Marriages involving partners both of whom have abnormal karyotypes are rare and are usually ascertained because of a history of infertility, repeated abortions, or the birth of a balanced translocation carrier or chromosomally abnormal offspring. Abnormalities which have been noted include sex chromosome aberrations in both parents or a sex chromosome abnormality in one parent and an autosomal abnormality in the other. Four papers have reported balanced reciprocal autosomal translocations in both parents, two couples representing a first cousin marriage. We present a case of a paternal 13;14 Robertsonian translocation and a maternal (7p;13q) reciprocal translocation in a couple with repeated fetal loss.
We report an unbalanced translocation involving chromosome 2 and 7 due to a balanced reciprocal translocation 2;7 in the father. The female fetus had a partial trisomy of the long arm of chromosome 2 with a partial monosomy of distal 7q. Ultrasound at the first trimester had indicated normal fetal anatomy, including normal intracranial structures. Parental karyotypes showed a paternal balanced translocation: 46,XY,t(2;7)(q37.3;-->q34). The unbalanced translocation in the fetus resulted in trisomy for 2q37.3 qter and monosomy for 7q34-->qter. Postnatal examination showed that the female abortus had a cleft lip and palate, and mild dysmorphic features. The clinical phenotype was in agreement with previous descriptions and allowed us to propose a fetal phenotype for this chromosomal abnormality.
We report on a Yq/15p translocation in a 23-year-old infertile male referred for Klinefelter Syndrome testing, who had azoospermia and bilateral small testes. Hormonal studies revealed hypergonadotropic hypogonadism. Conventional cytogenetic procedures giemsa trypsin giemsa (GTG) and high resolution banding (HRB) and molecular cytogenetic techniques Fluorescence In Situ Hybridization (FISH) performed on high-resolution lymphocyte chromosomes revealed the karyotype 46,XX, t(Y;15)(q12;p11). SRY-gene was confirmed to be present by classical Polymerase Chain Reaction (PCR) methods. His father carried de novo derivative chromosome 15 [45,X, t(Y;15)(q12;p11)] and was fertile; the karyotype of the father using G-band technique confirmed a reciprocal balanced translocation between chromosome Y and 15. In the proband, the der (15) has been inherited from the father because the mother had a normal karyotype (46,XX). In the proband, the der (15) could have produced genetic imbalance leading to unbalanced robertson translocation between chromosome Y and 15, which might have resulted in azoospermia and infertility in the proband. The paternal translocation might have lead to formation of imbalanced ova, which might be resulted infertility in the proband. Sister's karyotypes was normal (46,XX) while his brother was not analyzed.
46; XX male; azoospermia; Fluorescence In Situ Hybridization; infertility; Yq;15p translocation
We present clinical and cytogenetic data on a 7-year-old female child with partial trisomy for 9p22→9pter as a result of a maternal balanced reciprocal translocation. Her karyotype was ascertained as 46,XX,dec(4)t(4;9)(q35; p22)mat. The father had a normal karyotype, while the mother had an apparently balanced translocation involving chromosomes 4 and 9 [46,XX,t(4;9)(q35;p22)]. This case will be briefly compared with other published cases of a similar translocation.
Chromosome 9; Partial trisomy 9p; Maternal translocation
A case is reported in which a deleted Y chromosome was found in a fetal karyotype during a prenatal diagnosis performed because of maternal age anxiety. Quinacrine fluorescence studies demonstrated the same deleted Y in the child's father. The possibility of a reciprocal translocation in the father with a genetically unbalanced condition in the fetus was a concern. Careful examination of the father's karyotype and the study of other reported cases involving deleted Y chromosomes led to the conclusion that the fetal karyotype was genetically balanced. The prediction of a normal fetal development was confirmed at the child's birth.
Very few natural polymorphisms involving interchromosomal reciprocal translocations are known in amphibians even in vertebrates. In this study, thirty three populations, including 471 individuals of the spiny frog Quasipaa boulengeri, were karyotypically examined using Giemsa stain or FISH. Five different karyomorphs were observed. The observed heteromorphism was autosomal but not sex-related, as the same heteromorphic chromosomes were found both in males and females. Our results indicated that the variant karyotypes resulted from a mutual interchange occurring between chromosomes 1 and 6. The occurrence of a nearly whole-arm translocation between chromosome no. 1 and no. 6 gave rise to a high frequency of alternate segregation and probably resulted in the maintenance of the translocation polymorphisms in a few populations. The translocation polymorphism is explained by different frequencies of segregation modes of the translocation heterozygote during meiosis. Theoretically, nine karyomorphs should be investigated, however, four expected karyotypes were not found. The absent karyomorphs may result from recessive lethal mutations, position effects, duplications and deficiencies. The phylogenetic inference proved that all populations of Q. boulengeri grouped into a monophyletic clade. The mutual translocation likely evolved just once in this species and the dispersal of the one karyomorph (type IV) can explain the chromosomal variations among populations.
We report on a boy with non-syndromic hearing loss and an apparently balanced translocation t(10;15)(q26.13;q21.1). The same translocation was found in the normally hearing brother, father and paternal grandfather; however, this does not exclude its involvement in disease pathogenesis, for example, by unmasking a second mutation. Breakpoint analysis via FISH with BAC clones and long-range PCR products revealed a disruption of the arginyltransferase 1 (ATE1) gene on translocation chromosome 10 and the solute carrier family 12, member 1 gene (SLC12A1) on translocation chromosome 15. SNP array analysis revealed neither loss nor gain of chromosomal regions in the affected child, and a targeted gene enrichment panel consisting of 130 known deafness genes was negative for pathogenic mutations. The expression patterns in zebrafish and humans did not provide evidence for ear-specific functions of the ATE1 and SLC12A1 genes. Sanger sequencing of the 2 genes in the boy and 180 GJB2 mutation-negative hearing-impaired individuals did not detect homozygous or compound heterozygous pathogenic mutations. Our study demonstrates the many difficulties in unraveling the molecular causes of a heterogeneous phenotype. We cannot directly implicate disruption of ATE1 and/or SLC12A1 to the abnormal hearing phenotype; however, mutations in these genes may have a role in polygenic or multifactorial forms of hearing impairment. On the other hand, it is conceivable that our patient carries a disease-causing mutation in a so far unidentified deafness gene. Evidently, disruption of ATE1 and/or SLC12A1 gene function alone does not have adverse effects.
ATE1; Disease-associated balanced chromosome rearrangement; Non-syndromic hearing impairment; Reciprocal translocation; SLC12A1
Miller-Dieker syndrome involves a severe type of lissencephaly, which is caused by defects in the lissencephaly gene (LIS1). We report the case of a female infant with der(17)t(12;17)(q24.33;p13.3)pat caused by an unbalanced segregation of the parental balanced translocation of 17p with other chromosomes. The proband presented with facial dysmorphism, arthrogryposis, and intrauterine growth retardation. Most cases of Miller-Dieker syndrome have a de novo deletion involving 17p13.3. When Miller-Dieker syndrome is caused by an unbalanced translocation, mild-to-severe phenotypes occur according to the extension of the involved partner chromosome. However, a pure partial monosomy derived from a paternal balanced translocation is relatively rare. In this case, the submicroscopic cryptic deletion in the proband was initially elucidated by FISH, and karyotype analysis did not reveal additional chromosome abnormalities such as translocation. However, a family history of recurrent pregnancy abnormalities strongly suggested familial translocation. Sequential G-banding and FISH analysis of the father's chromosomes showed that the segment of 17p13.3→pter was attached to the 12qter. Thus, we report a case that showed resemblance to the findings in cases of a nearly pure 17p deletion, derived from t(12;17), and delineated by whole genome array comparative genomic hybridization (CGH). If such cases are incorrectly diagnosed as Miller-Dieker syndrome caused by de novo 17p13.3 deletion, the resultant improper genetic counseling may make it difficult to exactly predict the potential risk of recurrent lissencephaly for successive pregnancies.
Miller-Dieker syndrome; Lissencephaly; Array comparative genomic hybridization; Partial monosomy 17p
Thirty-six infants were identified by cytogenetic screening at birth as having balanced rearrangements of their autosomes, and 30 of them took part in a longitudinal study of their development, together with four of their affected sibs. With the exception of one child with a de novo reciprocal translocation who died, all children attended normal schools. Congenital malformations and short stature were present in only one child who had a de novo reciprocal translocation. The IQ scores of the 10 children with de novo translocations were significantly lower than those of the 20 children with familial translocations, but there were children in the de novo group of above average intelligence. Children with familial reciprocal translocations had significantly higher IQ scores than both the Robertsonian translocations and the controls, but the numbers in each category were small and a variety of different chromosomes were involved.
We present a three generation family in which a father and son have a balanced chromosome translocation between the short arms of chromosomes 5 and 11 (karyotype 46,XY,t(5;11)(p15.3;p15.3)). Two family members have inherited the unbalanced products of this translocation and are trisomic for chromosome 11p15.3-->pter and monosomic for chromosome 5p15.3-->pter (karyotype 46,XY,der(5)t(5;11)(p15.3;p15.3)pat). Paternally derived duplications of 11p15.5 are associated with Beckwith-Wiedemann syndrome (BWS) and both family members trisomic for 11p15.5 had prenatal overgrowth (birth weights >97th centile), macroglossia, coarse facial features, and broad hands. We review the clinical features of BWS patients who have a paternally derived duplication of 11p15.5 and provide evidence for a distinct pattern of dysmorphic features in those with this chromosome duplication. Interestingly, our family is the fifth unrelated family to be reported with a balanced reciprocal translocation between the short arms of chromosomes 5 and 11. The apparently non-random nature of this particular chromosome translocation is suggestive of sequence homology between the two chromosome regions involved in the translocation.
It has been suggested that translocations, and perhaps other chromosome rearrangements, disturb meiotic disjunction of uninvolved chromosome pairs and predispose to trisomic offspring. If so, then one would expect an excess of translocations not involving chromosome 21 among the parents of regular trisomic Down's syndrome patients. Such translocations have been reported, but mostly as anecdotal single case reports or very small series. In an attempt to collect a larger series, a collaborative study of regular Down's syndrome families was made in southern England. This was retrospective, and covered periods of 7 to 10 years since 1970. The number of regular trisomy families investigated was 1454. Only 945 of the 2908 parents were karyotyped, and 10 balanced reciprocal translocations not involving chromosome 21 were identified, together with one Robertsonian (13q14q). Expressing these as percentages of the parents tested (945), prevalences are as follows: reciprocals 1.06%, Robertsonians 0.11%, and all translocations 1.16%. Expressed as percentages of the total parents (2908), tested and untested, the prevalences are 0.34%, 0.03%, and 0.37% respectively. The 'true' prevalences, that is what would have been found had all parents been tested, must lie between these two sets of figures. The prevalence of reciprocal translocations exceeds that found for consecutive banded newborn infants, which is 0.16%, and this excess may reflect a real interchromosomal effect. Robertsonian translocations in the banded newborn series are at a frequency of 0.11%, identical to that found in the tested parents of regular trisomics. Interpretation of these figures is critically dependent upon the real prevalence of translocations among the newborn, estimates of which increase as technical methods are improving.
A phenotypically normal woman has an apparently balanced reciprocal translocation between chromosomes No. 9 and No. 18 (translocation 9p-; 18p+), which was transmitted in an unbalanced state to an infant and a fetus. In the latter instance, chromosome analysis of cultured amniotic cells disclosed an abnormal karyotype, which was identical to that of the first affected child. The therapeutically aborted fetus was grossly abnormal and resembled the affected child. The physical features noted are those frequently associated with chromosome abnormalities, although not diagnostic for any specific syndrome. We presume that the chromosome abnormality in the affected offspring represents partial duplication of the short arm of chromosome No. 9 and partial deletion of the short arm of chromosome No. 18. No marked resemblance is noted between these cases and reported cases of trisomy 9 or of partial deletion of the short arm of 18.
A familial reciprocal translocation t(6p+;11q−) is presented, unbalanced (6p+) in the craniorachischisic propositus and balanced in his phenotypically normal father, associated with relative infertility, multiple spontaneous abortions, and failure to produce normal offspring. The karyotype-phenotype relationship is discussed with reference to other published cases of partial trisomy for the distal portion of the long arm of chromosome 11, and the concept of deletionunmasking is briefly considered. The occurrence of major neural groove closure defects due to a variety of translocations in mice is noted. The gametic segregation of balanced and unbalanced karyotypes is unique to each particular translocation making recurrence risk projections hazardous in the absence of prior experience with the particular translocation. The questions of the relative importance of genetic inheritance, chromosomal abnormalities, and many environmental factors including possible specific teratogens in causing neural groove closure anomalies are still unsettled. The paucity of published chromosome studies in these malformations is noted. We urge that cytogenetic studies with banding techniques be undertaken on these cases and their parents in order to expand basic knowledge of the role of chromosomal errors in their aetiology.
Double translocation heterozygotes are rare, but need not necessarily pose more of a counselling problem than single reciprocal translocation heterozygotes. Nine cases of double translocation are presented, together with a review of the few reports published to date. An attempt is made to provide simple counselling guidelines in the assessment of the risk of producing a liveborn abnormal child. This is not based on theoretical considerations of segregation patterns, but extrapolated from what is known empirically about the viable segregation patterns in carriers of single reciprocal translocations. It assumes that there is no interference with the independent assortment of the two separate exchanges, unless a common participating chromosome is involved. The possibility of an interchromosomal effect has not been taken into consideration.
A female infant with severe mental retardation, general hypotonicity, and a history of generalised oedema, cyanosis, heart murmur, and nystagmus in the first days of life was found to have both a translocation and a deletion. Her karyotype was 46,XX,del(21)t(18;21)(18p ter leads to 18q11::21q21 leads to 21qter;21pter leads to 21q11::18q11 leads to 18q ter). The karyotype of both parents was normal. The proposita is the result of a three break point exchange and is monosomic for part of the dark band q11 q21 of chromosome 21. It is suggested that in cases with mental retardation and apparent balanced de novo reciprocal translocation a small undetected deletion in one of the chromosomes involved in the translocation could explain the mental retardation.
A female with Duchenne muscular dystrophy, diagnosed at the age of 3 years 8 months, is reported. Chromosome studies revealed an X;autosome reciprocal translocation t(X;5) (p21.2;q31.2). With the BrdU-Hoechst 33258-Giemsa technique, there was nonrandom preferential inactivation of the normal X. Our patient is the ninth reported case of Duchenne muscular dystrophy associated with an X;autosome translocation. In all cases the breakpoint in the X chromosome is in band p21 at or near the site of the DMD gene.
Angelman syndrome is a rare neurogenetic disorder that results in intellectual and developmental disturbances, seizures, jerky movements and frequent smiling. Angelman syndrome is caused by two genetic disturbances: either genes on the maternally inherited chromosome 15 are deleted or inactivated or two paternal copies of the corresponding genes are inherited (paternal uniparental disomy). A 16-month-old child was referred with minor facial anomalies, neurodevelopmental delay and speech impairment. The clinical symptoms suggested angelman syndrome. The aim of our study was to elucidate the genetic background of this case.
This study reports the earliest diagnosed angelman syndrome in a 16-month-old Hungarian child. Cytogenetic results suggested a de novo Robertsonian-like translocation involving both q arms of chromosome 15: 45,XY,der(15;15)(q10;q10). Molecular genetic studies with polymorphic short tandem repeat markers of the fibrillin-1 gene, located in the 15q21.1, revealed that both arms of the translocated chromosome were derived from a single paternal chromosome 15 (isodisomy) and led to the diagnosis of angelman syndrome caused by paternal uniparental disomy.
AS resulting from paternal uniparental disomy caused by de novo balanced translocation t(15q;15q) of a single paternal chromosome has been reported by other groups. This paper reviews 19 previously published comparable cases of the literature. Our paper contributes to the deeper understanding of the phenotype-genotype correlation in angelman syndrome for non-deletion subclasses and suggests that patients with uniparental disomy have milder symptoms and higher BMI than the ones with other underlying genetic abnormalities.
Angelman syndrome; Isodisomic 15; Uniparental disomy; Balanced translocation chromosome 15q
A 7 year old girl is described with congenital hypoplastic anaemia (Diamond-Blackfan anaemia, DBA) and an apparently balanced reciprocal translocation, 46,XX,t(X;19)(p21;q13). The girl has associated features including short stature, unilateral kidney hypoplasia, and a branchial cyst. Fluorescent in situ hybridisation (FISH) studies with 19q specific cosmids showed that the chromosome 19 breakpoint is located between the RYR1 and the XRCC11 loci spanning a physical region of 5 Mb. There is no family history of DBA and the parents and two healthy sibs have normal karyotypes. This is the first report of a balanced translocation associated with DBA and we suggest that the distinct phenotype has resulted from a de novo disruption of a functional gene. DBA can be inherited as an autosomal trait and our observation may indicate a candidate gene for the disorder in the 19q13 region.
The purpose of the present study was to investigate the contribution of chromosomal anomalies and the frequency of a particular type of aberration in couples with recurrent miscarriages.
A total of 1,162 couples with recurrent miscarriages were analyzed using G-banding and Fluorescence in situ hybridization where ever necessary.
Chromosomal anomalies were detected in 78 cases. This study describes majority of the cases with balanced reciprocal translocations. Among the abnormal karyotypes we also report for the first time three unique translocations involving (3;14), (18;22) and (X;22) chromosomes which were confirmed by molecular cytogenetic methods.
The review of literature and the overall incidence of the abnormalities suggest that chromosomal analysis in couples with recurrent miscarriages should be taken up by all the practioners at all levels. This not only helps to check the cytological abnormalities but also helps to correlate the recurrent abnormalities in a given population. Thus establishing and correlating the environmental and genetic condition of that particular phenotype and genotype.
Breakpoints; Chromosomal abnormalities; Recurrent miscarriages; Translocations
Carriers of balanced reciprocal translocations may have a (high) risk for producing liveborn children with an unbalanced karyotype. We report a large family in which a translocation between the long arm of chromosome 11 and the short arm of chromosome 13 is segregating in at least five generations. During the course of our study 15 carriers of the balanced translocation were identified and nine cases of partial trisomy of the long arm of chromosome 11 were detected during pre- and postnatal studies. Several of the patients were thoroughly clinically examined and compared with similar published cases.
A case of de novo, apparently balanced, three way exchange by translocation plus a pericentric inversion is described. The karyotype is 46,XX,t(6;11)(p21;q21),t(11;21) (q21;p13),inv(6)(p21q11) and was ascertained through second trimester amniocentesis. The structural rearrangements appear balanced. The child was phenotypically normal at birth. Growth and motor development were normal until 30 months, at which time linear growth dropped below the 5th centile. In addition, there was delayed speech development at 2 years of age. As far as we can determine, this is the first report of a three chromosome exchange including a pericentric inversion ascertained through genetic amniocentesis.
Unbalanced chromosomal rearrangements are not common; however, they have a significant clinical expression. The parental balanced translocation produces unbalanced chromosome, which is transmitted to next generation through fertilization of gametes carrying the derivative chromosome. The carriers of balanced rearrangements mostly do not have recognizable phenotypic expression. We report a family comprising of healthy and non-consanguineous young parents and their preemie newborn severely affected with congenital anomalies and systemic disorders. Conventional Gbanding analysis of somatic chromosomes identified a balanced translocation, t(6;10)(p23;q24), in mother and an unbalanced rearrangement, der(6)t(6:10)(p23;q24)mat, in the child. The child has inherited a derivative chromosome 6 with partial deletion of 6(p23-pter) and partial trisomy 10(q24-qter), which has resulted in fusion of genes of two different chromosomes. The prominent phenotypic features of del(6p), including high forehead, flat nasal bridge, agenesis of left ear, atrial septal defect (ASD), craniosynostosis, and growth retardation, are overlapping with specific Axenfeld-Reiger-, Larsen-, and Ritscher-Sinzel/3-C syndromes, however, lacking in ocular anomalies, skeletal laxity, or cerebellar malformation. Therefore, this paper rules out the isolated effect of del(6p23) or trisomy 10(q24) on distinct previously reported syndromes and proposes the combined effect of unbalanced chromosomal alteration.
To demonstrate that translocation carrier patients can be identified by analysis of chromosomes in preimplantation human embryos.
A report of 3 cases in which multiple embryos were found to possess consistent segmental imbalances by CCS. The parents then had a conventional karyotype performed.
In each case, parental karyotyping revealed the presence of an otherwise unknown balanced translocation. Original blastocyst CCS results were then reinterpreted to consider the presence of unbalanced derivative chromosomes and to modify the diagnosis of embryos eligible for transfer.
It is possible to identify patients that are carriers of balanced translocations through the analysis of chromosomes in their IVF-derived embryos. Given that translocation carrier screening is not routinely performed, the growing use of CCS may facilitate discovery and provide both an etiology of reproductive failure and an improved more focused treatment strategy going forward. Future work will involve a large retrospective study to define the sensitivity and frequency of detection using this methodology.
Balanced translocation; SNP microarray; Quantitative real-time PCR; Aneuploidy; Comprehensive chromosome screening
The distribution of the points of breakage and reunion of a series of 58 Robertsonian translocations, 53 reciprocal translocations, and 10 inversions is described. An excess of 13/14 and 14/21 rearrangements was found among the Robertsonian translocations, this excess being independent of the method of ascertainment of the proband. The distribution of break points between chromosome arms in the reciprocal translocations, with the possible exception of the long arms of chromosome 11, was no different from that expected on the basis of their relative lengths. However, within arms there appeared to be an excess of breaks in the terminal regions, an excess of terminal/centromeric translocations where ascertainment was through a balanced carrier and a possible excess of terminal/median translocations where ascertainment was through an unbalanced carrier. Nine inversions were analysed and three of these involved identical break points on chromosome 8.
Possible reasons for the apparent non-randomness of points of breakage and exchange are discussed and it is concluded that the techniques of preparation, methods of observations, and methods of ascertainment all affect the distribution of observed points of breakage and exchange and must therefore be taken into cognizance in any study of chromosome rearrangements in man.
Donnai–Barrow syndrome [Faciooculoacousticorenal (FOAR) syndrome; DBS/FOAR] is a rare autosomal recessive disorder resulting from mutations in the LRP2 gene located on chromosome 2q31.1. We report a unique DBS/FOAR patient homozygous for a 4-bp LRP2 deletion secondary to paternal uniparental isodisomy for chromosome 2. The propositus inherited the mutation from his heterozygous carrier father, whereas the mother carried only wild-type LRP2 alleles. This is the first case of DBS/FOAR resulting from uniparental disomy (UPD) and the fourth published case of any paternal UPD 2 ascertained through unmasking of an autosomal recessive disorder. The absence of clinical symptoms above and beyond the classical phenotype in this and the other disorders suggests that paternal chromosome 2 is unlikely to contain imprinted genes notably affecting either growth or development. This report highlights the importance of parental genotyping in order to give accurate genetic counseling for autosomal recessive disorders.
Donnai–Barrow (DBS/FOAR) syndrome; uniparental isodisomy (UPD); paternal chromosome 2; reduction to homoallelism