7. NDNL2/MAGE-G is a member of a large gene family that includes the X-linked MAGE cluster, MAGED1 (NRAGE), MAGEL2 and NDN, where the latter two genes are implicated in Prader-Willi syndrome. We have now determined that NDNL2/Ndnl2 is widely expressed in mouse and human fetal and adult tissues, and that it is apparently not subject to genomic imprinting by the PWS/AS Imprinting Center.ConclusionAlthough NDNL2/MAGE-G in the broadly defined chromosome 15 autistic disorder susceptibility region, it is not likely to be pathogenic based on its wide expression pattern and lack of imprinted expression.