Spectral karyotyping and fluorescence in situ hybridization analysis of de novo partial trisomy 7p (7p21.2-->pter) and partial monosomy 12q (12q24.33-->qter)

An 8-year-old boy presenting with hypotonia, moderate mental retardation, developmental delay, and psychomotor retardation is reported. Magnetic resonance imaging of the brain at age 3 years revealed a Dandy-Walker variant. Cytogenetic analysis of the peripheral blood revealed a derivative chromosome 12 with unknown additional material attached to the distal region of the long arm of chromosome 12. The parental karyotypes were normal. Spectral karyotyping (SKY) using the 24-color SKY probes and fluorescence in situ hybridization (FISH) using the specific 7p, 7q, 12p, and 12q telomeric probes confirmed a duplication of distal 7p and a deletion of terminal 12q. The karyotype of the proband was designated as 46,XY.ish der(12)t(7;12) (p21.2;q24. 33)(SKY+, 7pTEL+, 12qTEL-). The present case provides evidence for the association of partial trisomy 7p (7p21.2-->pter) and partial monosomy 12q (12q24.33-->qter) with a cerebellar malformation and the usefulness of SKY and FISH in the identification of a de novo aberrant chromosome resulting from an unbalanced translocation.     

No evidence for a paternal interchromosomal effect from analysis of the origin of nondisjunction in Down syndrome patients with concomitant familial chromosome rearrangements.

The parental origin of the extra chromosome 21 was determined with DNA polymorphisms in seven families in whom the proband and one of the parents carried an additional chromosome rearrangement (balanced translocation or pericentric inversion) not involving chromosome 21. The balanced rearrangement was inherited from the mother in two families and from the father in five families, whereas the additional chromosome 21 was derived from the mother in all seven families. These findings are not in agreement with the hypothesis of a paternal interchromosomal effect. The latter would imply that a balanced rearrangement in the father would favor nondisjunction during meiosis in the germ cells.     

Cytogenetic studies of a family with trisomy 21 mosaicism in two successive generations as the cause of Down's syndrome

Summary A family with trisomy-21 mosaicism in two successive generations and a Down's syndrome child in the third generation is presented. Cytogenetic studies of eight individuals of this family showed a marker chromosome 15ph+ and a heteromorphic chromosome 18 in some members. The standard trisomy 21 in the proband was derived from a trisomy-21 oogonium by secondary nondisjunction in his mother.     

46,XX, der(15),t(Y;15)(q12;p11) karyotype in an azoospermic male

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.     

A complex chromosomal rearrangement with a translocation 4;10;14 in a fertile male carrier: ascertainment through an offspring with partial trisomy 14q13-->q24.1 and partial monosomy 4q27-->q28 [corrected

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.     

Uniparental isodisomy for paternal 7p and maternal 7q in a child with growth retardation.

Uniparental isodisomy resulting from the simultaneous presence of isochromosomes of the p and q arms of a chromosome and absence of a normal homologue is an exceptionally rare event. We have observed a growth-retarded female infant in whom the normal chromosome 7 homologues were replaced by what appeared cytogenetically to be isochromosomes of 7p and 7q. Polymorphic microsatellite loci spanning the length of 7p and 7q were analyzed in the proband and her parents to ascertain the parental origin and extent of heterozygosity of the proband's rearranged chromosomes. These studies demonstrated that the 7p alleles of the proband were derived only from the father, the 7q alleles were derived only from the mother, and there was homozygosity for all chromosome 7 loci analyzed. The mechanisms leading to the formation of the proband's isochromosomes could reflect abnormalities of cell division occurring at meiosis, postfertilization mitosis, or both. We believe that the present case may result from incomplete mitotic interchange in the pericentromeric regions of chromosome 7 homologues, with resolution by sister-chromatid reunion in an early, if not first, zygotic division. Phenotypically, our proband resembled three previously reported cases of maternal isodisomy for chromosome 7, suggesting that lack of paternal genes from 7q may result in a phenotype of short stature and growth retardation.     

Segregation of two independent chromosomal translocations in one family

Summary A family with two independent reciprocal translocations t(3;19) and t(16;22) is described. The proband, a 4-week-old male, was phenotypically conspicious with multiple congenital anomalies. Cytogenetic examination revealed a balanced reciprocal translocation (3;19) and a supernumerary small marker chromosome. His mother carried two balanced reciprocal translocations, the one found in the proband and a reciprocal translocation (16;22). The maternal grandmother and a maternal uncle were identified as carriers of a single translocation (16;22). The findings in the family members permitted the identification of the proband's marker chromosome as a derivative chromosome 22 resulting in partial trisomy 16 and 22.     

Molecular confirmation of Wolf-Hirschhorn syndrome with a subtle translocation of chromosome 4.

Wolf-Hirschhorn syndrome is a clinically recognizable, multiple congenital anomaly syndrome usually associated with terminal deletion of the short arm of chromosome 4. A girl with clinical features of Wolf-Hirschhorn syndrome did not show an obvious deletion of chromosome 4, and a molecular defect was suspected. RFLPs of genomic DNA from the proband and her parents were studied using DNA probes from the distal region of chromosome 4p. Fluorescence in situ hybridization using a cosmid p847.351 containing the fragment 847 E-C was performed to investigate the possibility of a subtle translocation. Cytogenetic analyses done on the child and on both parents did not conclusively reveal abnormalities of chromosome 4. Molecular studies using two probes mapped to distal 4p showed the absence of the maternal haplotype in the child. These findings are thus consistent with a molecular deletion of 4p and confirm the diagnosis of Wolf-Hirschhorn syndrome. Cytogenetic experiments involving fluorescence in situ hybridization showed that the mother carried a subtle translocation between chromosomes 4 and 19, 46,XX,t(4,19)(p16.3; p13.3), which resulted in an unbalanced form in the child. Chorionic villus sampling for prenatal diagnosis in a subsequent pregnancy showed the fetus to be unaffected. This provides the first evidence, in chromosome 4p, of a molecular deletion due to a subtle, inherited translocation leading to the Wolf-Hirschhorn phenotype. Such subtle translocations may become an important mechanism for some recurrent genetic defects.     

Identification of a case of Y:18 translocation using a Y-specific repetitive DNA probe

Summary We have used a recombinant DNA clone derived from the Y-specific 3,4-kb repeats for in situ chromosome hybridization and Southern blotting analysis to identify a case of de novo Y;18 translocation. The proband has a chromosome complement of 46,XY and a variant chromosome 18 with a Q-bright and C-positive short arm. The father has a normal male karyotype of 46,XY. The mother has a female karyotype of 46,XX and an unusually large Q-bright satellite on one chromosome 22. In situ hybridization with the 3,4-kb probe to the metaphase preparations of family members indicated that the additional Q-bright material in the proband's variant chromosome 18 derived from the Y chromosome of his father, and not from the variant chromosome 22 of his mother. On Southern hybridization, the proband had approximately twice the amount of 3,4-kb repeats per cell as his father. These observations suggest a de novo genetic rearrangement in the proband which probably occurred during the father's spermatogenesis.     

De novo isochromosome 18p in a female dysmorphic child

Isochromosome 18p results in tetrasomy 18p. Most of the i(18p) cases reported so far in the literature are sporadic due to de novo formation, while familial and mosaic cases are infrequent. It is a rare chromosomal abnormality, occurring once in every 140,000 livebirths, affecting males and females equally. In the present investigation, we report a de novo i(18p) in a female dysmorphic child. The small metacentric marker chromosome was confirmed as i(18p) in the proband by cytogenetic and FISH analysis [47,XX+i(18p)]. Cytogenetic investigations in the family members revealed normal chromosome numbers, indicating the case as a de novo event of i(18p) formation. It could be due to the somewhat advanced maternal age (32 years) and/or expression of recessive genes in the proband, who is the progeny of consanguineous marriage, which could have led to misdivision and nondisjunction of chromosome 18 in meiosis I, followed by failure in the chromatid separation of 18p in meiosis II and by inverted duplication.     

Joubert syndrome co-existing with partial Xp trisomy: review of the literature

We report a five-year-old girl who has been clinically diagnosed as Joubert syndrome. Her cytogenetic analysis showed 46,XX,der(2)add(2q37) karyotype. Cytogenetic analysis of her mother and maternal grandmother revealed a karyogram designated as 46,X,t (X;2)(p11.2;q37). The proband's derivative chromosome was further confirmed to be a translocation chromosome 2 carrying segments from chromosome X, which originated from a segregation event of the maternal grandmother's balanced translocation passed on as a balanced translocation to the proband's mother either. So far, a number of candidate genes including EN1 on 2q were analyzed for Joubert syndrome. Based on our proband's abnormal karyotype, we suggest that further mapping studies for the syndrome should also be directed towards the chromosome X segments present on the derivative chromosome 2 of our proband.     

Molecular and cytogenetic characterization of a de novo t(5p;21q) in a patient previously diagnosed as monosomy 21.

Genomic single-copy DNA fragments were used to characterize an undetected chromosome translocation in an individual whose metaphase chromosome analysis revealed apparent monosomy 21. Eight RFLPs detected by six probes were used to identify homologous sequences from chromosome 21 in DNA digests from the proband and her parents. These family studies showed that the proband was disomic for the distal region of 21q. Reverse banding and in situ hybridization of chromosome 21-specific probes to metaphase chromosomes from the proband revealed a de novo translocation with breakpoints at 5p13 or 14 and 21q11 or 21. In situ hybridization permitted orientation of the translocated portion of chromosome 21 on the derivative chromosome 5 and, in conjunction with molecular analysis and previous mapping studies, refined the physical map for the long arm of chromosome 21.     

A dynamic study in two new cases of X chromosome translocations

Summary The authors discuss the clinical and cytogenetic problems raised in two new cases of X-chromosome translocations.The first case involves a child who presented marked growth retardation, behavioral anomalies, and discrete facial malformations at age 3 months. Chromosome analysis revealed the presence of a translocation between a 22 and X chromosome resulting in partial X monosomy and partial trisomy 22: 46,X,der(X),t(X;22)(q112;q13)mat. The balanced translocation form was detected in the mother. Dynamic study after 5-Brdu treatment revealed inactivation of the translocated X chromosome in the proband, while in the mother the normal X chromosome was inactivated.In addition to magnesium dependent hypocalcemia resulting from a specific absorption anomaly, Case 2 presented discrete malformations and psychomotor retardation. Chromosome analysis revealed an apparently balanced translocation between a 9 and X chromosome: 46,X,r(9;X)(q12; p22). Treatment with 5-Brdu demonstrated that the translocated X chromosome was inactivated but that inactivation did not extend to the translocated part of chromosome 9. Finally, a pericentric inversion of a 9 chromosome was detected in the father, grandfather, and brother of the proband.     

Partial isodisomy for maternal chromosome 7 and short stature in an individual with a mutation at the COL1A2 locus.

Uniparental disomy for chromosome 7 has been described previously in two individuals with cystic fibrosis. Here, we describe a third case that was discovered because the proband was homozygous for a mutation in the COL1A2 gene for type I procollagen, although his mother was heterozygous and his father did not have the mutation. Phenotypically, the proband was similar to the two previously reported cases with uniparental disomy for chromosome 7, in that he was short in stature and growth retarded. Paternity was assessed with five polymorphic markers. Chromosome 7 inheritance in the proband was analyzed using 12 polymorphic markers distributed along the entire chromosome. Similar analysis of the proband's two brothers established the phase of the alleles at the various loci, assuming minimal recombination. The proband inherited only maternal alleles at five loci and was homozygous at all loci examined, except one. He was heterozygous for an RFLP at the IGBP-1 locus at 7p13-p12. The results suggest that the isodisomy was not complete because of a recombination event involving the proximal short arms of two maternal chromosomes. In addition, the phenotype of proportional dwarfism in the proband suggests imprinting of one or more growth-related genes on chromosome 7.     

Inherited pericentric inversion of chromosome no. 2 with Robertsonian translocation (13q 14q) resulting in trisomy for chromosome 13q

This report includes a patient with an inherited pericentric inversion of chromosome No. 2 in addition to a Robertsonian translocation resulting in trisomy for chromosome 13q. The chromosomal constitution of the proband was 46,XX,inv(2) (pter leads to p11 : : q14 leads to p11 : : q14 leads to qter); t(13,14) (13qter leads to 13p11 : : 14q11 leads to 14qter). Sequential QFQ, RFA and GTG banding techniques were employed on the chromosomes of all family members. The chromosomal constitutions of the father and his first child were normal while the mother had an inversion of chromosome No. 2 [46,XX,inv(2) (pter leads to p11 : : q14 leads to p11 : : q14 leads to qter)]. The proband inherited this abnormal chromosome. In addition, she had a de novo Robertsonian translocation involving chromosomes 13q and 14q resulting in trisomy of chromosome 13q.     

A familial "balanced" 3;9 translocation with cryptic 8q insertion leading to deletion and duplication of 9p23 loci in siblings.

A child with phenotypic features of the 9p- syndrome, including metopic craniosynostosis, small ears, abdominal wall defect, and mental retardation, as well as hypopigmentation, was found to have a cytogenetically balanced 3;9 translocation, with breakpoints at 3p11 and 9p23, inherited from his phenotypically normal father. Molecular analysis showed heterozygous deletion of the TYRP (tyrosinase-related protein) locus, as well as loci D9S157, D9S274, D9S268, and D9S267, in the child but in neither parent. FISH analysis of the proband''s father indicated that loci deleted in his son, including TYRP, were present on neither the der(3) nor the der(9) translocation products but had been inserted into the long arm of chromosome 8. Therefore, the apparent deletion of these loci in the proband was the result of meiotic segregation of the father''s 3;9 translocation chromosomes together with his normal chromosome 8 (not bearing the insertion from 9p23). Neither the deletion of these 9p23 loci from the translocation chromosomes nor their insertion into 8q was detectable by standard chromosome banding techniques. The proband''s sister exhibited speech delay, mild facial dysmorphism, and renal malformation, and her karyotype was 46,XX. Molecular analysis showed that she had inherited normal chromosomes 3 and 9, as well as the chromosome 8 with the insertion of 9p23 material, from her father.(ABSTRACT TRUNCATED AT 250 WORDS)     

Partial translocation of NOR and its activity in a balanced carrier and in her cri-du-chat fetus

Summary Cytogenetic analysis of a balanced reciprocal translocation t(5;13) carrier and her unbalanced 5p-conceptus was carried out. This carrier mother had previously given birth to a child with cri-du-chat syndrome. Silver staining demonstrated the breakpoint on 13p within the nucleolus organizer region (NOR). In the carrier, the NORs both at the original site 13p0 and at the translocated site (5p) were silver-stained, indicating that the rRNA genes at both sites were transcribed. The NOR at the derivative chromosome 5 was also silver-stained in the fetus.     

Molecular analysis of a case of meiotic recombination leading to cri-du-chat syndrome

This paper describes a molecular investigation of a woman with an apparent large pericentric inversion of chromosome 5, inv(5)(p14;q35), and one normal chromosome 5 and her child, who was born with cri-du-chat syndrome. The four chromosome 5 homologs from the proband and his mother were isolated in somatic cell hybrids, and their haplotypes were determined at nine loci polymorphic for restriction enzyme sites. The deleted chromosome in the proband was shown to carry alleles from both maternal homologs, verifying molecularly that a meiotic recombination event in the mother gave rise to her son's deleted chromosome 5. The single crossover was presumably near the centromere.     

Molecular cytogenetic characterization of a familial balanced reciprocal translocation t(11;18) (q13.3; q23) associated with pregnancy wastage

A new male patient associated with a pregnancy wastage was detected in China. Cytogenetic analyses including G-banding, chromosome painting and observation of synaptonemal complexes (SCs) demonstrated that the pregnancy wastage was associated with a balanced reciprocal translocation t(11;18) (q13.3; q23). The proband was the carrier of the translocation and his karyotype was 46,XY,t(11;18)(11pter-->11q13.3:: 18q23-->18qter; 18pter-->18q23::11q13.3-->11qter). The pedigree was analyzed based on a G-banded karyotype of the nine familial members. The translocation chromosomes came from the proband's mother. The result of the SC observation in the proband showed that each of the spermatocytes displayed one quadrivalent during their pachytene stages. In the quadrivalents, there existed homologous and nonhomologous synapses and the latter occurred widely during early, middle and late pachytene stages. The reasons and genetic basis of the pregnancy wastage are discussed.     

Partial trisomy 4q: Two cases resulting from a familial translocation t(4;18)(q27;p11)

Summary Partial trisomy of the long arm of chromosome 4 was observed in two related patients, a child aged 2 years and a woman aged 42. Cytogenetic investigation revealed that their chromosome anomalies were due to segregation of a familial balanced translocation t(4;18)(q27;p11). Some clinical and cytogenetic considerations are noted.