D8S7 is consistently deleted in inverted duplications of the short arm of chromosome 8 (inv dup 8p)

Ten patients with inverted duplication of 8p (inv dup 8p) were studied with cytogenetic, biochemical and molecular techniques. The duplication for the region 8p12-p22 was always associated with a deletion of the locus D8S7 (mapped in 8p23.1) as demonstrated with the probe pSW50 by both in situ hybridization and Southern blot. Restriction fragment length polymorphisms detected by probes pSW50 (1 case) and by pG2LPL35 (locus LPL) (two cases) were informative as to a maternal origin of the anomaly. The activity of glutathione reductase, whose gene maps in the duplicated region at 8p21.1, was increased in all patients. The recognizable phenotype of inv dup 8p includes neonatal hypotonia, prominent forehead, large mouth with everted lower lip, abnormally shaped large ears, brain malformations and severe mental retardation. Our findings indicate that the chromosome rearrangement is homogeneous at least for the presence of the deletion and support the hypothesis of a common mechanism of origin.     

A fetus with recombinant of chromosome 8 inherited from her carrier father

Summary A pericentric inversion of chromosome 8, inv(8)(p23q22), in a male carrier resulted in an unbalanced recombinant, rec(8)dup q, inv(8)(p23q22), which was diagnosed prenatally. The features seen in the aborted fetus resembled the features seen in a previously affected child who received the identical recombinant from her carrier mother. In this particular inversion involving chromosome 8, both male and female carriers risk producing an unbalanced progeny. Different familial pericentric inversions are reviewed for the presence or absence of unbalanced recombinants.     

Olfactory receptor-gene clusters, genomic-inversion polymorphisms, and common chromosome rearrangements

The olfactory receptor (OR)-gene superfamily is the largest in the mammalian genome. Several of the human OR genes appear in clusters with > or = 10 members located on almost all human chromosomes, and some chromosomes contain more than one cluster. We demonstrate, by experimental and in silico data, that unequal crossovers between two OR gene clusters in 8p are responsible for the formation of three recurrent chromosome macrorearrangements and a submicroscopic inversion polymorphism. The first two macrorearrangements are the inverted duplication of 8p, inv dup(8p), which is associated with a distinct phenotype, and a supernumerary marker chromosome, +der(8)(8p23.1pter), which is also a recurrent rearrangement and is associated with minor anomalies. We demonstrate that it is the reciprocal of the inv dup(8p). The third macrorearrangment is a recurrent 8p23 interstitial deletion associated with heart defect. Since inv dup(8p)s originate consistently in maternal meiosis, we investigated the maternal chromosomes 8 in eight mothers of subjects with inv dup(8p) and in the mother of one subject with +der(8), by means of probes included between the two 8p-OR gene clusters. All the mothers were heterozygous for an 8p submicroscopic inversion that was delimited by the 8p-OR gene clusters and was present, in heterozygous state, in 26% of a population of European descent. Thus, inversion heterozygosity may cause susceptibility to unequal recombination, leading to the formation of the inv dup(8p) or to its reciprocal product, the +der(8p). After the Yp inversion polymorphism, which is the preferential background for the PRKX/PRKY translocation in XX males and XY females, the OR-8p inversion is the second genomic polymorphism that confers susceptibility to the formation of common chromosome rearrangements. Accordingly, it may be possible to develop a profile of the individual risk of having progeny with chromosome rearrangements.     

Partial monosomy 8p and partial trisomy 8p with moderate mental retardation.

A female patient with mosaicism for partial monosomy 8p and partial trisomy 8p is presented. Her karyotype is 46,XX, del(8)(p21)/46,XX, dup(8)(p21----pter). She showed minimal dysmorphic features, agenesis of the corpus callosum and moderate developmental delay. There is no previous report of mosaicism for partial monosomy and partial trisomy 8p. The clinical findings in the presently described patient are less severe than those reported in cases with only monosomy or trisomy of the distal part of chromosome 8.     

Cloning, sequencing, and analysis of inv8 chromosome breakpoints associated with recombinant 8 syndrome

Rec8 syndrome (also known as "recombinant 8 syndrome" and "San Luis Valley syndrome") is a chromosomal disorder found in individuals of Hispanic descent with ancestry from the San Luis Valley of southern Colorado and northern New Mexico. Affected individuals typically have mental retardation, congenital heart defects, seizures, a characteristic facial appearance, and other manifestations. The recombinant chromosome is rec(8)dup(8q)inv(8)(p23.1q22.1), and is derived from a parental pericentric inversion, inv(8)(p23.1q22.1). Here we report on the cloning, sequencing, and characterization of the 8p23.1 and 8q22 breakpoints from the inversion 8 chromosome associated with Rec8 syndrome. Analysis of the breakpoint regions indicates that they are highly repetitive. Of 6 kb surrounding the 8p23.1 breakpoint, 75% consists of repetitive gene family members-including Alu, LINE, and LTR elements-and the inversion took place in a small single-copy region flanked by repetitive elements. Analysis of 3.7 kb surrounding the 8q22 breakpoint region reveals that it is 99% repetitive and contains multiple LTR elements, and that the 8q inversion site is within one of the LTR elements.     

Genetic risk for recombinant 8 syndrome and the transmission rate of balanced inversion 8 in the Hispanic population of the southwestern United States.

A rec(8) dup(q) syndrome, secondary to a pericentric inversion--inv(8)(p23q22)--has been identified in 26 probands from Hispanic kindreds in the southwestern United States. The clinical phenotype of the Hispanic rec(8) syndrome includes a dysmorphic facies, cardiovascular and urinary-tract malformations, and mental retardation. Segregation analysis utilizing pedigree and cytogenetic data from 31 kindreds including five additional kindreds from additional sources has provided computation of genetic risks for counseling. An inv(8) carrier parent has a 6.2% risk of having a rec(8) child. The transmission rate of the inv(8) was significantly higher for inv(8) carrier mothers (59%) than for carrier fathers (42%). The combined transmission rate for both sexes was 53%. Risk for spontaneous abortion or stillbirth (11.3%) was not higher than the general population frequency of 13%-15%. It is significant that all kindreds identified to date are of Hispanic background with ancestors traced to the southern Colorado/northern New Mexico region. By means of extended pedigree information, three independently ascertained kindreds have been linked through common ancestry 4 generations in ascendance. The Hispanic background, geographic localization, and common ancestry in three kindreds suggest a single founder of the Hispanic inv(8) in the Southwest.     

Interstitial dup(1p) and severe intrauterine growth retardation

An 1,860 g baby girl was born spontaneously after a 38 weeks pregnancy with important foetal hypotrophy and died at 6 weeks of life. She had an inverted duplication of a small part of the short arm of chromosome 1p:46, XX, inv dup(1) (pter p31::p11p13::p31 ter). This observation is compared to three others reported in the literature with intrachromosomal duplication of 1p.     

Two complementary recombinant chromosomes 5 in a healthy woman

We report a healthy woman with two abortions who is a carrier for a rare heterozygous double recombinant of an inv(5) chromosome, karyotype 46,XX,rec(5)dup(5p) inv(5)(p13q22),rec(5)dup(5q)inv(5)(p13q22). Her father had a 46,XY,inv(5)(p13q22) karyotype; his consanguineous wife had died. Molecular investigation of 11 highly polymorphic markers spanning chromosome 5 revealed biparental inheritance for two markers (D5S406, D5S681) on 5p15.3 and 5q13.1, and an allele constellation not compatible with paternal heterodisomy for marker D5S623 on 5q11.2. Eight markers were not informative. Three mechanisms of formation are proposed: First, fertilization of a normal oocyte by a sperm carrying the two recombinant chromosomes 5, followed by postzygotic recombination between the normal maternal homologue and the rec(5)dup(5p), and by loss of the mitotically recombined maternal homologue, leading to segmental paternal heterodisomy 5q13-->qter (trisomic rescue). Second, postzygotic recombination in a 46,XX,inv(5)(p13q22) zygote resulting in the 46,XX,rec(5)dup(5p)inv(5)(p13q22),rec(5) dup(5q)inv(5)(p13q22) karyotype, followed by absence of the original cell line in lymphocytes. Third and most likely, both parents were inv(5) carriers and complementary recombinations in maternal and paternal meiosis resulted in a zygote with two recombinant chromosomes 5. Our patient refused any further studies but later reported the birth of a phenotypically normal child. This is the first report known to us of complementation by two non-homologous recombinant chromosomes in a phenotypically normal woman, and the first example of a child born to a carrier of complementary recombinant chromosomes.     

Inverted distal duplication of the long arm of chromosome 8: borderline intelligence and discrete dysmorphic syndrome.

In this report, we describe an 11-years-old girl with inverted duplication in the distal part of the long arm of chromosome 8 (inv dup(8)(q24.11----q24.3). The most remarkable finding is her borderline intelligence and her nearly normal phenotype.     

Molecular cytogenetic characterization of the first reported case of an inv dup (4p)(p15.1-pter) with a concomitant 4q35.1-qter deletion and normal parents

Inverted duplications associated with terminal deletions are complex anomalies described in an increasing of chromosome ends. We report on the cytogenetic characterization of the first de novo inv dup del(4) with partial 4p duplication and 4q deletion in a girl with clinical signs consistent with “recombinant 4 syndrome”. This abnormality was suspected by banding, but high-resolution molecular cytogenetic investigations allowed us to define the breakpoints of the rearrangement. The terminal duplicated region extending from 4p15.1 to the telomere was estimated to be 29.27 Mb, while the size of the terminal deletion was 3.114 Mb in the 4q35.1 region. Until now, 10 patients with duplicated 4p14-p15 and deleted 4q35 chromosome 4 have been described. In all cases the abnormal chromosome 4 was derived from a pericentric inversion inherited from one of the parents. In conclusion, we have identified the first case of inv dup del(4) with normal parents suggesting that, often, terminal duplications or terminal deletions mask complex rearrangements.     

The coagulation factor VII regulator is located on 8p23.1

Summary Cytogenetic and coagulation studies have been performed on two patients with different abnormalities of chromosome 8, i.e. del(8p23.1pter) and dup(8q23.1qter). Results confirm the existence of a regulatory mechanism for clotting factor VII on chromosome 8 and define its location to the p23.1p23.2 region.     

Recombination aneusomy of subtelomeric regions of chromosome 5, resulting from a large familial pericentric inversion inv(5)(p15.33q35.3)

We present a family with three cases of recombination aneusomy rec(5)dup(5q) originating from a large parental pericentric inversion of chromosome 5. The proband--a 6-year-old girl with mental retardation, speech delay, microcephaly, and slight facial dysmorphism--was referred for subtelomere testing. FISH with a Multiprobe Chromoprobe T System (CytoCell) and with several BAC clones mapping to both subtelomere regions of chromosome 5, revealed a recombinant chromosome rec(5)dup(5q) originating from a paternal pericentric inversion inv(5)(p15.33q35.3). The same inversion was present in the proband's father's twin-brother and rec(5)dup(5q) was also identified in his two mentally retarded daughters. The distance of breakpoints from the telomere was: 0.234-1.4 Mb for 5p and 4.1-4.8 Mb for 5q. HR-CGH analysis confirmed the duplication of the 5q subtelomeric region but did not identify any concomitant deletion in the 5p subtelomere. Precise mapping of the aneusomic regions in the proband enabled mapping the cat cry and speech delay to 5p15.33, making the earlier localizations of these features more precise. Our family shows that the large pericentric inversion with both breakpoints at subtelomeric regions of chromosome 5 is associated with a high risk of rec(5)dup(5q) in the progeny.     

Isolation and molecular analysis of inv dup(15) and construction of a physical map of a common breakpoint in order to elucidate their mechanism of formation

An inverted duplication of chromosome 15 [inv dup(15)] is the most common supernumerary marker chromosome, comprising approximately 50% of all chromosomes in this class. Structurally, the inv dup(15) is a mirror image with the central axis defining a distal break within either the heterochromatic alpha-satellite array or along the euchromatin in the long (q) arm of the chromosome. There are several types of inv dup(15), classified by the amount of euchromatic material present. Generally, they are bisatellited, pseudodicentric and have a breakpoint in 15q11-q14. A suggested mechanism of formation of inv dup(15) involves illegitimate recombination between homologous chromosomes followed by nondisjunction and centromere inactivation. The proximal portion of chromosome 15 contains several low-copy repeat sequence families and it has been hypothesized that errors in pairing among these repeats may result in structural rearrangements of this chromosome including the inv dup(15). To test this hypothesis and to determine the mechanism of formation, the inv dup(15) from four cases was isolated in somatic cell hybrids and polymerase chain reaction microsatellite markers were used to determine the origin of exchange. Two appeared to result from interchromosomal and two from intrachromosomal exchange, one of which occurred post-recombination. In addition, a detailed physical map of the breakpoint region in the largest inv dup(15) was constructed placing eight new sequence-tagged sites and ten new bacterial artificial chromosome markers in the region.     

Possible intrachromosomal duplication in a case of trisomy 9p

Summary A 5-year-old boy with multiple minor anomalies and mental retardation was found to have chromosomal condition of 46,XY,inv dup(9p)(pterp13::p21p24::p13qter). The clinical features of the propositus fit well with those of trisomy 9p which have been established to be a clinical entity.     

Duplication of chromosome 10p: confirmation of regional assignments of platelet-type phosphofructokinase.

A proband, clinically thought to have trisomy 10p, was found to have an inverted duplication of 10p [46, XY, inv dup(10)(qter----p15.3::p15.3----p 11.1:)]. The phenotypic findings and cytogenetic observations were supported by relevant biochemical studies. The activity of phosphofructokinase (platelet-type; PFKP), previously localized to 10p, and hexokinase-I (HKI), putatively on 10p, demonstrated 153% and 149% of control activity in the proband's fibroblasts. These gene-dosage effects confirmed the clinical and cytogenetic observations as well as the localization of HKI to 10p. Additionally, phosphofructokinase (PFK) and hexokinase (HK), which are control points in the glycolytic pathway, were shown to be syntenic.     

Cytogenetic and molecular characterization of inverted duplicated chromosomes 15 from 11 patients.

We have studied the inverted duplicated chromosomes 15 (inv dup(15)) from 11 individuals--7 with severe mental retardation and seizures, 3 with a normal phenotype, and 1 with Prader-Willi syndrome (PWS). Through a combination of FISH and quantitative DNA analyses, three different molecular sizes of inv dup(15) were identified. The smallest inv dup(15) was positive only for the centromeric locus D15Z1 (type 1); the next size was positive for D15Z1 and D15S18 (type 2); and the largest inv dup(15) was positive for two additional copies of loci extending from D15Z1 and D15S18 through D15S12 (type 3). Type 1 or type 2 was observed in the three normal individuals and the PWS patient. Type 3 was observed in all seven individuals with mental retardation and seizures but without PWS or Angelman Syndrome (AS). The PWS patient, in addition to being mosaic for a small inv dup(15), demonstrated at D15S63 a methylation pattern consistent with maternal uniparental inheritance of the normal chromosomes 15. The results from this study show (a) two additional copies of proximal 15q loci, D15S9 through D15S12, in mentally retarded patients with an inv dup(15) but without AS or PWS and (b) no additional copies of these loci in patients with a normal phenotype or with PWS.     

Supernumerary microchromosomes identified as inverted duplications of chromosome 15: A report of three cases

Summary Supernumerary bisatellited microchromosomes detected in three unrelated patients were identified as inverted duplications of chromosome 15. Each of these chromosomes contained a small euchromatic interstitial band presumably derived from the proximal portion of region 15q1. The clinical significance of this material was difficult to assess. Two of our cases were ascertained as the result of routine amniotic fluid studies. One of the affected fetuses had an unusual form of mosaicism 46,XY/48,XY, + inv dup(15), + inv dup(15), but no apparent developmental abnormalities. The inv dup (15) of the second fetus was familial in origin; no phenotypic abnormalities or evidence of mosaicism were detected in the carrier parent. The third inv dup(15) was found in a 20.5-month-old boy referred for developmental retardation. The clinical findings in this case were similar to those seen in patients with large inv dup(15)'s and did not suggest Prader-Willi syndrome.     

Molecular cytogenetic evidence for a common breakpoint in the largest inverted duplications of chromosome 15.

Chromosomes from 20 patients were used to delineate the breakpoints of inverted duplications of chromosome 15 (inv dup[15]) that include the Prader-Willi syndrome/Angelman syndrome (PWS/AS) chromosomal region (15q11-q13). YAC and cosmid clones from 15q11-q14 were used for FISH analysis, to detect the presence or absence of material on each inv dup(15). We describe two types of inv dup(15): those that break between D15S12 and D15S24, near the distal boundary of the PWS/AS chromosomal region, and those that share a breakpoint immediately proximal to D15S1010. Among the latter group, no breakpoint heterogeneity could be detected with the available probes, and one YAC (810f11) showed a reduced signal on each inv dup(15), compared with that on normal chromosomes 15. The lack of breakpoint heterogeneity may be the result of a U-type exchange involving particular sequences on either homologous chromosomes or sister chromatids. Parent-of-origin studies revealed that, in all the cases analyzed, the inv dup(15) was maternal in origin.     

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. Received: 23 May 1996 / Revised: 7 August 1996     

Small supernumerary marker chromosome (sSMC) derived from chromosome 22 in an infertile man with hypogonadotropic hypogonadism

We describe the first case of a supernumerary inv dup(22)(q11.1) in an infertile male with hypogonadotropic hypogonadism. This case supports the opinion that supernumerary inv dup(22)(q11.1) could play a role in male infertility. We suggest that the breakpoint in the region 22q11.1 and/or fourfold dosage of centromeric/pericentromeric sequences of the chromosome 22 may be the cause of hypogonadotropic hypogonadism resulting in impaired spermatogenesis and infertility in our patient.