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1.  Der(22)t(11;22) resulting from a paternal de novo translocation, adjacent 1 segregation, and maternal heterodisomy of chromosome 22. 
Journal of Medical Genetics  1996;33(11):952-956.
The t(11;22) (q23;q11) translocation is the most frequently identified familial reciprocal translocation in humans. In translocation carriers, 3:1 meiotic segregation with tertiary trisomy can occur resulting in abnormal progeny with the der(22) as the supernumary chromosome. Affected children have a distinct phenotype with multiple anomalies and severe mental retardation. We have identified a child with developmental delay and multiple anomalies consistent with the der(22) phenotype. Cytogenetic analysis showed an abnormal chromosome complement of 47,XX,+der(22)t(11;22)(q23; q11) in all 50 cells analysed. FISH analysis using chromosome 11 and 22 painting probes showed a pattern consistent with a reciprocal translocation of the distal bands 11q23 and 22q11 respectively. Parental karyotypes were normal. RFLP analysis of locus D22S43, which maps above the t(11;22) breakpoint, showed that the der(22) was paternal in origin and indicated that the normal chromosomes 22 were the probable result of maternal heterodisomy. RFLP analysis of locus D22S94, which maps below the t(11;22) breakpoint, also suggested that both normal chromosomes 22 of the child represented the two maternal homologues. Non-paternity was excluded through the analysis of 10 microsatellite markers distributed on 10 different chromosomes and three VNTRs on three different chromosomes. To the best of our knowledge, this is the first reported case of a patient with an abnormal karyotype resulting from a de novo translocation in the paternal germline with probable unbalanced adjacent 1 segregation and maternal non-disjunction of chromosome 22 in meiosis I.
PMCID: PMC1050791  PMID: 8950677
2.  46,XX, der(15),t(Y;15)(q12;p11) karyotype in an azoospermic male 
Indian Journal of Human Genetics  2012;18(2):241-245.
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.
PMCID: PMC3491303  PMID: 23162305
46; XX male; azoospermia; Fluorescence In Situ Hybridization; infertility; Yq;15p translocation
3.  A Novel de novo Balanced Reciprocal Translocation t(18;22) Associated with Recurrent Miscarriages: A Case Report 
Recurrent miscarriage is a major concern in the couples with reproductive problems. The chromosomal abnormalities, mainly balanced rearrangements are reported in variable phenotypes and the prevalence of them is 2-8% in such couples.
Case Presentation
In this study, the clinical, cytogenetic and molecular cytogenetic evaluations were performed on a couple with RM. The cytogenetic analysis of the husband revealed a balanced reciprocal translocation of t(18;22)(q21.1;q12) whereas wife had a normal karyotype of 46,XX. Further spectral karyotyping was performed to rule out the involvement of any other chromosomal aberrations present in the genome. Additional whole chromosome paint FISH (Fluorescence in situ hybridization) with paint probes 18 and 22 confirmed the translocation.
To our knowledge, this is the first report of a novel (18;22) translocation with unique breakpoints and their association with RM. The reciprocal translocations provide a good opportunity for the identification of disease associated genes. However, in recurrent miscarriages, most of them do not disrupt any gene at the breakpoint but can lead to unbalanced gametes and hence poor reproductive outcome like RM or birth of a child with malformations and intellectual disability. The translocation breakpoints might be risk factors for RM. Moreover, the impact of the balanced translocations in association with RM is discussed in this report.
PMCID: PMC4032968  PMID: 24918085
Balanced translocation; FISH; GTG banding; Recurrent miscarriages; SKY
4.  Molecular and genomic characterisation of cryptic chromosomal alterations leading to paternal duplication of the 11p15.5 Beckwith‐Wiedemann region 
Journal of Medical Genetics  2006;43(8):e39.
Beckwith‐Wiedemann syndrome (BWS) is an overgrowth disorder with increased risk of paediatric tumours. The aetiology involves epigenetic and genetic alterations affecting the 11p15 region, methylation of the differentially methylated DMR2 region being the most common defect, while less frequent aetiologies include mosaic paternal 11p uniparental disomy (11patUPD), maternally inherited mutations of the CDKN1C gene, and hypermethylation of DMR1. A few patients have cytogenetic abnormalities involving 11p15.5.
Screening of 70 trios of BWS probands for 11p mosaic paternal UPD and for cryptic cytogenetic rearrangements using microsatellite segregation analysis identified a profile compatible with paternal 11p15 duplication in two patients.
Fluorescence in situ hybridisation analysis revealed in one case the unbalanced translocation der(21)t(11;21)(p15.4;q22.3) originated from missegregation of a cryptic paternal balanced translocation. The second patient, trisomic for D11S1318, carried a small de novo dup(11)(p15.5p15.5), resulting from unequal recombination at paternal meiosis I. The duplicated region involves only IC1 and spares IC2/LIT1, as shown by fluorescent in situ hybridisation (FISH) mapping of the proximal duplication breakpoint within the amino‐terminal part of KvLQT1.
An additional patient with Wolf‐Hirschorn syndrome was shown by FISH studies to carry a der(4)t(4;11)(p16.3;p15.4), contributed by a balanced translocation father. Interestingly, refined breakpoint mapping on 11p and the critical regions on the partner 21q and 4p chromosomal regions suggested that both translocations affecting 11p15.4 are mediated by segmental duplications. These findings of chromosomal rearrangements affecting 11p15.5–15.4 provide a tool to further dissect the genomics of the BWS region and the pathogenesis of this imprinting disorder.
PMCID: PMC2649021  PMID: 16882733
Beckwith‐Wiedemann syndrome; chromosomal rearrangements; imprinting 11p15 region; segmental duplicons
5.  A novel chromosomal translocation and heteromorphism in a female with recurrent pregnancy loss—a case study 
To evaluate the clinical, biochemical and cytogenetic analyses of a couple with reproductive failure.
A couple with a history of recurrent pregnancy loss was referred to the Institute of Genetics for cytogenetic evaluation. Chromosomal analysis of the phenotypically normal parents was done to ascertain the role of chromosomal abnormalities and offer appropriate genetic counseling. Further, advanced karyotype analysis by spectral karyotyping was also carried out in the couple and parents of the female partner.
Clinical and hormonal profile of the couple revealed normal phenotypes. The ultrasound scan of the female showed normal uterus and ovaries. Chromosomal analysis of the couple revealed a normal 46, XY karyotype in the male spouse, and a unique balanced reciprocal translocation 46, XX, t(12;13) (q13;q33) + 15pstk+ chromosomal constitution in the female partner. Cytogenetic analysis of her parents revealed a similar translocation between chromosomes 12 and 13 in the father and 15pstk+ in the mother. Further, corroboration of the chromosome abnormalities was carried out by spectral karyotyping.
A unique and novel familial transmission of paternally derived balanced reciprocal translocation and maternally derived heteromorphism in a female with the history of recurrent pregnancy loss was reported as an original investigation.
PMCID: PMC3401254  PMID: 22476504
Recurrent pregnancy loss; Balanced translocation; Heteromorphism; Spectral karyotype; Familial transmission; Hormonal profile; Chromosomal defect; Miscarriage
6.  Paternally inherited duplications of 11p15.5 and Beckwith-Wiedemann syndrome. 
Journal of Medical Genetics  1997;34(10):819-826.
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.
PMCID: PMC1051088  PMID: 9350814
7.  Miller-Dieker Syndrome with der(17)t(12;17)(q24.33;p13.3)pat Presenting with a Potential Risk of Mis-identification as a de novo Submicroscopic Deletion of 17p13.3 
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.
PMCID: PMC3111033  PMID: 21239872
Miller-Dieker syndrome; Lissencephaly; Array comparative genomic hybridization; Partial monosomy 17p
8.  Identification of a balanced complex chromosomal rearrangement involving chromosomes 3, 18 and 21 with recurrent abortion: case report 
Complex chromosome rearrangements (CCRs) are constitutional structural rearrangements involve more than two breakpoints on two or more chromosomes. Balanced CCR carriers are often phenotypically normal but associated with high risk of spontaneous abortion and having abnormal offspring with unbalanced karyotype. Here, we report a new familial case of complex chromosome structural aberrations involving chromosomes 3, 18 and 21 and four breakpoints.
Cytogenetic investigations showed a complex chromosomal chromosome rearrangement involving chromosomes 3, 18 and 21 with four breakpoints. 2 of 4 breakpoints were within the long arm of chromosome 18. Three-color fluorescence in situ hybridization (FISH) confirmed the complexity of the rearrangement and showed the derivative 21 to be composed of 3 distinct segments derived from chromosomes 21, 18, and 3. The karyotype of CCR carrier was determined as 46,XX,t(3;21;18)(3pter → 3q12::18q23 → 18qter;21pter → 21q22.1::18q21.1 → 18q23::3q12 → 3qter; 18pter → 18q21.1::21q22.1 → 21qter).
A new complex balanced CCR was characterized using conventional high resolution banding and molecular cytogenetic analysis. The results provided an explanation of recurrent abortion and abnormal child for balanced CCR carriers. Genetic counselling and prenatal diagnosis for couples with a balanced CCR is necessary since they have a high risk of having a child with unbalanced karyotype. Additional studies to reveal the molecular mechanism of CCRs would help reveal the rule of inherited CCRs in offspring.
PMCID: PMC4066826  PMID: 24959204
Complex chromosomal rearrangements (CCRs); Recurrent spontaneous abortions; Genetic counseling; Fluorescence in situ hybridization
9.  Early detection of Angelman syndrome resulting from de novo paternal isodisomic 15q UPD and review of comparable cases 
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.
PMCID: PMC3846355  PMID: 24011290
Angelman syndrome; Isodisomic 15; Uniparental disomy; Balanced translocation chromosome 15q
10.  Partial trisomy 2q(2q37.3-->qter) and monosomy 7q(7q34--->qter) due to paternal reciprocal translocation 2;7: a case report. 
Journal of Korean Medical Science  2003;18(1):112-113.
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.
PMCID: PMC3055003  PMID: 12589098
11.  Inheritance of a Chromosome 3 and 21 Translocation in the Fetuses, with One also Having Trisomy 21, in Three Pregnancies in One Family 
The majority of chromosome rearrangements are balanced reciprocal and Robertsonian translocations. It is now known that such abnormalities cause no phenotypic effect on the carrier but lead to increased risk of producing unbalanced gametes. Here, we report the inheritance of a translocation between chromosomes 3 and 21 in a family with one of two fetuses with Down Syndrome carrying the same translocation and the other also carrying the same translocation without the additional chromosome 21. Chromosomal analysis from fetal amniotic fluid and peripheral blood lymphocytes from the family were performed at the Çukurova University Hospital at Adana, Turkey. We assessed a family in which the translocation between chromosomes 3 and 21 segregates: one of the three progenies carried the 47,XX,+21,t(3;21)(q21;q22) karyotype and presented with Down Syndrome; another of the three progenies carried the 46,XX,t(3;21) (q21;q22) karyotype and the third had the 46,XY karyotype. Their mother is phenotypically normal. Apparently this rearrangement occurred due to an unbalanced chromosome segregation of the mother [t(3;21)(q21;q22)mat]. This family will enable us to explain the behavior of segregation patterns and the mechanism for each type of translocation from carrier to carrier and their effects on reproduction and numerical aberrations. These findings can be used in clinical genetics and may be used as an effective tool for reproductive guidance and genetic counseling.
PMCID: PMC4001423  PMID: 24778571
Cytogenetics; Diagnosis of reciprocal translocation; Fetal amniotic fluid; Down Syndrome
12.  Embryos of Robertsonian Translocation Carriers Exhibit a Mitotic Interchromosomal Effect That Enhances Genetic Instability during Early Development 
PLoS Genetics  2012;8(10):e1003025.
Balanced chromosomal rearrangements represent one of the most common forms of genetic abnormality affecting approximately 1 in every 500 (0.2%) individuals. Difficulties processing the abnormal chromosomes during meiosis lead to an elevated risk of chromosomally abnormal gametes, resulting in high rates of miscarriage and/or children with congenital abnormalities. It has also been suggested that the presence of chromosome rearrangements may also cause an increase in aneuploidy affecting structurally normal chromosomes, due to disruption of chromosome alignment on the spindle or disturbance of other factors related to meiotic chromosome segregation. The existence of such a phenomenon (an inter-chromosomal effect—ICE) remains controversial, with different studies presenting contradictory data. The current investigation aimed to demonstrate conclusively whether an ICE truly exists. For this purpose a comprehensive chromosome screening technique, optimized for analysis of minute amounts of tissue, was applied to a unique collection of samples consisting of 283 oocytes and early embryos derived from 44 patients carrying chromosome rearrangements. A further 5,078 oocytes and embryos, derived from chromosomally normal individuals of identical age, provided a robust control group for comparative analysis. A highly significant (P = 0.0002) increase in the rate of malsegregation affecting structurally normal chromosomes was observed in association with Robertsonian translocations. Surprisingly, the ICE was clearly detected in early embryos from female carriers, but not in oocytes, indicating the possibility of mitotic rather than the previously suggested meiotic origin. These findings have implications for our understanding of genetic stability during preimplantation development and are of clinical relevance for patients carrying a Robertsonian translocation. The results are also pertinent to other situations when cellular mechanisms for maintaining genetic fidelity are relaxed and chromosome rearrangements are present (e.g. in tumors displaying chromosomal instability).
Author Summary
Translocations involve exchange of material between two or more chromosomes and are a common form of genetic abnormality. The rearrangements are difficult to process during meiosis, frequently producing gametes with missing/extra pieces of the affected chromosomes. It has been suggested that translocations might also disrupt the segregation of structurally normal chromosomes, a so-called interchromosomal effect (ICE), but the published data is contradictory. Here we report results from a unique collection of samples, consisting of oocytes and embryos from translocation carriers. Examination of more than 210,000 chromosomes revealed no evidence of an ICE in oocytes, but a significant effect in embryos tested three days after fertilization (6–10 cell stage) in a subset of patients. Clinically, this means that some translocation carriers are at even higher risk of chromosomally abnormal pregnancies than previously suspected, a factor that should be considered during genetic counselling. Scientifically, the results illuminate a poorly understood stage of human development, characterized by chromosomal instability, reminiscent of that observed in some tumors. The restriction of the ICE to a narrow developmental window was unexpected, yet may explain why some earlier studies could not agree on the existence of an ICE.
PMCID: PMC3486902  PMID: 23133396
13.  Down syndrome: characterisation of a case with partial trisomy of chromosome 21 owing to a paternal balanced translocation (15;21) (q26;q22.1) by FISH. 
Journal of Medical Genetics  1997;34(1):50-54.
A patient with a typical Down syndrome (DS) phenotype and a normal karyotype was studied by FISH. Using painting probes, we found that the patient had partial trisomy of chromosome 21 owing to an unbalanced translocation t(15;21) (q26; q22.1) of paternal origin. To correlate genotype with phenotype as accurately as possible, we localised the breakpoint using a contig of YACs from the long arm of chromosome 21 as probes and performed FISH. We ended up with two YACs, the most telomeric giving signal on the der (15) in addition to signal on the normal chromosome 21 and the most centromeric giving signal only on both normal chromosomes 21. From these results we could conclude that the breakpoint must be located within the region encompassing YACs 280B1 and 814C1, most likely near one end of either YAC or between them, since neither YAC814C1 nor 280B1 crossed the breakpoint (most likely between marker D21S304 and marker D21S302) onband 21q22.1. The same study was performed on the chromosomes of the father and of a sister and a brother of the patient; all three carried a balanced translocation between chromosomes 15 and 21 and had a normal phenotype. We also performed a prenatal study using FISH for the sister. The fetus was also a carrier of the balanced translocation.
PMCID: PMC1050847  PMID: 9032650
14.  Cryptic deletions are a common finding in “balanced” reciprocal and complex chromosome rearrangements: a study of 59 patients 
Journal of Medical Genetics  2007;44(12):750-762.
Using array comparative genome hybridisation (CGH) 41 de novo reciprocal translocations and 18 de novo complex chromosome rearrangements (CCRs) were screened. All cases had been interpreted as “balanced” by conventional cytogenetics. In all, 27 cases of reciprocal translocations were detected in patients with an abnormal phenotype, and after array CGH analysis, 11 were found to be unbalanced. Thus 40% (11 of 27) of patients with a “chromosomal phenotype” and an apparently balanced translocation were in fact unbalanced, and 18% (5 of 27) of the reciprocal translocations were instead complex rearrangements with >3 breakpoints. Fourteen fetuses with de novo, apparently balanced translocations, all but two with normal ultrasound findings, were also analysed and all were found to be normal using array CGH. Thirteen CCRs were detected in patients with abnormal phenotypes, two in women who had experienced repeated spontaneous abortions and three in fetuses. Sixteen patients were found to have unbalanced mutations, with up to 4 deletions. These results suggest that genome‐wide array CGH may be advisable in all carriers of “balanced” CCRs. The parental origin of the deletions was investigated in 5 reciprocal translocations and 11 CCRs; all were found to be paternal. Using customised platforms in seven cases of CCRs, the deletion breakpoints were narrowed down to regions of a few hundred base pairs in length. No susceptibility motifs were associated with the imbalances. These results show that the phenotypic abnormalities of apparently balanced de novo CCRs are mainly due to cryptic deletions and that spermatogenesis is more prone to generate multiple chaotic chromosome imbalances and reciprocal translocations than oogenesis.
PMCID: PMC2652810  PMID: 17766364
15.  Autism Spectrum Disorder in a Girl with a De Novo X;19 Balanced Translocation 
Case Reports in Genetics  2012;2012:578018.
Balanced X-autosome translocations are rare, and female carriers are a clinically heterogeneous group of patients, with phenotypically normal women, history of recurrent miscarriage, gonadal dysfunction, X-linked disorders or congenital abnormalities, and/or developmental delay. We investigated a patient with a de novo X;19 translocation. The six-year-old girl has been evaluated due to hyperactivity, social interaction impairment, stereotypic and repetitive use of language with echolalia, failure to follow parents/caretakers orders, inconsolable outbursts, and persistent preoccupation with parts of objects. The girl has normal cognitive function. Her measurements are within normal range, and no other abnormalities were found during physical, neurological, or dysmorphological examinations. Conventional cytogenetic analysis showed a de novo balanced translocation, with the karyotype 46,X,t(X;19)(p21.2;q13.4). Replication banding showed a clear preference for inactivation of the normal X chromosome. The translocation was confirmed by FISH and Spectral Karyotyping (SKY). Although abnormal phenotypes associated with de novo balanced chromosomal rearrangements may be the result of disruption of a gene at one of the breakpoints, submicroscopic deletion or duplication, or a position effect, X; autosomal translocations are associated with additional unique risk factors including X-linked disorders, functional autosomal monosomy, or functional X chromosome disomy resulting from the complex X-inactivation process.
PMCID: PMC3447256  PMID: 23074688
16.  A cryptic deletion of 2q35 including part of the PAX3 gene detected by breakpoint mapping in a child with autism and a de novo 2;8 translocation 
Journal of Medical Genetics  2002;39(6):391-399.
We report a de novo, apparently balanced (2;8)(q35;q21.2) translocation in a boy with developmental delay and autism. Cross species (colour) paint (Rx) and SKY FISH, forward and reverse chromosome painting, and FISH with subtelomeric probes were used to examine the patient's karyotype, but further rearrangements were not detected. FISH with region specific clones mapping near 2q35 and 8q21.2 breakpoints and STS mapping performed on the isolated derivative chromosomes were used to refine the location of the breakpoints further. A cryptic deletion of between 4.23 and 4.41 Mb in extent and involving at least 13 complete genes or transcription units was found at the breakpoint on 2q35. The deletion includes the promoter and 5` untranslated region of the paired box 3 (PAX3) gene. The child has very mild dystopia canthorum which may be associated with the PAX3 haploinsufficiency. The 8q21.2 breakpoint is within MMP16 which encodes matrix metalloproteinase 16. We postulate that the cryptic deletion and rearrangement are responsible for the patient's phenotype and that a gene (or genes) responsible for autism lies at 2q35 or 8q21.2. The results present a step towards identifying genes predisposing to autism.
PMCID: PMC1735133  PMID: 12070244
17.  Unexpected Inheritance of a Balanced Homologous translocation t(22q;22q) from father to a phenotypically normal daughter 
Rearrangements between homologous chromosomes are extremely rare and manifest mainly as monosomic or trisomic offsprings. There are remarkably few reports of balanced homologous chromosomal translocation t (22q; 22q) and only two cases of transmission of this balanced homohologous rearrangement from mother to normal daughter are reported. Robersonian translocation carriers in non-homologous chromosomes have the ability to have an unaffected child. However, it is not possible to have an unaffected child in cases with Robersonian translocations in homologous chromosomes. Carriers of homologous chromosome 22 translocations with maternal uniparental disomy do not have any impact on their phenotype. We are presenting a family with a history of multiple first trimester miscarriages and an unexpected inheritance of balanced homologous translocation of chromosome 22 with paternal uniparental disomy. There are no data available regarding the impact of paternal UPD 22 on the phenotype. We claim this to be the first report explaining that paternal UPD 22 does not impact the phenotype.
PMCID: PMC4065487  PMID: 24959022
Balanced homologous chromosomal translocation; inheritance; uniparental disomy
18.  First Birth after Sperm Selection through Discontinuous Gradient Centrifugation and Artificial Insemination from a Chromosomal Translocation Carrier  
Case Reports in Genetics  2014;2014:906145.
Introduction. Balanced chromosomal carriers, though usually healthy, are confronted with recurrent spontaneous abortions and malformations in the offspring. Those are related to the transmission of an abnormal, chromosomally unbalanced genotype. We evidenced that the proportion of unbalanced spermatozoa can be significantly decreased through a sperm preparation process called discontinuous gradient centrifugation (DGC). We therefore started offering intrauterine inseminations with this procedure to couples with a male translocation carriers. Case Presentation. We report the case of a 37-year-old man carrying a t(3;10)(q25;p13) reciprocal translocation. He and his partner had had trouble conceiving for ten years and had four spontaneous abortions. DGC in this patient decreased the proportion of unbalanced spermatozoa from 63.6% to 52.3%. They were therefore offered intrauterine insemination with DGC, which eventually led to the birth of a healthy female child carrying the paternal translocation. Conclusion. We showed that translocation carriers could be offered intrauterine inseminations with DGC. Before this, the only two options were natural conception with prenatal diagnosis and termination of chromosomally unbalanced fetuses or preimplantation genetic diagnosis, which is a much heavier and costly procedure. We are currently offering this option through a multicentric program in France, and this is the first birth originating from it.
PMCID: PMC3920970  PMID: 24587925
19.  Chromosomal Microarray versus Karyotyping for Prenatal Diagnosis 
The New England journal of medicine  2012;367(23):2175-2184.
Chromosomal microarray analysis has emerged as a primary diagnostic tool for the evaluation of developmental delay and structural malformations in children. We aimed to evaluate the accuracy, efficacy, and incremental yield of chromosomal microarray analysis as compared with karyotyping for routine prenatal diagnosis.
Samples from women undergoing prenatal diagnosis at 29 centers were sent to a central karyotyping laboratory. Each sample was split in two; standard karyotyping was performed on one portion and the other was sent to one of four laboratories for chromosomal microarray.
We enrolled a total of 4406 women. Indications for prenatal diagnosis were advanced maternal age (46.6%), abnormal result on Down’s syndrome screening (18.8%), structural anomalies on ultrasonography (25.2%), and other indications (9.4%). In 4340 (98.8%) of the fetal samples, microarray analysis was successful; 87.9% of samples could be used without tissue culture. Microarray analysis of the 4282 nonmosaic samples identified all the aneuploidies and unbalanced rearrangements identified on karyotyping but did not identify balanced translocations and fetal triploidy. In samples with a normal karyotype, microarray analysis revealed clinically relevant deletions or duplications in 6.0% with a structural anomaly and in 1.7% of those whose indications were advanced maternal age or positive screening results.
In the context of prenatal diagnostic testing, chromosomal microarray analysis identified additional, clinically significant cytogenetic information as compared with karyotyping and was equally efficacious in identifying aneuploidies and unbalanced rearrangements but did not identify balanced translocations and triploidies. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others; number, NCT01279733.)
PMCID: PMC3549418  PMID: 23215555
20.  Identification of a rare de novo three-way complex t(5;20;8)(q31;p11.2;p21) with microdeletions on 5q31.2, 5q31.3, and 8p23.2 in a patient with hearing loss and global developmental delay: case report 
Complex chromosome rearrangements (CCRs), which involve more than two breakpoints on two or more chromosomes, are uncommon occurrences. Although most CCRs appear balanced at the level of the light microscope, many demonstrate cryptic, submicroscopic imbalances at the translocation breakpoints.
We report a female with hearing loss and global developmental delay with a complex three-way unbalanced translocation (5;20;8)(q31;p11.2;p21) resulting in microdeletions on 5q31.2, 5q31.3, and 8p23.2 identified by karyotyping, microarray analysis and fluorescence in situ hybridization.
The microdeletion of bands 8p23.2 may be associated with the hearing impairment. Furthermore, the characterization of this patient's chromosomal abnormalities demonstrates the importance of integrated technologies within contemporary cytogenetics laboratories.
PMCID: PMC2654037  PMID: 19128483
21.  18, X, Y aneuploidies and transmission electron microscopy studies in spermatozoa from five carriers of different reciprocal translocations 
Asian Journal of Andrology  2009;11(3):325-332.
We analysed ejaculated spermatozoa from five infertile men with different balanced reciprocal translocations to contribute to the study of meiotic segregation of chromosomes 18, X and Y and also to evaluate sperm morphology by transmission electron microscopy (TEM) analysis. Conventional lymphocyte karyotype analyses highlighted different reciprocal balanced translocations: t(12;13), t(4;9), t(X;8), t(8;10) and t(3;16). Semen analysis was performed by light and TEM. Fluorescence in situ hybridization was performed directly on sperm nuclei using centromeric probes for chromosomes 18, X and Y. The carriers of the balanced reciprocal translocations considered in the present study showed a very similar pattern of sperm pathologies: diffused presence of apoptosis and immaturity. All patients showed meiotic segregation derangements, highlighted by the presence of sperm diploidies and sex chromosome disomies particularly related to the failure of the first meiotic division. However, an increased incidence of chromosome 18 aneuploidy was detected in spermatozoa from t(X;8) and t(8;10) carriers. We have also reported values from sex chromosomes such as t(X;8), although the X chromosome was involved in translocation. Since patients with reciprocal translocations and spermatogenetic impairment are candidates for intracytoplasmic sperm injection cycles, the study of sperm parameters, and particularly of the level of aneuploidy rates, would provide better information for couples at risk and would contribute to the data in the literature for a better understanding of the effects of chromosomal rearrangement on the whole meiotic process and, in particular, on chromosomes not involved in translocation.
PMCID: PMC3735288  PMID: 19349951
electron microscopy; fluorescence in situ hybridization; altered karyotype; spermatozoa; reciprocal translocation
22.  Early developmental milestones and risk of schizophrenia. A 45-year follow-up of the Copenhagen Perinatal Cohort 
Schizophrenia research  2010;118(0):41-47.
The aim of the present study was to investigate the relationship between age of neuromotor milestone attainment and risk of adult schizophrenia. 5765 mothers of the Copenhagen Perinatal Cohort recorded 12 developmental milestones during the child’s first year of life. Cohort members were followed until they were 46–48 years old through record linkage with the Danish Psychiatric Central Research Register. The age at which milestones were met in the 92 individuals who later developed schizophrenia was compared with milestone attainment in the 691 individuals who developed other psychiatric disorders and in the 4982 cohort controls who were never admitted to a psychiatric department. Group comparisons were adjusted for gender, mother’s age, father’s age, parental social status, breadwinner’s education, single mother status and parity. Individuals who developed schizophrenia reached all developmental milestones later than controls and differed significantly from the controls with respect to the mean age of reaching the 12 milestones. Five developmental milestones in particular (smiling, lifting head, sitting, crawling, and walking) differed significantly. Individuals who later developed psychiatric disorders other than schizophrenia reached most developmental milestones earlier than those who developed schizophrenia, but later than the controls. The two psychiatric groups only differed significantly with respect to age of walking without support. The findings corroborate and methodologically extend previous research from prospective longitudinal cohort studies suggesting developmental delays observable as early as within the first year of life. These early developmental delays may not only characterize schizophrenia, but may be associated with a range of psychiatric disorders.
PMCID: PMC3676634  PMID: 20181463
developmental milestones; schizophrenia; neurodevelopment
23.  Prenatal evaluation in a case of familial Y chromosome long arm deletion (Yq—) 
Journal of Medical Genetics  1974;11(4):367-370.
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.
PMCID: PMC1013206  PMID: 4443985
24.  Isolated trisomy 7q21.2-31.31 resulting from a complex familial rearrangement involving chromosomes 7, 9 and 10 
Genotype-phenotype correlations for chromosomal imbalances are often limited by overlapping effects of partial trisomy and monosomy resulting from unbalanced translocations and by poor resolution of banding analysis for breakpoint designation. Here we report the clinical features of isolated partial trisomy 7q21.2 to 7q31.31 without overlapping phenotypic effects of partial monosomy in an 8 years old girl. The breakpoints of the unbalanced rearranged chromosome 7 could be defined precisely by array-CGH and a further imbalance could be excluded. The breakpoints of the balanced rearranged chromosomes 9 and 10 were identified by microdissection of fluorescence labelled derivative chromosomes 9 and 10.
The proband's mother showed a complex balanced translocation t(9;10)(p13;q23) with insertion of 7q21.2-31.31 at the translocation breakpoint at 9p13. The daughter inherited the rearranged chromosomes 9 and 10 but the normal chromosome 7 from her mother, resulting in partial trisomy 7q21.2 to 7q31.31. The phenotype of the patient consisted of marked developmental retardation, facial dysmorphism, short stature, strabism, and hyperextensible metacarpophalangeal joints.
For better understanding of genotype-phenotype correlation a new classification of 7q duplications which will be based on findings of molecular karyotyping is needed. Therefore, the description of well-defined patients is valuable. This case shows that FISH-microdissection is of great benefit for precise breakpoint designation in balanced rearrangements.
PMCID: PMC3261807  PMID: 22136633
chromosome microdissection; array-CGH; developmental delay; hypotonia; speech-delay; short stature; epicanthus; partial trisomy 7q21.2-7q31.31
25.  Partial trisomy 6p: 46,XX, -10, der(10),t(6;10) (p22;q26)pat and HLA localisation. 
Journal of Medical Genetics  1981;18(3):231-234.
A child with multiple facial anomalies showed partial trisomy 6p, 46,XX, -10,der(10), t(6;10)(p22;q26)pat. Family studies suggested that the HLA complex is probably between 6p22.4 and 6p21.05. The HLA system had previously been localised between 6p21 and 23(12) and more precisely located by Berger et al3 above 6p21.05. We have studied the clinical presentation and the HLA system of the family of a child with partial trisomy 6p derived from a paternal translocation. Since Breuning et al4 collected and studied the first six known cases of trisomy 6p, 12 cases have been found with similar clinical manifestations, varying in the breakpoint and the part of 6p which was triplicated. Independent of the classification of the clinical manifestations of new syndromes, the importance of duplication-deficiency chromosomal abnormalities is determined by the localised of gene loci. The HLA system was localised by Berger et al3 at above 6p21.05. Our results suggest that the HLA system is below 6p22.4, the breakpoint found in the balanced translocation 6p22;10q26 of the father which produced the partial trisomy 6p22 leads to pter of the proband.
PMCID: PMC1048712  PMID: 7241548

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