Prenatal diagnosis and molecular cytogenetic characterization of mosaic ring chromosome 13

We present prenatal diagnosis and molecular cytogenetic characterization of de novo mosaic r(13). A 32-year-old woman underwent amniocentesis at 18 weeks of gestation because of maternal anxiety. Amniocentesis revealed a karyotype of 46,XY,r(13)[33]/45,XY,-13[19]. aCGH on uncultured amniocytes at repeated amniocentesis detected a 4.22-Mb deletion at 13q34. Interphase FISH on 100 uncultured amniocytes showed the ratio of r(13):-13:idic r(13) as 85%:13%:2%. The cord blood had a karyotype of 46,XY,r(13)[91]/46,XY,idic r(13)[6]/45,XY,-13[3]. The placenta had a karyotype of 46,XY,mar(13)[31]/45,XY,-13[3]. Metaphase FISH confirmed that the marker chromosomes in placenta were derived from chromosome 13. aCGH on cultured placental cells detected a 77.81-Mb deletion at 13q13.3–q34. The fetus postnatally manifested facial dysmorphism. Prenatal diagnosis of r(13) should alert mosaicism for deletion/duplication of r(13) and distal 13q deletion. Fetoplacental chromosomal discrepancy of r(13) may exist in case of mosaic r(13) detected by amniocentesis.     

The ring chromosome 13 syndrome

Summary A study of the ring chromosome 13 syndrome is presented with detailed clinical and cytogenetic features of three new unrelated cases. The clinical limits of this syndrome can now be defined. An analysis of these cases together with those in the literature indicates that the syndrome forms a continuous spectrum, and no further taxonomic subdivision is possible at this stage of knowledge. The chromosome breakpoints in the first two cases are 13p11 and 13q32 and in the third case 13p11 and 13q33 or 13q34. All described cases of the ring 13 syndrome have breakpoints within the region bounded by bands 13q21 to 13q34. All rings are negative for silver banding. Peripheral blood cultures showed an average of 88% of metaphases to be 46.XX,r(13), with the remaining 12% manifesting either random loss or ring duplication. The rings vary in size and show a variable number of centromeres. An estimate of the birth incidence of this condition in the Anglo-Saxon population is 1 in 58,000. Parents of affected children are clincally and cytogenetically normal, the rings in affected offspring being meiotic in origin.     

Proximal monosomy 13

A 45,XX,-13, der(22), rcp(13;22)(q12;q13)mat karyotype was observed in a 7-month-old female with multiple congenital anomalies. Her mother is a balanced t(13;22)(q12;q13) carrier.     

Partial trisomy 13 due to maternal translocation t(2;13)]

The authors report an observation of partial trisomy 13p13 leads to qter and suggest a clinical map of chromosome 13. Increase of fetal hemoglobin seems to be controlled by region 1 of 13q. Bands q13 q14 and q21 seem to be responsible for inner organ malformations. Lastly, the distal segment q22 leads to qter is responsible for trigonocephaly and limb abnormalities.     

Regional mapping of clotting factors VII and X to 13q34. Expression of factor VII through chromosome 8

Summary Blood clotting factors were investigated in a patient with trisomy 8 mosaicism, a patient with an r(13), and a patient with distal trisomy 13q. Results are compatible with the assignment of the structural genes of factors VII and X to 13q34 and the existence of a regulatory mechanism associated with chromosome 8 controlling the expression of factor VII alone.     

Linkage of the Wilson disease gene to chromosome 13 in North-American pedigrees.

Wilson disease (WD) is an autosomal recessive disorder resulting in copper accumulation to toxic levels. Patients may present with neurologic, hepatic, or hematologic disease at any age between the first and fifth decade of life. Because of clinical heterogeneity, genetic heterogeneity in the etiology of the disease has been proposed. Recently, linkage of the WD locus to loci on 13q has been demonstrated in five Middle-Eastern kindreds. We have used esterase D and several polymorphic markers on 13q to investigate linkage in WD pedigrees from the United States and Canada. Ten kindreds, three with hepatic and seven with neurologic presentations, were informative, yielding a lod score of 2.189 at a recombination fraction of .06 with probe 7F12 at D13S1. Patients were generally of mixed European background, but one particularly informative pedigree was Hispanic. Our data confirm the provisional assignment of the gene for WD to 13q. More specifically, our findings indicate that, irrespective of ethnic background or clinical presentation, the linkage to 13q will be present in most pedigrees. The relative lack of linkage heterogeneity indicates that closely linked polymorphic loci on 13q can be useful in prenatal and presymptomatic diagnosis and in heterozygote detection.     

Partial trisomy of 13(pter→q12) due to 47,XY,+der(13),t(13;22)(q12;q13)mat

Summary A 36-month-old boy presented with short stature, short neck, shield-shaped chest, and mental retardation. Chromosome analysis showed trisomy for the short arm and the proximal portion of the long arm of chromosome 13 [47,XY,+der(13),t(13;22)(q12;q13)mat]. The patient's mother has a balanced translocation between the long arms of chromosomes 13 and 22 [46,XX,t(13;22)(q12;q13)]. The patient's neutrophils showed an elevated number of nuclear projections and his fetal hemoglobin level was undetectable.     

Giemsa banding in the t(13q13q) carrier mother of a translocation trisomy 13 abortus

Summary The abortus of a woman who had had three miscarriages and no normal pregnancies had a 46,XX,D-,t(DqDq)+karyotype. The mother was shown to carry the translocation in balanced state; Giemsa banding demonstrated the abnormal chromosome to be t(13q13q)

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Zusammenfassung Die Abortfrucht einer Frau mit 3 Fehlgeburten und keiner normal ausgetragenen Schwangerschaft hat einen Karyotyp 46,XX,D-,t(DqDq)+.Die Mutter hat die gleiche Translokation im balancierten Zustand. Mit Hilfe der Giemsafärbung erwies sich das abnorme Chromosom als t(13q13q).

     

Molecular cytogenetic analysis of eight inversion duplications of human chromosome 13q that each contain a neocentromere

Neocentromeres are fully functional centromeres that have arisen in previously noncentromeric chromosomal locations on rearranged chromosomes. The formation of neocentromeres results in the mitotic stability of chromosomal fragments that do not contain endogenous centromeres and that would normally be lost. Here we describe a unique collection of eight independent patient-derived cell lines, each of which contains a neocentromere on a supernumerary inversion duplication of a portion of human chromosome 13q. Findings in these patients reveal insight into the clinical manifestations associated with polysomy for portions of chromosome 13q. The results of FISH and immunofluorescent analysis of the neocentromeres in these chromosomes confirm the lack of alpha-satellite DNA and the presence of CENtromere proteins (CENP)-C, -E, and hMAD2. The positions of the inversion breakpoints in these chromosomes have been placed onto the physical map of chromosome 13, by means of FISH mapping with cosmid probes. These cell lines define, within chromosome 13q, at least three distinct locations where neocentromeres have formed, with five independent neocentromeres in band 13q32, two in band 13q21, and one in band 13q31. The results of examination of the set of 40 neocentromere-containing chromosomes that have thus far been described, including the 8 neocentromere-containing chromosomes from chromosome 13q that are described in the present study, suggest that chromosome 13q has an increased propensity for neocentromere formation, relative to some other human chromosomes. These neocentromeres will provide the means for testing hypotheses about sequence requirements for human centromere formation.     

A Chromosome 13q+in a patient with characteristics of the trisomy 13 syndrome

Summary In a patient with moderate multiple congenital anomalies, a chromosome 13q+was consistently present in lymphocytes and fibroblast cells. The additional segment replicates its DNA synchronously with the distal late replicating portion of chromosome 13. The patient exhibits several features common in the trisomy 13 syndrome, among others increased HbF and low HbA₂ values as compared to age matched controls. From these data, it is concluded that the patient carries a duplication of the distal third of chromosome 13 long arm. As a possible mechanism for the origin of this duplication, a meiotic pairing disorder due to repetitive gene constitution is discussed.

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Zusammenfassung Bei einem Mädchen mit nur mäßigen multiplen Mißbildungen fand sich ein Chromosom 13q+in allen untersuchten Zellen aus Blut und Bindegewebe. Das zusätzliche Chromosomensegment schließt die DNS-Synthese synchron mit dem distalen, relativ spät replizierenden Abschnitt von Chromosom 13 ab. Die Patientin zeigt zahlreiche klinische Merkmale der Trisomie 13, unter anderem erhöhte HbF- und niedere HbA₂-Werte im Vergleich zu altersgleichen Kontrollen. Aus diesen Befunden ist zu schließen, daß das Kind eine Duplikation für das distale Drittel des langen Armes eines Chromosome 13 trägt. Als möglicher Mechanismus für die Entstehung dieser Duplikation wird eine Störung der meiotischen Paarung diskutiert, die durch repetitive Sequenzen bedingt sein könnte.

     

The phenotype in partial 13q trisomies,apropos of a familial (13;15)(q22;q26) translocation

Summary A 12 month-old male patient with a karyotype 46, XY,-15,+der(15),t(13;15)(q22;q26)pat is presented. His stillborn sib showed malformations compatible with the 13q deletion syndrome, probably due to a 46,XY, der(13) karyotype. Phenotypic analysis of 41 cases from the literature with partial distal 13q (D13q) trisomies indicate that the segment 13q22 qter in trisomy with or without another concomitant aneusomy is sufficient to produce the majority of the trisomy 13 syndrome features, some of which (cleft palate, increased HbF and projections in PMN) are present in different non-overlapping partial 13q trisomies. About 82% of the D13q trisomies are inherited, more frequently from the mother.     

Trisomy 13 with a 13q14q translocation.

A sporadic case of Patau syndrome with 46,XY,14-,t(13q14q)+ karyotype is reported in a 2-month-old child. Dermatoglyphic and cytogenetic findings of the propositus and cytogenetic study of his parents are presented.     

Significant involvement of chromosome 13q deletions in progression of larynx cancer, detected by comparative genomic hybridization

Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous group of tumours with various clinical characteristics. These tumours generally exhibit complex karyotypes. Few studies of genomic imbalances have been performed exclusively in subgroups of larynx cancer samples at different stages of the disease. In the present study, chromosomal gains and losses were investigated in 52 larynx tumours, by using comparative genomic hybridization (CGH). The mean number of observed alterations was 37.7 per tumour. The most common sites of losses were 1p, 13q, Xp, and the most common gains were located in 1p, 9q, 16q. The overall number of gains was negatively associated with cancer grading. G1 tumours were also characterized by a higher frequency of deletions in 13q32 and amplifications in 1q23, than tumours in other grades (p < 0.05). The frequency of losses of 13q22 also positively associated with tumour size. There was no association between the frequency of losses in 13q and the presence of lymph node metastases at the time of diagnosis. Another statistically significant association was observed for gains at 1q22-23 and tumour size (p < 0.01). No statistically significant difference in the frequency of most common imbalances was detected between primary tumours with lymph node metastases and those without metastases. In conclusion, we discovered a significant involvement of 13q deletions in the progression of larynx cancer. All the other significant changes observed in the present study were reported previously as being important for HNSCC progression. It seems that multiple genes are disrupted in the process of neoplastic transformation in the larynx, and the networks of events remain to be elucidated.     

An 800-kb region of deletion at 13q14 in human prostate and other carcinomas

Deletions of regions at 13q14 have been detected by various genetic approaches in human cancers including prostate cancer. Several studies have defined one region of loss of heterozygosity (LOH) at 13q14 that seems to reside in a DNA segment of 7.1 cM between genetic markers D13S263 and D13S153. To define the smallest region of overlap (SRO) for deletion at 13q14, we first applied tissue microdissection and multiplex PCR to detect homozygous deletion and/or hemizygous deletion at 13q14 in 134 prostate cancer specimens from 114 patients. We detected deletions at markers D13S1227, D13S1272, and A005O48 in 13 (10%) of these tumor specimens. Of the 13 tumors with deletions, 12 were either poorly differentiated primary tumors or metastases of prostate cancer. To fine-map the deletion region, we then constructed a high-resolution YAC/BAC/STS/EST physical map based on experimental and database analyses. Several markers encompassing the deletion region were analyzed for homozygous deletion and/or hemizygous deletion in 61 cell lines/xenografts derived from human cancers of the prostate, breast, ovary, endometrium, cervix, and bladder, and a region of deletion was defined by duplex PCR assay between markers A005X38 and WI-7773. We also analyzed LOH at 13q14 in the 61 cell lines/xenografts using the homozygosity mapping of deletion approach and 26 microsatellite markers. We found 24 (39%) of the cell lines/xenografts to show LOH at 13q14 and defined a region of LOH by markers M1 and M5. Combination of homozygous or hemizygous deletion and LOH results defined the SRO for deletion to be an 800-kb DNA interval between A005X38 and M5. There are six known genes located in or close to the SRO for deletion. This region of deletion is at least 2 Mb centromeric to the RB1 tumor-suppressor gene and the leukemia-associated genes 1 and 2, each of which is located at 13q14. These data suggest that the 800-kb DNA segment with deletion contains a gene whose deletion may be important for the development of prostate and other cancers. This study also provides a framework for the fine-mapping, cloning, and identification of a novel tumor-suppressor gene at 13q14.     

Homozygosity for a Robertsonian translocation (13q14q) in three offspring of heterozygous parents

A family containing three homozygous carriers for a Robertsonian (13q14q) translocation, 44,XX or XY,t(13q14q),t(13q14q), is reported. Their parents are first cousins, and both are heterozygous carriers of the same (13q14q) translocation. The fertility of both the heterozygous and homozygous carriers is discussed.     

Investigation of 15q11-q13, 16p11.2 and 22q13 CNVs in Autism Spectrum Disorder Brazilian Individuals with and without Epilepsy

Copy number variations (CNVs) are an important cause of ASD and those located at 15q11-q13, 16p11.2 and 22q13 have been reported as the most frequent. These CNVs exhibit variable clinical expressivity and those at 15q11-q13 and 16p11.2 also show incomplete penetrance. In the present work, through multiplex ligation-dependent probe amplification (MLPA) analysis of 531 ethnically admixed ASD-affected Brazilian individuals, we found that the combined prevalence of the 15q11-q13, 16p11.2 and 22q13 CNVs is 2.1% (11/531). Parental origin could be determined in 8 of the affected individuals, and revealed that 4 of the CNVs represent de novo events. Based on CNV prediction analysis from genome-wide SNP arrays, the size of those CNVs ranged from 206 kb to 2.27 Mb and those at 15q11-q13 were limited to the 15q13.3 region. In addition, this analysis also revealed 6 additional CNVs in 5 out of 11 affected individuals. Finally, we observed that the combined prevalence of CNVs at 15q13.3 and 22q13 in ASD-affected individuals with epilepsy (6.4%) was higher than that in ASD-affected individuals without epilepsy (1.3%; p<0.014). Therefore, our data show that the prevalence of CNVs at 15q13.3, 16p11.2 and 22q13 in Brazilian ASD-affected individuals is comparable to that estimated for ASD-affected individuals of pure or predominant European ancestry. Also, it suggests that the likelihood of a greater number of positive MLPA results might be found for the 15q13.3 and 22q13 regions by prioritizing ASD-affected individuals with epilepsy.     

Del (13) (q33). Exclusion of esterase D (ESD) from 13q33 and q34]

A de novo del (13) (q33) was found in a 14-month-old boy with hypospadias. Phenotype anomalies included growth retardation, psychomotor retardation (QD = 64), microcephaly with brachycephaly, a round, flat and asymmetrical facies, a normal nose bridge, a small, pointed chin. The patient is heterozygous ESD 2-1. The gene localization may thus be excluded from bands 13q33 and q34 and assigned to bands q31 or q32, if its previous assignment to the q3 region is confirmed.     

Physical localisation of the chromosomal marker D13S31 places the Wilson disease locus at the junction of bands q14.3 and q21.1 of chromosome 13

D13S31 is the marker closest to the Wilson disease locus according to genetic analysis. Its physical localisation was refined by fluorescent in situ hybridisation to the junction to chromosomal bands 13q14.3 and 13q21.1. Using polymerase chain reaction analysis, D13S31 and D13S59 (the closest proximal and distal marker, respectively) were found to be located on the end of the der(13) consisting of 13pter-13q14.3: in the somatic cell hybrid ICD, and to be absent from the cell lines WC-H38B3B6 containing a del(13) (13pter-q13::13q21.1-qter) and KSF39 containing a del(13) (13pter-q14.1:).