Proximal 15q Research Articles

Trisomy 2q11.2-->q21.1 resulting from an unbalanced insertion in two generations.

In this communication, we describe two cases of proximal 2q trisomy (2q11.2--> q21.1) resulting from an interchromosomal insertion. The chromosomal origin of the insertion was confirmed by fluorescence in situ...

Prader-Willi and Angelman Syndromes: Disorders of Genomic Imprinting

Prader-Willi and Angelman syndromes are 2 clinically distinct disorders associated with multiple anomalies and mental retardation. They are only discussed together because they share a similar and uncommon genetic basis: they involve genes that are located in the same region in the genome and are characterized by genetic imprinting. This normal process has contributed to these 2 complex and severe conditions through inactivation of 1 copy of the genes relevant to each disorder: the maternally derived copy of genes for Prader-Willi syndrome in proximal 15q are normally silent, and a paternally derived copy of 1 gene for Angelman syndrome in 15q is normally silent. For both disorders, when the normally active copy of the gene or genes is missing, abnormality results. Since the genes for these 2 disorders are located very close together, and since the center involved in inactivating the genes involved in imprinting may be the same, both these disorders usually result from the same chromosomal deletion; which disorder results depends on the parent of origin of the chromosome 15 that becomes deleted. Both Prader-Willi and Angelman syndrome can also occur as a result of having both members of the chromosome 15 pair derived from 1 parent, a condition known as uniparental disomy. Both can also result from a structural abnormality of the imprinting center, known as an imprinting mutation. In addition, Angelman syndrome can be caused by a mutation in the gene that causes it; a comparable cause is not present in Prader-Willi syndrome since it results from abnormality in more than 1 gene. Finally, despite the complexity of possible causes, all but the single gene mutation of the Angelman syndrome gene can be detected through methylation-sensitive DNA probes, since DNA methylation is the process by which the genes for these 2 disorders are imprinted. This unusual property of specific areas of the DNA holds promise for future treatment of these and other disorders related to imprinting through reversal of the imprinting process.

Unusual features in children with inv dup(15) supernumerary marker: a study of genotype-phenotype correlation in Taiwan.

Recent molecular cytogenetic studies have elucidated the origin and nature of extra structurally abnormal chromosomes (ESACs) or small supernumerary chromosomes, which are often associated with developmental delay and malformations. We studied the prevalence of inv dup(15) in a nationwide screening programme for mentally retarded children in Taiwan and tried to correlate the genotype and phenotype in those patients. Fluorescence in situ hybridization (FISH) analysis using D15Z, D15Z1, and the cosmids from the Prader-Willi/Angelman syndrome chromosome region (PW/ASCR) was performed on 54 patients (0.45%) with ESACs from 11893 probands within a 5-year period. Of them, inv dup(15) was confirmed in 25 children (46.3%) by FISH analysis. The PW/ASCR probes were used to clarify the size and DNA composition of the markers. Patients with inv dup(15) chromosomes, containing only the heterochromatin or little euchromatin of the proximal 15q (i.e., pter-->q11:q11-->pter) may have a rather mild or nearly normal phenotype (group 1). Only one patient had some features suggestive of Angelman syndrome, but was considered to be a result of deleted (15)(q12) in the chromosome 15 homologue. Additional copies within D15S11 through GABRB3 (15q11.2-13) resulted in an abnormal phenotype which involved mental and developmental delay but was different from the classical phenotype of PW/AS (groups 2, 3). Signs of autistic behavior did occur in each group. FISH combined with microsatellite analyses showed that the marker was often of maternal origin in de novo cases (n = 12, 86%), or inherited from the mother in only one familial case. Down-inv dup(15) was mentioned in two cases. Unusual features including diaphragmatic eventration, hyperlaxity of joints, arachnodactyly, brain atrophy, epilepsy (particularly infantile spasm), ataxia, genital abnormalities, and cleft lip/palate were noted in those patients. This observation expands the range of phenotypic expression associated with this relatively common ESAC. Marked phenotypic diversities exist in children with inv dup(15), dependent upon the size or genetic composition of the markers, degree of mosaicism, parental origin and familial occurrence or not. Patients with a larger inv dup(15) marker chromosome including the PW/ASCR may have a higher risk of abnormalities, but not the typical Prade-Willi/Angelman syndrome phenotype.

Genetics of autism

Autism is influenced by complex, yet strong genetic factors. The strongest evidence for genetic factors comes from twin studies that show a high concordance for autism in monozygotic twins and relatively small concordance in dizygotic twins. The strong decrease in risk from monozygotic twins to dizygotic twins and siblings suggests that two or more genes interact to contribute to autism susceptibility. Statistical modeling of the genetics of autism suggests that two to five susceptibility genes are acting in concert. The recurrence risk for siblings (4.5%) is 45–90 times greater than the population risk (0.05–0.1%), providing further evidence for a complex and strong genetic contribution. In addition to an increased risk of autism for relatives, relatives have been found to have an increased frequency of lesser variants of autism including social, language, and cognitive difficulties. Autism has been associated with several single gene disorders, particularly tuberous sclerosis. Several chromosomal abnormalities have been identified in autism, including the fragile X syndrome, Down's syndrome, and Turner's syndrome. More recently, duplications of the Prader-Willi/Angelman syndrome region of proximal 15q have been reported in patients with autism. The parent of origin of such proximal 15q duplications may influence the risk for autism. Because of the similarity of the phenotype of 15q11–13 duplications in typical autism, linkage analysis has been conducted in autism, and linkage and linkage disequilibrium have been reported for markers on 15q11–13. Several genome-wide screens are under way, with the first full report suggesting a potential susceptibility locus on 7q. Heterogeneity and the multiplicative nature of autism susceptibility genes increase the number of families needed to demonstrate and replicate linkage. Conversely, when susceptibility genes are identified, there will be several potential targets for conventional pharmacotherapy, which often modifies gene expression, as well as direct gene therapy. MRDD Research Reviews 1998;4:113–120. © 1998 Wiley-Liss, Inc.

Genetics of autism

Autism is influenced by complex, yet strong genetic factors. The strongest evidence for genetic factors comes from twin studies that show a high concordance for autism in monozygotic twins and relatively small concordance in dizygotic twins. The strong decrease in risk from monozygotic twins to dizygotic twins and siblings suggests that two or more genes interact to contribute to autism susceptibility. Statistical modeling of the genetics of autism suggests that two to five susceptibility genes are acting in concert. The recurrence risk for siblings (4.5%) is 45–90 times greater than the population risk (0.05–0.1%), providing further evidence for a complex and strong genetic contribution. In addition to an increased risk of autism for relatives, relatives have been found to have an increased frequency of lesser variants of autism including social, language, and cognitive difficulties. Autism has been associated with several single gene disorders, particularly tuberous sclerosis. Several chromosomal abnormalities have been identified in autism, including the fragile X syndrome, Down's syndrome, and Turner's syndrome. More recently, duplications of the Prader-Willi/Angelman syndrome region of proximal 15q have been reported in patients with autism. The parent of origin of such proximal 15q duplications may influence the risk for autism. Because of the similarity of the phenotype of 15q11–13 duplications in typical autism, linkage analysis has been conducted in autism, and linkage and linkage disequilibrium have been reported for markers on 15q11–13. Several genome-wide screens are under way, with the first full report suggesting a potential susceptibility locus on 7q. Heterogeneity and the multiplicative nature of autism susceptibility genes increase the number of families needed to demonstrate and replicate linkage. Conversely, when susceptibility genes are identified, there will be several potential targets for conventional pharmacotherapy, which often modifies gene expression, as well as direct gene therapy. MRDD Research Reviews 1998;4:113–120. © 1998 Wiley-Liss, Inc.

Inherited Interstitial Duplications of Proximal 15q: Genotype-Phenotype Correlations

We present the cytogenetic, molecular cytogenetic, and molecular genetic results on 20 unrelated patients with an interstitial duplication of the proximal long arm of chromosome 15. Multiple probes showed that the Prader-Willi/Angelman critical region (PWACR) was included in the duplication in 4/20 patients, each ascertained with developmental delay. The duplication was also found in two affected but not in three unaffected sibs of one of these patients. All four probands had inherited their duplication from their mothers, three of whom were also affected. Two of the affected mothers also carried a maternally inherited duplication, whereas the duplication in the unaffected mother and in an unaffected grandmother was paternal in origin, raising the possibility of a parental-origin effect. The PWACR was not duplicated in the remaining 16 patients, of whom 4 were referred with developmental delay. In the 14 families for which parental samples were available, the duplication was inherited with equal frequency from a phenotypically normal parent, mother or father. Comparative genomic hybridization undertaken on two patients suggested that proximal 15q outside the PWACR was the origin of the duplicated material. The use of PWACR probes discriminates between a large group of duplications of no apparent clinical significance and a smaller group, in which a maternally derived PWACR duplication is consistently associated with developmental delay and speech difficulties but not with overt features of either Prader-Willi syndrome or Angelman syndrome.

A molecular and FISH approach to determining karyotype and phenotype correlations in six patients with supernumerary marker(22) chromosomes.

In a cytogenetic, molecular, and clinical study of patients with autosomal supernumerary marker chromosomes (SMC), 6 out of 72 (8.3%) were shown by fluorescence in situ hybridisation (FISH) to be derived from chromosome 22. PCR microsatellite analysis and FISH using primers and cosmids from proximal 22q showed 3 of the 6 to contain euchromatin. The first, a de novo nonmosaic bisatellited, dicentric SMC, was acsertained in a patient with cat eye syndrome and Duane anomaly. Microsatellite analysis showed the SMC was maternal in origin with euchromatin extending to D22S427, i.e., proximal to the DiGeorge syndrome critical region (DGSCR). The second, a nonmosaic bisatellited, dicentric marker, was found in a child with severe hypotonia and developmental delay and had been inherited from the patient's phenotypically normal father. FISH showed the SMC to contain euchromatin extending into the DGSCR. The third, a de novo SMC, was ascertained antenatally and was shown to contain 22q euchromatin extending distal to the DGSCR. The 19-week terminated fetus was phenotypically normal at autopsy. Two of the three SMC(22)s not containing detectable proximal 22q euchromatin were ascertained coincidentally in phenotypically normal individuals, whereas the third, the only mosaic with a minority euploid cell line, was found in a patient with mild developmental delay. These results suggest that SMC(22)s devoid of proximal 22q euchromatin are not associated with adverse phenotypic effects whereas SMC(22)s containing euchromatin may be found in individuals with phenotypes ranging from cat eye syndrome to normal.

Prader-Willi syndrome.

Prader-Willi syndrome is a complex disorder affecting multiple systems with many manifestations relating to hypothalamic insufficiency. Major findings include infantile hypotonia, developmental delay and mental retardation, behaviour disorder, characteristic facial...

The necdin gene is deleted in Prader-Willi syndrome and is imprinted in human and mouse.

Human chromosome 15q11-q13 contains genes that are imprinted and expressed from only one parental allele. Prader-Willi syndrome (PWS) is due to the loss of expression of one or more paternally expressed genes on proximal human chromosome 15q, most often by deletion or maternal uniparental disomy. Several candidate genes and a putative imprinting centre have been identified in the deletion region. We report that the human necdin-encoding gene (NDN) is within the centromeric portion of the PWS deletion region, between the two imprinted genes ZNF127 and SNRPN. Murine necdin is a nuclear protein expressed exclusively in differentiated neurons in the brain. Necdin is postulated to govern the permanent arrest of cell growth of post-mitotic neurons during murine nervous system development. We have localized the mouse locus Ndn encoding necdin to chromosome 7 in a region of conserved synteny with human chromosome 15q11-q13, by genetic mapping in an interspecific backcross panel. Furthermore, we demonstrate that expression of Ndn is limited to the paternal allele in RNA from newborn mouse brain. Expression of NDN is detected in many human tissues, with highest levels of expression in brain and placenta. NDN is expressed exclusively from the paternally inherited allele in human fibroblasts. Loss of necdin gene expression may contribute to the disorder of brain development in individuals with PWS.

Clinical and Genetic Evidence for Autosomal Dominant North Carolina Macular Dystrophy in a German Family

To describe a German family with clinical and genetic evidence of autosomal dominant North Carolina macular dystrophy. Twenty-six individuals from a five-generation family from northern Germany were investigated clinically. In addition, we performed genetic linkage analyses using polymorphic markers from proximal 6q. The affected family members showed clinical abnormalities consistent with North Carolina macular dystrophy including multiple drusen, choroidal neovascularization in one patient, and geographic atrophy in elderly patients. The DNA analyses demonstrated significant linkage to the North Carolina macular dystrophy locus on chromosome 6q14-q16.2. Our findings provide strong evidence of a German pedigree with an autosomal dominant macular dystrophy manifesting with clinical abnormalities consistent with North Carolina macular dystrophy.

Proximal interstitial 6q deletion: A recognizable syndrome

We report on an 8-year-old boy with a proximal interstitial deletion of the long arm of chromosome 6 with breakpoints q13 to q14.2. He has a characteristic facial appearance that is seen in several of the previously described cases. Details of his clinical course are reviewed and compared with the nine previous reported cases of the proximal deletion 6q syndrome.

Proximal interstitial 6q deletion: A recognizable syndrome

Proximal interstitial 6q deletion: A recognizable syndrome

Delayed diagnosis in patients with Prader-Willi syndrome due to maternal uniparental disomy 15

Prader-Willi syndrome (PWS) results from absence of the normally active paternally inherited genes on proximal 15q, due to del(15)(q11q13) or by maternal uniparental disomy (UPD) 15 in most cases. In addition to a higher frequency of hypopigmentation among deletion patients, minor phenotypic differences between deletion and UPD patients have recently been reported, including lower birth weight in the deletion group, shorter birth length in males with UPD, and shorter course of gavage feeding and later onset of hyperphagia in females with UPD. We previously reported that those with UPD had a less "typical" facial appearance, and they less often had skin picking, skill with puzzles, and high pain threshold. There were no children younger than 3.5 years of age in the UPD group, in contrast to several of them in the deletion group, suggesting a possible diagnostic delay in the UPD group. To assess this possibility and seek reasons for it, we reviewed the charts of 60 PWS patients with complete molecular testing. Mean age at diagnosis of patients with UPD was significantly higher than in the deletion group. Mean percentiles of birth weights and lengths of patients with UPD were significantly lower than in those with deletion. Mean duration of gestation, mean duration of gavage feeding, and mean age at onset of hyperphagia did not differ significantly between groups. Delay in the diagnosis of patients with UPD, which may influence the management and impact of the disorder, might be explained by a lower frequency of typical facial anomalies in this group.

Inherited DNA amplification of the proximal 15q region: cytogenetic and molecular studies.

In a 15 year old girl, referred for growth retardation, conventional cytogenetic analysis detected an abnormal 15q+ chromosome with extra material in the proximal region, inherited from her father and...

Refined molecular characterization of the breakpoints in small inv dup(15) chromosomes.

Inv dup(15) is the most common supernumerary marker chromosome in humans. To investigate the mechanism responsible for this frequent chromosome rearrangement, we characterized the breakpoints in 18 individuals with small inv dup(15) chromosomes [i.e., negative for the Prader-Willi (PWS)/Angelman syndrome (AS) critical region]. Since two proximal breakpoint regions ("hotspots") for PWS/AS deletions have been previously identified with the most proximal 15q markers D15S541/S542 and S543, we hypothesized that formation of the small inv dup(15) chromosomes may involve one or both of these breakpoint hotspots. By analysis with S542, both breakpoint regions were found to be involved in approximately equal frequencies. In ten cases, the inv dup(15) was negative for S542 (Class I), indicating the breakpoint is between the centromere and the most proximal marker on chromosome 15. For the other eight cases, S542 was positive by fluorescence in situ hybridization (5/5) and/or microsatellite analysis (7/7), but S543 was negative (Class II). These two breakpoint regions appear to be the same as the two proximal breakpoints reported in the common PWS/AS deletions. To initiate cloning and sequencing of the Class II breakpoint, the gap in the yeast artificial chromosome (YAC) contig between S541/S542 and S543 was filled by screening the CEPH YAC and mega-YAC libraries. YACs 705C2 and 368H3 were found to bridge this gap, and therefore contain the more distal breakpoint region. The finding of consistent breakpoints in small inv dup(15), like that found in PWS/AS deletions, provides strong evidence for hotspots for chromosome breakage in this region. In addition, our results show that two extra copies (tetrasomy) of the region from 15cen to the euchromatic region containing S542 are present in individuals with Class II breakpoints. Since most individuals carrying a small inv dup(15) are phenotypically normal, the euchromatin region included in the small inv dup(15) chromosomes does not appear to contain genes with clinically significant dosage effects.

Susceptible chiasmate configurations of chromosome 21 predispose to non-disjunction in both maternal meiosis I and meiosis II.

The cause of non-disjunction of chromosome 21 remains largely unknown. Advanced maternal age is associated with both maternal meiosis I (MI) and meiosis II (MII) non-disjunction events. While reduced genetic recombination has been demonstrated in maternal MI errors, the basis for MII errors remains uncertain. We studied 133 trisomy 21 cases with maternal MII errors to test the hypothesis that segregation at MII may also be influenced by genetic recombination. Our data support a highly significant association: MII non-disjunction involves increased recombination that is largely restricted to proximal 21q. Thus, while absence of a proximal recombination appears to predispose to non-disjunction in MI, the presence of a proximal exchange predisposes to non-disjunction in MII. These findings profoundly affect our understanding of trisomy 21 as they suggest that virtually all maternal non-disjunction results from events occurring in meiosis I.

Proximal trisomy 1q in a girl with developmental delay and minor anomalies.

We report on a girl with developmental delay, macrocephaly, facial asymmetry, small downturned palpebral fissures, high and narrow palate, micrognathia, short neck, a heart defect, and unilateral renal agenesis. Cytogenetic analysis showed a proximal tandem duplication of the long arm of chromosome one (1q12-->q21.3). This abnormality was suggested by G- and C-banding but it was specifically characterized by fluorescent in situ hybridization (FISH). Clinical findings in our patient are compared with those of the literature in an attempt to delineate the phenotype in patients with proximal 1q duplication.

Molecular Analysis of an Extra inv dup(15)(q13) Chromosome in Two Patients with Angelman Syndrome

Angelman syndrome (AS) is caused by the loss of function of yet unidentified gene(s) which map within 15q 11-13 and show monoallelic expression from the maternal allele. Lack of the maternal allele(s), due to either a deletion on the maternal chromosome 15 (about 70% of AS patients) or a paternal uniparental disomy (UPD)15 (<5%), are the most common molecular defects in AS. Prader-Willi syndrome (PWS) also maps to proximal 15q, but is caused by the loss of function of paternally expressed gen(s) [1]. Here we describe clinical, cytogenetic and molecular data for two non-related patients with AS who carry a nonmosaic extra cromosome inv dup(15).

Replication banding and molecular studies of a mosaic, unbalanced dic(X;15)(xpter→xq26.1::15p11→15qter)

We present a patient with a chromosomal mosaicism involving the X chromosome. One cell line is 45,X and the other has a de novo paternally derived dicentric X;15 translocation. Her karyotype is therefore 45,X/45,X,dic(X;15)(Xpter-->Xq26.1::15p11-->15 qter) based on G-banding. The presence of 2 centromeres on the derivative X was confirmed by fluorescence in situ hybridization (FISH) and a deletion of Xq26.1-->qter was confirmed by polymerase chain reaction (PCR) using DXS52 and DXYS154. Replication banding studies indicate that the derivative X is late replicating. Based on these studies, it is unclear whether inactivation has spread to proximal 15q. The patient has a unique phenotype distinct from Ullrich-Turner or Prader-Willi syndromes, but includes ataxia and language delay which are commonly seen in Angelman syndrome. These findings are contrary to those anticipated since deficiency of paternal genes at 15q12 typically leads to Prader-Willi syndrome. Molecular analysis of PCR-based polymorphisms of chromosome 15 and X indicates that uniparental disomy is not present for the X chromosome or chromosome 15 in either cell line. It is hypothesized that her phenotype results from the interaction of the 2 abnormal genotypes. Each abnormality may be diluted by the mosaicism and, in the derivative X line, by the possible variation among cells of inactivation spreading to chromosome 15.

Allelic imbalance of chromosome 6q in ovarian tumours

Previous work has implicated putative tumour-suppressor (ts) genes at 6q27 and a broad region at 6p12-q23. Here we report the results of a coded, randomised study of allelic imbalance at 12 loci on 6q on 40 pairs of coded tumour-blood pairs from patients with ovarian tumours. Our results provide clear evidence for the involvement of different regions of 6q in tumours of different histological subtypes. The involvement in serous tumours of a ts gene at the distal site is confirmed. However, proximal 6q presents a complex picture, with possibly three further ts genes: one at 6q21-23.3 involved at high frequency in benign and endometrioid tumours, another at 6q14-q15, also involved in endometrioid tumours, and a third suggested by a smallest region of deletion at 6q16.3-q21, between D6S275 and D6S300, that appears to be involved in early stage tumours. These observations point the way to a statistical study of the involvement of 6q in tumours of different histological type and staging performed on larger cohorts of samples.