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Familial complex chromosome rearrangement giving rise to balanced and unbalanced recombination products
Abstract
We report on a family ascertained through a 14-month-old girl with a terminal deletion of chromosome 8p23.1. Analysis of the karyotype of other relatives showed that the mother is the carrier of a balanced complex 4-break chromosome rearrangement, which she and her brother inherited from their father following recombination. This complex chromosome rearrangement (CCR) was confirmed by fluorescence in-situ hybridization (FISH) using libraries for chromosomes 1, 8, and 9, and telomeric probes for the long arm of chromosome 9. The karyotype of the maternal grandfather was 46,XY,t(1;8) (p31;q21.1),t(8;9) (p23.1;q34). The karyotype of his daughter is 46,XX,rec(8)t(1;8) (p31;q21.1)t(8;9)(p23.1;q34)pat. The karyotype of the proposita is 46,XX,rec(8)t(8;9) (p23.1;q34)mat, and that of her abnormal elder sister is 46,XX,t(1;8)(p31;q21.1)rec(8) t(8;9) (p23.1;q34)mat,der(9)t(8;9) (p23.1;q34) mat. Unbalanced segregation and/or recombination during maternal meiosis gave rise to the two abnormal sisters, one effectively with 8p trisomy and the other with monosomy for that same 8p segment. To our knowledge, this is the first case of a familial CCR giving rise to unbalanced recombination products.
... Only five were maternally inherited (Bellec and de Perdigo, 1991;Delaroche et al., 1995;Lee et al., 2002;Bourthoumieu et al., 2004;Migliori et al., 2004) and one was inherited from the father (Soler et al., 2005). A significant proportion (45%) of CCRs detected prenatally represents a 're-building' of the initial rearrangement through recombination, giving rise to simpler (Tihy et al., 2005) or more complicated karyotypes (Bass et al., 1985;Masuno et al., 1993;Zahed et al., 1998;Berend et al., 2002;Soler et al., 2005). ...
... The first type constitutes the most common class of CCRs, including cases where three chromosomes break and exchange chromosomal segments. These CCRs are principally familial and can be transmitted from generation to generation (Meer et al., 1981;Farrell et al., 1994;Zahed et al., 1998). The group of exceptional CCRs involves rearrangements in which more than one breakpoint per chromosome is found (Bass et al., 1985;Batanian and Eswara, 1998). ...
... The third type of CCR, the double or triple two-way translocation, must undergo two (or three) separate and independently operating quadrivalent configurations. Several examples of such CCRs have been described in the literature (Tabor et al., 1981;Miller and Flatz, 1984;Zahed et al., 1998;Soler et al., 2005). Bowser-Riley et al. (1988) proposed an empirical risk calculation to assess the segregation mode of both double and triple two-way translocation, based on the principle that each separate translocation risk can be estimated and the extrapolated total risk should be additive. ...
Complex chromosomal rearrangements (CCRs) describe structural rearrangements, essentially translocations, involving at least three breakpoints on two or more chromosomes. Although they are rare in humans, their clinical identification is important since CCR carriers can display various phenotypes which include phenotypically normal subjects, infertile males and patients with mental retardation and/or congenital abnormalities. The rearrangement can be de novo or familial. The use of fluorescent in situ hybridization assays and molecular techniques for the characterization of CCRs have indicated that the rearrangements could be more complex than initially assumed. Accumulating data have revealed that the mechanisms underlying the genesis of CCRs remain elusive.
We performed a large PubMed search in order to summarize the current knowledge in this field and address important aspects of CCR formation and meiotic behavior, highlighting the complexity of these rearrangements at the chromosomal and genomic level.
The review of published data indicates that the complexity of CCRs is becoming increasingly known, thanks to the application of more and more efficient molecular techniques. These approaches have allowed the precise sequence analysis of breakpoints and the identification of insertions, deletions, inversions and recombination events. New models have been proposed for the formation of CCRs, based on replication-based mechanisms and specific sequence elements. Their meiotic behavior has been discussed in the light of these new molecular data.
Despite the increasing understanding of the mechanisms involved in their genesis, CCRs arise as unique, complex events for which the genetic and reproductive counseling of carriers remains a challenge.
... Only five were maternally inherited (Bellec and de Perdigo, 1991;Delaroche et al., 1995;Lee et al., 2002;Bourthoumieu et al., 2004;Migliori et al., 2004) and one was inherited from the father (Soler et al., 2005). A significant proportion (45%) of CCRs detected prenatally represents a 're-building' of the initial rearrangement through recombination, giving rise to simpler (Tihy et al., 2005) or more complicated karyotypes (Bass et al., 1985;Masuno et al., 1993;Zahed et al., 1998;Berend et al., 2002;Soler et al., 2005). ...
... The first type constitutes the most common class of CCRs, including cases where three chromosomes break and exchange chromosomal segments. These CCRs are principally familial and can be transmitted from generation to generation (Meer et al., 1981;Farrell et al., 1994;Zahed et al., 1998). The group of exceptional CCRs involves rearrangements in which more than one breakpoint per chromosome is found (Bass et al., 1985;Batanian and Eswara, 1998). ...
... The third type of CCR, the double or triple two-way translocation, must undergo two (or three) separate and independently operating quadrivalent configurations. Several examples of such CCRs have been described in the literature (Tabor et al., 1981;Miller and Flatz, 1984;Zahed et al., 1998;Soler et al., 2005). Bowser-Riley et al. (1988) proposed an empirical risk calculation to assess the segregation mode of both double and triple two-way translocation, based on the principle that each separate translocation risk can be estimated and the extrapolated total risk should be additive. ...
To directly study the meiotic segregation of a complex reciprocal translocation (CCR) as well as the occurrence of an interchromosomal effect.
In situ sperm fluorescence in situ hybridization (FISH) analysis.
Department of Cytogenetics and INSERM research center.
A male carrier of a balanced complex reciprocal translocation t(5;13;14)(q23;q21;q31).
Sperm samples from the carrier and direct FISH analysis on sperm slide preparations.
Meiotic segregation pattern determined on sperm nuclei and estimation of the incidence of unbalanced spermatozoa and an interchromosomal effect (ICE).
Only 27% of spermatozoa displayed a normal or balanced chromosome complement. The rate of unbalanced sperm was 69.4%, including different types of 3:3, 4:2, and 5:1 segregations. There was no evidence for the occurrence of an interchromosomal effect in autosomal chromosomes, but the gonosomes displayed a statistically significant increase in disomy rates.
These results are consistent with the formation of a hexavalent configuration at the pachytene stage of meiosis and a high prevalence of imbalance production. The mechanisms of formation of CCRs must be examined with regard to these direct results and new molecular data on the formation of genomic rearrangements.
... Only six families with recombination derived from a parental CCR have been reported [4][5][6][7][8][9] In the first five reports all offspring had an apparently balanced karyotype showing maternal transmission, with the exception of one report with paternal transmission. 6 Zahed et al 9 were the second authors to report recombination with paternal transmission leading, for the first time, to offspring with an unbalanced karyotype. ...
... Only six families with recombination derived from a parental CCR have been reported [4][5][6][7][8][9] In the first five reports all offspring had an apparently balanced karyotype showing maternal transmission, with the exception of one report with paternal transmission. 6 Zahed et al 9 were the second authors to report recombination with paternal transmission leading, for the first time, to offspring with an unbalanced karyotype. ...
... So far, at least 60 such cases have been reported. 2,9 These cases can be divided into three groups. 8 1 simple three-way translocations with an additional pericentric inversion in one of the chromosomes; Actually, recombination has been observed in only six of the 60 reports with the possibility of producing recombinant offspring, and all six belong to the group 3 described by Madan et al. 8 The karyotype of the father described in our report also belongs to this group with as many as two chromosomes made up of segments of three different chromosomes (derivative 18 with segments of chromosomes 6, 7, and 18; derivative 21 with segments of chromosomes 7, 18, and 21). ...
We report on a family with a balanced complex chromosomal rearrangement (CCR) involving eight breakpoints between chromosomes 6, 7, 18, and 21 in the father. All three sons inherited one derivative chromosome from the father and in addition each inherited a different recombinant chromosome resulting in a partial trisomy 6q in the first, an apparently balanced karyotype in the second, and a partial trisomy 7q in the third son. Fluorescence in situ hybridisation (FISH) and microsatellite analysis were essential for the identification of the breakpoints. In addition, the results were confirmed by a 24-colour FISH experiment using the spectral karyotyping (SKYtrade mark) system. Paternal origin of the de novo CCR in the father was demonstrated for the first time by haplotype analysis. This is the second report of a CCR leading to simpler but unbalanced translocations in offspring as a consequence of recombination during gametogenesis, and the first report of a family case of CCR exhibiting as many as eight breakpoints in the transmitting carrier. The initial prediction that viable offspring would be quite unlikely had to be revised after the birth of three children. Genetic counselling of carriers of balanced complex rearrangements has to consider a higher probability for unbalanced recombinations than has been so far commonly assumed.
... Estimated reproductive risk is up to 53.7% for abnormal pregnancy outcome or 50% for RSA for CCR carriers. (Gorski et al., 1988;Batista et al., 1994;Cifuentes et al., 1998;Zahed et al., 1998;Fauth et al., 2006). In addition to abnormal segregation due to the parental CCR, there is the possibility of crossing over, which gives rise to live born children with recombinant chromosomal abnormalities, with gain or loss of material or even 'breakage pathology' (Zahed et al., 1998;Rothlisberger et al., 1999). ...
... (Gorski et al., 1988;Batista et al., 1994;Cifuentes et al., 1998;Zahed et al., 1998;Fauth et al., 2006). In addition to abnormal segregation due to the parental CCR, there is the possibility of crossing over, which gives rise to live born children with recombinant chromosomal abnormalities, with gain or loss of material or even 'breakage pathology' (Zahed et al., 1998;Rothlisberger et al., 1999). Moreover, a painting FISH study would not be sensitive enough to demonstrate a subtle deletion produced during paternal meiosis or to identify changes in direct gene position. ...
Complex chromosomal rearrangements (CCRs) are rare events in human pathology and are usually considered to induce severe reproductive impairment by disturbing the meiotic process and producing unbalanced gametes responsible for high reproductive risk. One-third of all CCRs are familial and tend to implicate fewer breakpoints and fewer chromosomes than de novo cases. CCRs are rarely transmitted through spermatogenesis and are primarily ascertained by male infertility. We report a familial balanced CCR, with seven breakpoints involving three chromosomes, which was detected prenatally in a female fetus conceived after intracytoplasmic sperm injection (ICSI) in a couple initially thought to be a carrier of a paternal reciprocal translocation involving two chromosomal breakpoints. Fluorescent in-situ hybridization (FISH) was used to elucidate the complexity of this CCR. The karyotype of the female CCR carrier was balanced and determined as 46,XX.ish t(1;4)(q42;q32)(WCP1+, D1Z5+, WCP4+, D1S3738-, D4S2930+; WCP4+, D4Z1+, WCP1+, D4S2930-, D1S3738+), ins(1;11)(q41;q23q24)(WCP1+,WCP11+, D11S2071-, MLL+; WCP11+, D11S2071+, WCP1-, MLL-), ins(4;11)(q23;q14q23)(WCP4+,WCP11+; WCP11+,WCP4-). The same balanced CCR was confirmed in her oligozoospermic father. We report, to our knowledge, the first case of ICSI performed in an infertile male with CCR, resulting in a balanced CCR carrier female with a normal clinical follow-up at 4 years of age. This particular case stresses the point of the relevance and feasibility of ICSI procedure in cases of balanced CCRs.
... (18) Varios autores han reportado este tipo de RCC como familiar y que podría ser transmitido de generación en generación. (19)(20)(21) En los pacientes estudiados solo podemos definir un hombre con un reordenamiento probablemente denovo, el portador de la t(1;3;20)(q21.1;p21;p12), los cromosomas de sangre periférica de sus padres fueron normales y no se puede descartar un mosaicismo gonadal, en alguno de los progenitores, aunque el mosaicismo de reordenamientos estructurales es un evento infrecuente. ...
Complex chromosomal rearrangements (CCRs) are aberrations involving three or more chromosomes or three or more breakpoints, are extremely rare and approximately more than half are associated with affected phenotypes. Diagnosis is usually made by applying methods such as molecular karyotyping (aCGH) and fluorescence in situ hybridization (FISH). For the cytogenetic analysis we used peripheral blood lymphocyte culture stimulated with phytohemagglutinin using conventional cytogenetic methods
adapted to the conditions of the Cytogenetics Laboratory of the National Center of Medical Genetics.
Fifteen metaphases per patient were analyzed with a resolution of 450 bands per haploid set. The method of classification of the RCCs created by Kausch and collaborators was used. The patients studied came from the Assisted Reproduction Clinic of the Ramón González Coro Hospital where they presented reproductive disorders. They were evaluated in an interdisciplinary consultation and
referred to the cytogenetics laboratory for analysis of their chromosomal complement. In the analysis and genetic counseling of these three patients carrying RCC, all the aspects mentioned above should be taken into consideration, with the obvious limitation in our environment of not having molecular tests available for the detection of some type of cryptic rearrangement or some specific mutation in a
certain gene. However, with the use of conventional cytogenetic methods, personalized genetic counseling can be established for each RCC carrier, taking into account the chromosomes involved, the breakpoint, the size of the translocated segment and the possible genes involved in the breakpoint.
... (18) Varios autores han reportado este tipo de RCC como familiar y que podría ser transmitido de generación en generación. (19)(20)(21) En los pacientes estudiados solo podemos definir un hombre con un reordenamiento probablemente denovo, el portador de la t(1;3;20)(q21.1;p21;p12), los cromosomas de sangre periférica de sus padres fueron normales y no se puede descartar un mosaicismo gonadal, en alguno de los progenitores, aunque el mosaicismo de reordenamientos estructurales es un evento infrecuente. ...
Los rearreglos cromosómicos complejos (RCC) constituyen aberraciones que involucran tres o más cromosomas o tres o más puntos de rupturas, son extremadamente raros y aproximadamente más de la mitad están asociados a fenotipos afectados. Generalmente el diagnóstico se realiza aplicando métodos como el cariotipo molecular (aCGH) e hibridación in situ por fluorescencia (FISH). Para el análisis citogenético se utilizó cultivo de linfocitos en sangre periférica estimulados con fitohemaglutinina usando los métodos de citogenética convencional y adaptados a las condiciones del Laboratorio de Citogenética del Centro Nacional de Genética Médica. Fueron analizadas 15 metafases por pacientes con una resolución de 450 bandas por set haploide. Se empleó el método de clasificación de las RCC creado por Kausch y colaboradores. Los pacientes estudiados, provenían de la consulta de Reproducción Asistida del Hospital Ramón González Coro donde, acudieron por presentar trastornos reproductivos. Fueron evaluados en consulta interdisciplinaria y se remitieron al laboratorio de citogenética para el análisis de su complemento cromosómico. En el análisis y asesoramiento genético de estos tres pacientes portadores de RCC se deben tomar en consideración todos los aspectos anteriormente mencionados, con la evidente limitación en nuestro medio de no disponer de pruebas moleculares para la detección de algún tipo de reordenamiento críptico o alguna mutación puntual en determinado gen. No obstante, con la utilización de los métodos de la citogenética convencional se puede establecer en cada portador de RCC un asesoramiento genético personalizado teniendo en cuenta los cromosomas implicados, el punto de ruptura, el tamaño del segmento translocado y los posibles genes implicados en el punto de ruptura.
... First, 2 or more independent translocations leading to 2 or more meiotic quadrivalents of which each can segregate in a balanced or an unbalanced way. These CCRs are generally familial and can be transmitted from one generation to the next [Meer et al., 1981;Farrell et al., 1994;Zahed et al., 1998]. Second, 'true' CCRs involving 'n' chromosomes with 'n' breakpoints leading to the formation of a meiotic multivalent (2n). ...
Complex chromosome rearrangements (CCRs) are currently defined as structural genome variations that involve more than 2 chromosome breaks and result in exchanges of chromosomal segments. They are thought to be extremely rare, but their detection rate is rising because of improvements in molecular cytogenetic technology. Their population frequency is also underestimated, since many CCRs may not elicit a phenotypic effect. CCRs may be the result of fork stalling and template switching, microhomology-mediated break-induced repair, breakage-fusion-bridge cycles, or chromothripsis. Patients with chromosomal instability syndromes show elevated rates of CCRs due to impaired DNA double-strand break responses during meiosis. Therefore, the putative functions of the proteins encoded by ATM, BLM, WRN, ATR, MRE11, NBS1, and RAD51 in preventing CCRs are discussed. CCRs may exert a pathogenic effect by either (1) gene dosage-dependent mechanisms, e.g. haploinsufficiency, (2) mechanisms based on disruption of the genomic architecture, such that genes, parts of genes or regulatory elements are truncated, fused or relocated and thus their interactions disturbed - these mechanisms will predominantly affect gene expression - or (3) mixed mutation mechanisms in which a CCR on one chromosome is combined with a different type of mutation on the other chromosome. Such inferred mechanisms of pathogenicity need corroboration by mRNA sequencing. Also, future studies with in vitro models, such as inducible pluripotent stem cells from patients with CCRs, and transgenic model organisms should substantiate current inferences regarding putative pathogenic effects of CCRs. The ramifications of the growing body of information on CCRs for clinical and experimental genetics and future treatment modalities are briefly illustrated with 2 cases, one of which suggests KDM4C(JMJD2C) as a novel candidate gene for mental retardation.
... Certain familial CCRs can change from one generation to another. For example, carriers of double two-way translocations may lead to a more complex rearrangement in their offspring [31][32][33][34], or carriers of, e.g., three-way translocations may father children with two simple reciprocal translocations [35]. Such rebuilding and rearrangement, leading to simpler or more complicated aberrations, arises in approximately 45% of CCR cases [17]. ...
Structural aberrations involving more than two breakpoints on two or more chromosomes are known as complex chromosomal rearrangements (CCRs). They can reduce fertility through gametogenesis arrest developed due to disrupted chromosomal pairing in the pachytene stage. We present a familial case of two infertile brothers (with azoospermia and cryptozoospermia) and their mother, carriers of an exceptional type of CCR involving chromosomes 1 and 7 and three breakpoints. The aim was to identify whether meiotic disruption was caused by CCR and/or genomic mutations. Additionally, we performed a literature survey for male CCR carriers with reproductive failures. The characterization of the CCR chromosomes and potential genomic aberrations was performed using: G-banding using trypsin and Giemsa staining (GTG banding), fluorescent in situ hybridization (FISH) (including multicolor FISH (mFISH) and bacterial artificial chromosome (BAC)-FISH), and genome-wide array comparative genomic hybridization (aCGH). The CCR description was established as: der(1)(1qter->1q42.3::1p21->1q42.3::7p14.3->7pter), der(7)(1pter->1p2 1::7p14.3->7qter). aCGH revealed three rare genes variants: ASMT, GARNL3, and SESTD1, which were ruled out due to unlikely biological functions. The aCGH analysis of three breakpoint CCR regions did not reveal copy number variations (CNVs) with biologically plausible genes. Synaptonemal complex evaluation (brother-1; spermatocytes II/oligobiopsy; the silver staining technique) showed incomplete conjugation of the chromosomes. Associations between CCR and the sex chromosomes (by FISH) were not found. A meiotic segregation pattern (brother-2; ejaculated spermatozoa; FISH) revealed 29.21% genetically normal/balanced spermatozoa. The aCGH analysis could not detect smaller intergenic CNVs of few kb or smaller (indels of single exons or few nucleotides). Since chromosomal aberrations frequently do not affect the phenotype of the carrier, in contrast to the negative influence on spermatogenesis, there is an obvious need for genomic sequencing to investigate the point mutations that may be responsible for the differences between the azoospermic and cryptozoospermic phenotypes observed in a family. Progeny from the same parents provide a unique opportunity to discover a novel genomic background of male infertility.
... It is interesting that male carriers with CCRs have an increased risk of primary infertility due to disturbed spermatogenesis as well as pre-and post-implantation loss (Saadallah and Hulten, 1985;Gorski et al. 1986;Madan et al. 1997). Several reports of CCRs in fertile males have been documented with associated recurrent spontaneous abortions in their partners, or birth of an abnormal offspring with multiple congenital anomalies, dysmorphic features or mental retardation (Saadallah and Hulten, 1985;Johannisson et al. 1988;Zahed et al. 1998;Cai et al. 2001;Grasshoff et al. 2003). Similar to our report, several cases of phenotypically normal females with CCRs and an associated history of recurrent pregnancy loss are summarized in Table 1. ...
Complex chromosomal rearrangements (CCRs) are rare structural rearrangements involving three or more chromosomes. Balanced CCRs are often seen in phenotypically normal females who may later present with fertility problems. We report a 25-year old female with an adverse obstetric history and a de novo CCR involving chromosomes 7, 13 and 15 detected after GTG-banding. The de novo origin was confirmed because the karyotypes of the proband's parents and male sibling were normal. Cytogenetic analysis of the proband revealed the following complex karyotype: 46,XX,t(7;15;13)(p15;q21;q31). This case illustrates the importance of identifying de novo, apparently balanced CCRs in patients with adverse obstetric histories. Further, offspring of female carriers of apparently balanced CCRs may be affected as a result of abnormal meiosis during gametogenesis. This makes it imperative to karyotype women with adverse obstetric histories to rule out the presence of chromosomal rearrangements and facilitate genetic counseling of the patient, family planning, and prenatal diagnosis of future pregnancies.
... First, 2 or more independent translocations leading to 2 or more meiotic quadrivalents of which each can segregate in a balanced or an unbalanced way. These CCRs are generally familial and can be transmitted from one generation to the next [Meer et al., 1981;Farrell et al., 1994;Zahed et al., 1998]. Second, 'true' CCRs involving 'n' chromosomes with 'n' breakpoints leading to the formation of a meiotic multivalent (2n). ...
... First, 2 or more independent translocations leading to 2 or more meiotic quadrivalents of which each can segregate in a balanced or an unbalanced way. These CCRs are generally familial and can be transmitted from one generation to the next [Meer et al., 1981;Farrell et al., 1994;Zahed et al., 1998]. Second, 'true' CCRs involving 'n' chromosomes with 'n' breakpoints leading to the formation of a meiotic multivalent (2n). ...
Complex chromosome rearrangements (CCRs) are currently defined as structural genome variations that involve more than 2 chromosome breaks and result in exchanges of chromosomal segments. They are thought to be extremely rare, but their detection rate is rising because of improvements in molecular cytogenetic technology. Their population frequency is also underestimated, since many CCRs may not elicit a phenotypic effect. CCRs may be the result of fork stalling and template switching, microhomology-mediated break-induced repair, breakage-fusion-bridge cycles, or chromothripsis. Patients with chromosomal instability syndromes show elevated rates of CCRs due to impaired DNA double-strand break responses during meiosis. Therefore, the putative functions of the proteins encoded by ATM , BLM , WRN , ATR , MRE11 , NBS1 , and RAD51 in preventing CCRs are discussed. CCRs may exert a pathogenic effect by either (1) gene dosage-dependent mechanisms, e.g. haploinsufficiency, (2) mechanisms based on disruption of the genomic architecture, such that genes, parts of genes or regulatory elements are truncated, fused or relocated and thus their interactions disturbed – these mechanisms will predominantly affect gene expression – or (3) mixed mutation mechanisms in which a CCR on one chromosome is combined with a different type of mutation on the other chromosome. Such inferred mechanisms of pathogenicity need corroboration by mRNA sequencing. Also, future studies with in vitro models, such as inducible pluripotent stem cells from patients with CCRs, and transgenic model organisms should substantiate current inferences regarding putative pathogenic effects of CCRs. The ramifications of the growing body of information on CCRs for clinical and experimental genetics and future treatment modalities are briefly illustrated with 2 cases, one of which suggests KDM4C (JMJD2C) as a novel candidate gene for mental retardation.
... Double, two-way complex chromosome rearrangements (CCRs) are rare events defined by at least two independent structural rearrangements, such as reciprocal or Robertsonian translocations (Bijlsma et al., 1978;Hansen et al., 1983;Watt and Couzin, 1983;Bell and Warburton, 1977) or inversions. Double, two-way CCRs are considered to be the simplest CCRs (Bass et al., 1985;Batanian and Eswara, 1998), when compared with three-way exchange CCRs (which involve three chromosomes and are generally hereditary; Meer et al., 1981;Farrell et al., 1994;Zahed et al., 1998) and exceptional CCRs (which are mainly de novo and characterized by one chromosome with at least two breakpoints). In general, CCR involves at least three breakpoints on two or more chromosomes, with an exchange of genetic material (Pai et al., 1980). ...
Individuals with two independent chromosome rearrangements are rare and meiotic segregation studies are few.Two brothers (P1 and P2) and a cousin (P3) were karyotyped and found to have the same familial reciprocal translocation between the long arm of chromosome 8 and the short arm of chromosome 9: 46,XY,t(8;9)(q24.3;p24). In addition, one brother also had a different de novo reciprocal translocation between the long arm of chromosome 1 and the short arm chromosome 16: 46,XY,t(1;16)(q21;p11.2)dn,t(8;9)(q24.3;p24)mat. Using locus-specific probes for segments involved in the translocations and for other chromosomes, sperm-FISH analysis was used to investigate the products of meiotic segregation of the translocations and the possibility of an interchromosomal effect. Sperm nucleus fragmentation was also evaluated.For the t(8;9) translocation the proportion of unbalanced products was higher for P1 (66.3%, p<0.0001) than P2 (51.9%) and P3 (50.4%), and the proportion consistent with each meiosis I segregation mode was also different for P1. In addition, for P1, 61.6% of the products of the t(1;16) were unbalanced, and 85.6% of spermatozoa overall included both translocations. No evidence of an interchromosomal effect was found and sperm nucleus fragmentation rates were similar.Our study suggests that co-segregation of the t(8;9) and the t(1;16) resulted in modifying the proportions of t(8;9) meiotic segregation products found in spermatozoa. This could be due to selection associated with meiotic checkpoints and germ cell death.
... Yet, there are two more similar examples. A CCR t(1;8;9) described by Zahed et al. [1998] in the mother of an unbalanced propositus arose from t(1;8) and t(1;9) in the grandfather. Soler et al. [2005] presented a child with a CCR t(14;15;21) that had arisen by recombination from two translocations, t(14;15) and t(14;21) in the father. ...
This review examines the reproductive consequences for carriers of a balanced complex chromosome rearrangement (CCR). It is based on an analysis of CCRs in 103 adults referred for reproductive problems, including male infertility. The main focus is on reproductive risks based on data from 84 CCRs. Carriers of balanced CCRs have a high risk of an abortion and/or a chromosomally unbalanced child. I have identified roughly four different types of CCRs (I-IV); most (44%) belong to Type I with a simple 3-way or 4-way exchange of segments and risk factors similar to those for reciprocal translocations. There were only three CCRs (4%) of type II, which involve an inversion. Type III CCRs (21%) involve one or more insertions with ∼35% risk of a child with a duplication or a deletion of the inserted segment. Type IV CCRs (31%) involve a "middle segment" in a derivative chromosome with segments from at least three chromosomes. In ∼35% of these CCRs, recombination occurs in this segment, which can produce imbalance but in many cases it changes a CCR into a simpler balanced rearrangement in the next generation. Balanced CCRs, which have been often considered together in one group, can now be split into four types, each with a risk of a different type of imbalance. This analysis provides a better understanding of the reproductive consequences for carriers of balanced CCRs and should be useful in prenatal diagnosis and genetic counseling.
... The first class is three-way rearrangements which include three chromosomes break and exchange chromosomal segments. This class of CCRs is mainly familial [9]. The second class is exceptional CCRs in which more than one breakpoint per chromosome is found and as many as 7 chromosomes with as many as 15 breakpoints can be involved [6] and mainly detected in de novo CCRs [10]. ...
While XXY aneuploidy is the most common disorder of sex chromosomes in men, complex chromosomal rearrangements (CCRs) are rare in humans.
Here we describe clinical and cytogenetic findings in a male referred to our cytogenetic laboratory by an infertility clinic. The patient's age was 35 at the time of referral. Total azoospermia was confirmed on semen analysis.
The karyotype of peripheral blood showed 47,XXY,t(1;3;5)(p22;q29;q22). The mother had the same CCRs.
To our best of our knowledge this is the first case of 47,XXY with CCRs. We think it is important to report such a unique chromosomal occurrence.
... Disturbances in spermatogenesis as well as pre-and post implantation losses are discussed as reasons for this phenomenon [6]. Zahed et al. [1998] suggested that the scarcity of the number of transmitting males with CCRs is usually attributed to either a lower risk of producing abnormal progeny therefore, a lower probability of ascertainment, or to infertility attributed to problems in chromosome pairing at spermatogen- esis [21]. There are only few reports on fertile male CCR carriers referred for cytogenetic evaluation due to spontaneous abortions of spouses or due to abnormal offsprings, which were well reviewed by Grasshoff et al. [2003] as presented here [5]. ...
Complex chromosomal rearrangements (CCRs) are defined as structural chromosomal rearrangements with at least three breakpoints and exchange of genetic material between two or more chromosomes. Complex chromosomal translocations are rarely seen in the general population but the frequency of occurrence is anticipated to be much higher due balanced states with no phenotypic presentation. Here, we report a severely mentally retarded fertile male patient in whom further delineation of CCR involving chromosomes 1, 4 and 2 was carried out by using high resolution multicolor banding (MCB) technique. As a FISH based novel chromosome banding approach, high resolution MCB allows for the differentiation of chromosome region specific areas at band and subband levels.
Cytogenetic studies using high resolution banding of the proband necessitated further delineation of the breakpoints because of their uncertainty: 46,XY,t(1;4;2)(p21~31;q31.3;q31). After using high resolution MCB based on microdissection derived region-specific libraries, the exact nature of chromosomal rearrangements for chromosomes 1, 2 and 4 were revealed and these breakpoints were located on 1p31.1, 1q24.3 and 4q31.3 giving rise to a balanced situation.
Further delineations are certainly required to provide detailed information about the relationship between balanced CCRs and their phenotypes in order to offer proper counseling to the families concerned. Carriers must be investigated with high resolution banding and molecular cytogenetic techniques to determine the exact locations of the breakpoints. High resolution MCB is an alternative and an efficient method to other FISH based chromosome banding techniques and can serve in clarifying the nature of CCR.
To report a de novo exceptional complex chromosomal rearrangement (CCR) with four breakpoints in the male partner of a couple with recurrent abortions.
Case report and review of the literature.
Genetics laboratory in a private hospital.
A couple referred for recurrent abortions.
Cytogenetic and sperm fluorescence in situ hybridization (FISH) techniques.
Karyotype and FISH sperm results.
The couple was phenotypically normal, with no family history of miscarriage or infertility. Female karyotype was normal. Male karyotype followed by FISH analysis showed a de novo CCR with four breakpoints: t(5,13,16)(q11.1, q14.3, q12.2), ins(16;13)(q12.2;q?q14.2). ish t(5;13;16)(wcp5+,wcp13+), ins(16;13)(wcp13+).
Exceptional de novo CCR male carriers with recurrent abortions are extremely rare. Patients with CCRs have limited options to achieve a normal pregnancy. Careful consideration and assessment should be provided upon counseling of couples with CCRs.
Recurrent interstitial deletion of a region of 8p23.1 flanked by the low copy repeats 8p-OR-REPD and 8p-OR-REPP is associated with a spectrum of anomalies that can include congenital heart malformations and congenital diaphragmatic hernia (CDH). Haploinsufficiency of GATA4 is thought to play a critical role in the development of these birth defects. We describe two individuals and a monozygotic twin pair discordant for anterior CDH all of whom have complex congenital heart defects caused by this recurrent interstitial deletion as demonstrated by array comparative genomic hybridization. To better define the genotype/phenotype relationships associated with alterations of genes on 8p23.1, we review the spectrum of congenital heart and diaphragmatic defects that have been reported in individuals with isolated GATA4 mutations and interstitial, terminal, and complex chromosomal rearrangements involving the 8p23.1 region. Our findings allow us to clearly define the CDH minimal deleted region on chromosome 8p23.1 and suggest that haploinsufficiency of other genes, in addition to GATA4, may play a role in the severe cardiac and diaphragmatic defects associated with 8p23.1 deletions. These findings also underscore the importance of conducting a careful cytogenetic/molecular analysis of the 8p23.1 region in all prenatal and postnatal cases involving congenital defects of the heart and/or diaphragm.
To determine an unusual complex chromosome rearrangement found in a man with oligospermia with a normal phenotype.
Case report with a review of the literature.
Academic research environment.
A man with oligospermia but otherwise apparently healthy.
Peripheral blood lymphocytes were used for karyotyping, and metaphases were analyzed by the fluorescence in situ hybridization (FISH) procedure. Further characterization of the karyotype was done by using multicolor banding (MCB) probes.
Physical examination, semen analysis, GTG banding, FISH, MCB.
The semen analysis revealed oligospermia. The lymphocytic karyotype detected an unusual complex chromosome rearrangement involving chromosomes 2, 13, and 18 determined by banding cytogenetics. Karyotype was established as 46,XY,t(2;13;18)ins(2;13)(2qter-->2p25.1::13q13-->13q22::18q12.3-->18qter;13pter-->13q13::2p25-->2pter;18pter-->18q12.3::13q22-->13qter) after MCB analysis.
The association of an unusual complex chromosome rearrangement with three recurrent spontaneous abortions was reported.
Familial complex chromosomal rearrangements (CCRs) are rare and tend to involve fewer breakpoints and fewer chromosomes than CCRs that are de novo in origin. We report on a CCR identified in a child with congenital heart disease and dysmorphic features. Initially, the child's karyotype was thought to involve a straightforward three-way translocation between chromosomes 3, 8, and 16. However, after analyzing the mother's chromosomes, the mother was found to have a more complex rearrangement that resulted in a recombinant chromosome in the child. The mother's karyotype included an inverted chromosome 2 and multiple translocations involving chromosomes 3, 5, 8, and 16. No evidence of deletion or duplication that could account for the clinical findings in the child was identified.
Constitutional de novo complex chromosomal rearrangements (CCRs) are a rare finding in patients with mild to severe mental retardation. CCRs pose a challenge to the clinical cytogeneticist: generally CCRs are assumed to be the cause of the observed phenotypic abnormalities, but the complex nature of these chromosomal changes often hamper the accurate delineation of the chromosomal breakpoints and the identification of possible imbalances. In a first step towards a more detailed molecular cytogenetic characterization of CCRs, we studied four de novo CCRs using multicolor fluorescent in situ hybridization (M-FISH), comparative genomic hybridization (CGH), and FISH with region specific probes. These methods allowed a more refined characterization of the breakpoints in three of the four CCRs. The occurrence of 7q breakpoints in three out of these four CCRs and in 30% of reported CCRs suggested preferential involvement of this chromosomal region in the formation of CCRs. Further analysis of these 7q breakpoints revealed a 2 Mb deletion at 7q21.11 in one patient and involvement of the same region in a cryptic insertion in a second patient. This particular region contains at least 5 candidate genes for mental retardation. The other patient had a breakpoint more proximal to this region. The present data together with these from the literature provide evidence that a region within 7q21.11 may be prone to breakage and formation of CCRs.
We describe two cases of sonographic abnormalities associated with unusual chromosomal aberrations. Case 1 presented with a cystic hygroma at 12 weeks' gestation. Cytogenetic analysis revealed an unbalanced complex chromosome rearrangement implicating chromosomes 6, 13 and 21 (karyotype: 47,XX,t(6;21;14)(q14;q21;q21)mat,+21) and corresponding to a complete trisomy 21. This anomaly resulted from malsegregation of a maternal balanced three-way translocation. For case 2, an alobar holoprosencephaly was identified by ultrasonography at 23 weeks' gestation. Chromosomal analysis showed a recombinant rec (13), dup q chromosome, secondary to unequal crossing-over of a paternal pericentric inversion of chromosome 13, giving rise to partial trisomy 13q (karyotype: 46,XX,rec(13)dup(13q)inv(13)(p11q21)pat). These two cases illustrate the role of ultrasound in leading to detection not only of foetal chromosomal aberrations but also of rare balanced chromosomal rearrangements presented by one of the two parents.
Complex chromosomal rearrangements (CCRs) are usually associated with infertility or subfertility in male carriers. If fertility is maintained, there is a high risk of abnormal pregnancy outcome. Few male carriers have been identified by children presenting with mental retardation/congenital malformations (MR/CM) or by spontaneous abortions of the spouses. We report a de novo CCR with five breakpoints involving chromosomes 4, 10 and 14 in a male carrier who was ascertained through a son presenting with MR/CM due to an unbalanced karyotype with partial trisomy 14 and partial monosomy 4. The child has a healthy elder brother. In the family history no abortions were reported. No fertility treatment was necessary. Cytogenetic analysis from the affected son showed a reciprocal translocation t(4;10) with additional chromosomal material inserted between the translocation junctions in the derivative chromosome 10. The father showed the same derivative chromosome 10 but had additionally one aberrant chromosome 14. Further molecular cytogenetic analyses determined the inserted material in the aberrant chromosome 10 as derived from chromosome 14 and revealed a small translocation with material of chromosome 4 inserted into the derivative chromosome 14. Thus the phenotype of the son is supposed to be associated with a partial duplication 14q13-->q24.1 and a partial monosomy 4q27-->q28. Including our case we are aware of eleven CCR cases with fertile male carriers. In eight of these families normal offspring have been reported. We propose that exceptional CCRs in fertile male carriers might form comparatively simple pachytene configurations increasing the chance of healthy offspring.
We report an unusual case of a familial complex chromosome rearrangement (CCR), ascertained through prenatal diagnosis. The fetus carried an apparently balanced CCR with a recombinant 3-segment chromosome derived from two paternal reciprocal translocations involving both homologs of chromosome 14 and chromosomes 15 and 21, respectively. A probably normal phenotype was predicted and confirmed after birth. His older sister carried an unbalanced karyotype with partial trisomy 14 and partial monosomy 21, and displayed an apparently normal, paternally derived chromosome 14 that resulted from recombination between two derivative chromosomes. Fluorescent in situ hybridization (FISH) and molecular studies were essential for the characterization of the rearrangement. The "rebuilding," through recombination, of a chromosome involved in two different translocations in a progenitor, was demonstrated for the first time by molecular analysis. Our family is another good example of how balanced familial complex translocations are in a state of flux and can change from one generation to the next.
We report on the diagnosis of a complex chromosome rearrangement in a mother and the transmission of a simplified translocation in her fetus. The mother had mental retardation, short stature, facial dysmorphism, and hydronephrosis, but was never investigated before she was pregnant. A blood sample was taken for karyotyping at the time of amniocentesis for advanced maternal age. The mother's karyotype revealed two translocations involving chromosome 5, chromosome 16 twice, and chromosome 20 as follow: 46,XX,t(5;16;20)(5pter-->5q11.2::16q12.1-->16q23::20p11.2-->20pter;16pter-->16q12.1::5q11.2-->5qter;16qter-->16q23::20p11.2-->20qter). The amniocentesis revealed a female karyotype with an apparently balanced translocation: 46,XX,t(16;20)(q23;p11.2). The translocation of the fetus probably resulted from a meiotic recombination between the derived 5 and the normal 16 in the mother. The baby was born and presented the same facial dysmorphism and hydronephrosis. The simplification of a complex rearrangement through recombination into a balanced product has only been rarely described and it is to our knowledge the first time that both the carrier of the complex rearrangement and her descendant with a simplified rearrangement share phenotypic abnormalities.
To report a live birth after successful preimplantation genetic diagnosis (PGD) for carriers of complex chromosomal rearrangements (CCRs) with translocation and deletion.
Fluorescent in situ hybridization (FISH) was applied to PGD for CCR carriers.
University-based centers for reproductive medicine.
Three CCR carriers, patient A with 46,XX,t(6;10;8)(q25.1;q21.1;q21.1), patient B with 46,X,del(X)(p22.3),t(2;18)(q14.1;q21)[48]/45,X, t(2;18)(q14.1;q21)[12], and patient C with 46,XY,t(5;13;8)(q21.2;q14.3;q24.3).
Balanced or normal embryos were diagnosed by PGD and transferred.
Diagnosis rate of FISH, pregnancy outcome, and karyotype of amniocentesis.
Blastomeres were biopsied from 56 embryos in four PGD cycles, and 54 embryos (96.4%) were successfully diagnosed by FISH. Among them, four embryos were diagnosed as transferable in two cycles of patient B and one cycle of patient C. After three cycles of embryo transfer, a pregnancy was achieved in the second PGD cycle of patient B, and the karyotype of amniocentesis was 46,XY,t(2;18)(q14.1;q21). A healthy baby was delivered at 40 weeks of gestation by cesarean section.
This is the first report for a live birth after PGD in the CCR carriers associated with translocation and deletion, 46,X,del(X)(p22.3),t(2;18)(q14.1;q21)[48]/45,X,t(2;18)(q14.1;q21)[12]. Preimplantation genetic diagnosis for CCRs needs more consideration and advanced techniques for full karyotyping.
The clinical manifestations and cytogenetic details of five patients with a de novo deletion of the short arm of chromosome 8, del(8)(p23), are described. Of the four surviving children all had mild mental retardation and subtle facial anomalies; three of the five had cardiac abnormalities. The clinical features seen in these patients are compared with those of three previous single case reports with del(8)(p23), and with patients described as having the '8p-' syndrome associated with del(8)(p21). The findings in these patients suggest that major congenital anomalies, especially congenital heart defects, are frequent even in small distal 8p deletions, but facial dysmorphism may be subtle and mental retardation less severe than in those with deletions associated with more proximal breakpoints. The five patients were detected within a four year period, suggesting that this deletion syndrome is relatively frequent. The possible mechanisms for the formation of terminal deletions are discussed.
A female patient with a 46,XX,del(8)(p23----pter) karyotype is presented. She was mentally retarded and showed a few dysmorphic features. Her red cell glutathione reductase level was within normal limits. This terminal deletion, on the short arm of chromosome 8, appears to be the smallest segment hitherto reported.
Using in situ hybridisation, we identified interstitial telomeric sequences in seven chromosomal translocations present in normal and in syndromic subjects. Telomeric sequences were also found at the centromeric ends of a 4p and a 4q caused by centric fission of one chromosome 4. We found that rearrangements leading to interstitial telomeric sequences were of three types: (1) termino-terminal rearrangements with fusion of the telomeres of two chromosomes, of which we report one case; (2) rearrangements in which an acentric fragment of one chromosome fuses to the telomere of another chromosome. We describe four cases of Prader-Willi syndrome with the 15q1-qter transposed to the telomeric repeats of different recipient chromosomes; (3) telomere-centromere rearrangements in which telomeric sequences of one chromosome fuse with the centromere of another chromosome. We describe two examples of these rearrangements in which not only telomeric sequences but also remnants of alphoid sequences were found at the fusion point. Instability at the fusion point of the derivative chromosome was found in the Prader-Willi translocations but we were unable to correlate this instability with culture conditions. The two subjects with the termino-terminal rearrangement and the centric fission respectively have normal phenotypes. The two patients with telomere-centromere fusions were unbalanced for the short arm of an acrocentric chromosome and had failure to thrive; one of them also had dysmorphic facies. We postulate that these phenotypes could be the result of uniparental disomy.
We report an unusual case of a balanced reciprocal translocation with a recombinant chromosome which has arisen from a familial balanced complex translocation. Fluorescence in situ hybridization studies were essential for the identification of the breakpoints. A review of 60 cases of balanced complex translocations (BCT) has revealed three cases similar to ours. Carriers of BCT have a high risk of having spontaneous abortions or a child with an unbalanced karyotype. Certain types of balanced rearrangements involving an insertion can give rise to a simpler balanced translocation as a result of crossover. Our observations support the assumption that the chance that a de novo balanced complex translocation is associated with an abnormal phenotype increases with the number of breakpoints.
A complex and unique, apparently balanced translocation involving three autosomes and an X in a phenotypically abnormal child is described. Family studies using glucose 6 phosphate dehydrogenase as a marker provided biochemical evidence of non-random expression of this Xq locus and suggested that this de novo abnormality in the proband could be paternal in origin - the first such instance to be recorded.
The mechanism(s) for the origin of jumping translocations (JTs) are unknown. To assess the possible involvement of telomeric
sequences in the jumping process, metaphases of a patient with hydrops fetalis having a JT were analyzed for the presence
of interstitial telomeres. Telomere DNA sequences were detected at the junction sites of the donor and the recipient chromosomes.
Interstitial telomeric sequences have so far only been detected in JTs involving chromosome 15q in patients with Prader-Willi
syndrome. Our finding of interstitial telomeric sequences in a JT with a chromosome different from chromosome arm 15q in a
patient without Prader-Willi syndrome implies that telomere sequences may be common to all telomeric JTs. The possible role
of telomeric sequences as a cause of the observed chromosomal mosaicism is discussed.
The word telomere derives from the Greek word telos meaning 'end', roughly translating as 'the thing at the end' when the end is that of a chromosome. Telomeres belie their apparent simplicity of structure by being involved in a wide range of diverse biological phenomena. Much of our understanding of telomere behaviour comes from studies in lower eukaryotes such as ciliates and yeast, the subject of many recent reviews. Here we concentrate on the mammalian telomere, recent progress in its study, and how recent evidence for an involvement of telomeres in the regulation of gene expression and DNA replication in yeast points to new aspects of mammalian telomere function yet to be explored.
We report a family in which three members presented with minimal phenotypic abnormalities, normal intelligence to mild mental retardation, and a cytogenetically terminal chromosome deletion at band 8p23.1 Whole chromosomal painting with a chromosome 8-specific DNA library confirmed this familial chromosome abnormality as a deletion, while fluorescence in situ hybridization with telomeric probes demonstrated the presence of telomeres at the deletion site. Coagulation studies were additionally performed to evaluate the purported location of the coagulation factor VII regulator gene at 8p23.1. A review of the clinical findings of seven cases of del(8)(p23.1) is presented.
We describe a novel chromosome structure in which telomeric sequences are present interstitially, at the apparent breakpoint junctions of structurally abnormal chromosomes. In the linear chromosomes with interstitial telomeric sequences, there were three sites of hybridization of the telomere consensus sequence within each derived chromosome: one at each terminus and one at the breakpoint junction. Telomeric sequences also were observed within a ring chromosome. The rearrangements examined were constitutional chromosome abnormalities with a breakpoint assigned to a terminal band. In each case (with the exception of the ring chromosome), an acentric segment of one chromosome was joined to the terminus of an apparently intact recipient chromosome. One case exhibited apparent instability of the chromosome rearrangement, resulting in somatic mosaicism. The rearrangements described here differ from the telomeric associations observed in certain tumors, which appear to represent end-to-end fusion of two or more intact chromosomes. The observed interstitial telomeric sequences appear to represent nonfunctional chromosomal elements, analogous to the inactivated centromeres observed in dicentric chromosomes.
The DNA of telomeres--the terminal DNA-protein complexes of chromosomes--differs notably from other DNA sequences in both structure and function. Recent work has highlighted its remarkable mode of synthesis by the ribonucleoprotein reverse transcriptase, telomerase, as well as its ability to form unusual structures in vitro. Moreover, telomere synthesis by telomerase has been shown to be essential for telomere maintenance and long-term viability.
The instability of chromosomes with breaks induced by X-irradiation led to the proposal that the natural ends of chromosomes are capped by a specialized structure, the telomere. Telomeres prevent end-to-end fusions and exonucleolytic degradation, enable the end of the linear DNA molecule to replicate, and function in cell division. Human telomeric DNA comprises approximately 2-20 kilobases (kb) of the tandemly repeated sequence (TTAGGG)n oriented 5'----3' in towards the end of the chromosome, interspersed with variant repeats in the proximal region. Immediately subtelomeric lie families of unrelated repeat motifs (telomere-associated sequences) whose function, if any, is unknown. In lower eukaryotes the formation and maintenance of telomeres may be mediated enzymatically (by telomerase) or by recombination; in man the mechanisms are poorly understood, although telomerase has been identified in HeLa cells. Here we describe an alpha thalassaemia mutation associated with terminal truncation of the short arm of chromosome 16 (within band 16p13-3) to a site 50 kb distal to the alpha globin genes, and show that (TTAGGG)n has been added directly to the site of the break. The mutation is stably inherited, proving that telomeric DNA alone is sufficient to stabilize the broken chromosome end. This mechanism may occur in any genetic disease associated with chromosome truncation.
A terminal deletion in the short arm of chromosome 8 was found in a 2.5-year-old boy: 46,XY,del(8) (p22.0) and in a 1-year-old girl: 46,XX,del(8) (p23.1) with dysmorphic craniofacial features and developmental retardation. Erythrocyte GSR activities of the boy and of his parents were within normal limits. Vitamin K dependent coagulation factors in the girl and her parents gave normal results. Clinical findings were compared with previously reported cases and suggested a recognizable syndrome.
We have analyzed the DNA sequences associated with four different human telomeres. Two are members of distinct repeated sequence families which are located mainly but not exclusively at telomeres. Two are unique in the genome, one deriving from the long arm telomere of chromosome 7 and the other from the pseudoautosomal telomere. One telomere-associated repeated sequence has a polymorphic distribution among the chromosome ends, being present at a different combination of ends in different individuals. These data thus identify a new source of human genetic variation and indicate that the canonical features of the organization of telomere-associated DNA are widely conserved in evolution.
In this report we present a 9-year-old boy with mental retardation, behavioural problems and terminal deletion of the short arm of chromosome 8(8pter----8p23.1:). In contrast with previously reported patients with larger terminal and interstitial 8p deletions he did not present major phenotypic abnormalities.
We have determined the empirical reproductive risks for heterozygous carriers of complex chromosome rearrangements (CCRs). CCRs are structural rearrangements involving at least three chromosomes and three or more chromosomal breakpoints. Pregnancy outcome, the frequency and type of chromosomal imbalance in the offspring, and the localization and distribution of chromosome breakpoints were analyzed in 25 CCR families ascertained by the birth of a malformed child or repeated spontaneous abortions. This study included two newly ascertained familial CCRs and a total of 67 informative pregnancies. Analysis of the data, after correction for ascertainment bias, showed that the incidence of spontaneous abortions in CCR families was 48.3%. Approximately one in ten pregnancies and 18.4% of all live births to CCR carriers resulted in phenotypically abnormal offspring. One-half of all CCR carrier liveborn offspring were also CCR carriers. There was a 53.7% incidence of an abnormal pregnancy outcome to CCR carriers. We failed to detect any evidence for a non-random involvement of specific chromosomes in CCRs. However, we did observe a non-random distribution of specific breakpoints at sites 1q25, 4q13, 6q27, 7p14, 9q12, 11p11, 11p15, 12q21, 13q31, and 18q21.
A highly conserved repetitive DNA sequence, (TTAGGG)n, has been isolated from a human recombinant repetitive DNA library. Quantitative hybridization to chromosomes sorted by flow cytometry indicates that comparable amounts of this sequence are present on each human chromosome. Both fluorescent in situ hybridization and BAL-31 nuclease digestion experiments reveal major clusters of this sequence at the telomeres of all human chromosomes. The evolutionary conservation of this DNA sequence, its terminal chromosomal location in a variety of higher eukaryotes (regardless of chromosome number or chromosome length), and its similarity to functional telomeres isolated from lower eukaryotes suggest that this sequence is a functional human telomere.
Congenital complex chromosome rearrangements (CCR) compatible with life are rare in man. Thus patients with CCR usually present considerable diagnostic difficulties both clinically and cytogenetically. We studied a 12-year-old mentally retarded male with minor congenital anomalies as described below and his first-degree relatives. The propositus had an unbalanced karyotype with eight break points and seven derivative chromosomes; two deletions, del(6) (q25----qter) and del(14) (q31----qter), and four translocations, t(2;11), t(5;15), t(6;11), t(6;20) were present. Parental chromosomes were normal; however, the mother had a few metaphases with abnormal chromosomes suggestive of chromosome instability. These findings and a review of reported patients with CCR are presented with regard to speculations about etiology, pathogenesis, phenotypic expression, and prognosis. Physicians should be aware of CCR and broader indications for cytogenetic studies appear warranted in view of these data.
A family showing a complex translocation between chromosomes 7, 8, and 9 with breakpoints at 7q21, 7q33, 8p23, and 9p23 is described. The proband had been referred because of repeated spontaneous abortions. This is only the second family to be ascertained in this way. Twenty-three other cases of complex translocations are briefly reviewed, eight of which were de novo in origin and 15 familial. All but one of the familial cases showed maternal transmission only. The present family shows both maternal and paternal transmission and is thought to be the first exhibiting recombination from a male carrier. The origin and transmission of the complex translocation is followed through three generations.
Two persons within the same family were discovered to be trisomic for the segment 7qter. However, several features differed from those described in other patients with this syndrome, for example, normal birth weight and neck size, cleft palate, and beaked nose. In addition to the phenotypic variation, there were three independently segregating autosomal translocations in the pedigree: t(1;7)(q43;q32), t(1;6) (p22.3;q14.1), and t(3;10)(q26.1;p11.21). This is a finding that, to our knowledge, has not been previously reported.
A phenotypically normal mother had two apparently balanced translocations involving chromosomes 5, 7, and 12. Her karyotype was 46,XX,t(5;7) (5;12) (p14q34;p14;q21), while her daughter, who was also phenotypically normal, had inherited only one of the translocations. Her karyotype was 46,XX,-5,-7,+rec(5)t(5;7) (q34;p14)mat,+der(7)t(5;7) (q34;p14)mat. The other was lost during a meiotic crossing over, giving the daughter an apparently balanced chromosome complement.
Telomeres are the protein-DNA structures at the ends of eukaryotic chromosomes. In yeast, and probably most other eukaryotes, telomeres are essential. They allow the cell to distinguish intact from broken chromosomes, protect chromosomes from degradation, and are substrates for novel replication mechanisms. Telomeres are usually replicated by telomerase, a telomere-specific reverse transcriptase, although telomerase-independent mechanisms of telomere maintenance exist. Telomere replication is both cell cycle- and developmentally regulated, and its control is likely to be complex. Because telomere loss causes the kinds of chromosomal changes associated with cancer and aging, an understanding of telomere biology has medical relevance.
We have characterized and compared a series of naturally occurring chromosomal truncations involving the terminal region of the short arm of human chromosome 16 (16p13.3). All six broken chromosomes appear to have been stabilized by the direct addition of telomeric repeats (TTAGGG)n to nontelomeric DNA. In five of the six chromosomes, sequence analysis shows that the three of four nucleotides preceding the point of telomere addition are complementary to and in phase with the putative RNA template of human telomerase. Otherwise we have found no common structural features around the breakpoint regions. These findings, together with previously reported in vitro data, suggest that chromosome-healing events in man can be mediated by telomerase and that a small region of complementarity to the RNA template of telomerase at the end of a broken chromosome may be sufficient to prime healing in vivo.
A complex chromosome rearrangement (CCR) involving chromosomes 7, 8, and 13 was detected in a phenotypically normal woman ascertained through her mentally retarded son with abnormal phenotype. He had a karyotype with 47 chromosomes including an extra der(13). In initial banding studies the CCR in the mother was interpreted as a three-way translocation. Fluorescence in situ hybridization with whole chromosome libraries and a telomere-specific probe was used to better characterize the rearrangement. Combined data allowed us to reinterpret the CCR as a translocation and an insertion. A review of 35 familial CCRs involving at least three chromosomes led to the following observations: 1) familial CCRs tend to have fewer chromosomes involved and fewer break-points than do de novo CCRs; 2) familial transmission is mainly observed through female carriers although the origin of de novo cases is paternal; 3) an apparent excess of balanced female carriers among the offspring of index carriers was noted; and 4) meiotic segregation resulting in malformed liveborn infants is most frequently due to adjacent-1 segregation, followed by 4:2 segregation; no adjacent-2 segregation was observed.
In situ hybridization of a telomeric (TTA-GGG)n
sequence to metaphases from three cases of ring chromosome, involving respectively chromosomes 4, 16, and 20, showed the presence of the cognate sequences in all three rings. To investigate whether these ring chromosomes originated by telomere-telomere fusion, we determined, by in situ hybridization, whether telomere-associated sequences and/or specific distal sequences were still present in the ring chromosomes. The finding that these sequences were preserved in all the ring chromosomes strongly indicates that they originated by telomere-telomere fusion. All three subjects carrying the ring chromosomes are affected by the so-called ring syndrome, with failure to thrive, minor dysmorphic signs and no major anomalies. The r(4) patient has the ring in mosaic form with a normal cell line and has normal intelligence. The r(16) and the r(20) patients have moderate mental retardation and suffer from seizures. We conclude that the ring syndrome, even in its more severe manifestation, is caused by ring chromosome instability.
We report on a baby with a nonreciprocal de novo unbalanced translocation between chromosomes 12 and 15. Her karyotype was 45,XX, -12, -15, +der(12)t(12;15)(pter-->qter::q13-->qter). The paternal origin of the 15q11-13 region was shown by DNA marker studies and, consistent with this, the baby had the Prader-Willi (PWS) phenotype. The breakpoint on 12q was distal to D12S11 (lambda MS43) which maps to 12q24.3-qter. Fluorescent in situ hybridization using the oligonucleotides (TTAGGG)7 and (AATCCC)7 showed that the 12q telomere was still present within the translocated chromosome. Thus, the translocation was within or onto the end of the telomere of 12q. This unusual translocation is further evidence of an unexplained instability of the 15q11-13 region.
We report on a 19-month-old girl with a derivative chromosome 9 and a recombinant chromosome 12 resulting from a maternal balanced complex rearrangement involving chromosomes 8, 9, and 12. The karyotype of the phenotypically normal mother was 46,XX,t(8;12) (9;12) (8qter-->8p23::12q12-->12q 15::9q32-->9qter;9pter-->9q32::12q15--> 12qter; 12pter-->12q12::8p23-->8pter). The child's karyotype was 46,XX,-9,-12, +der(9) (9pter-->9q32::12q15-->12qter), +rec(12) (12pter-->12q15::9q32-->9qter) mat. The child had severe growth retardation, minor anomalies including trigonocephaly, hypertelorism, broad nasal root, apparently low-set and posteriorly angulated ears, triangular face, pectus carinatum, clinodactyly of fifth fingers, and almost normal psychomotor development. To the best of our knowledge, there have been only 3 previous reports of recombination derived from parental complex chromosome rearrangements. In the recombination products, the chromosomes were apparently balanced and the offspring had no clinical abnormalities. The present case exhibited abnormalities and may have a submicroscopic aberration of 12q arising from crossing over during maternal meiotic pairing, although her chromosomes appeared to be balanced.
We report on a male with Kallmann syndrome (KS) and an apparently balanced complex chromosome rearrangement (CCR): 46,XY,t(3; 9)(9;12)(q13.2;q21.2p13;q15). This is the first known report of a CCR in the KS and the second reported case of a definitive autosomal chromosome abnormality with KS. Possible relationships between the cytogenetic abnormality and KS are discussed.
We report on a mother and her two sons who had a direct duplication of chromosome region 8p22-8p23.1 without dysmorphic features and only mild mental retardation. The patients have been studied using G banding, chromosome painting, and FISH using cosmid probes specific for the region 8p23.1-8pter. Comparison of the phenotypes of our patients and of published patients with an inversion duplication of the short arm of chromosome 8 indicates that trisomy for chromosome band 8p21 causes the more severe clinical picture in the latter.