A case of duplication of 13q32-->qter and deletion of 18p11.32-->pter with mild phenotype: Patau syndrome and duplications of 13q revisited.

A mild clinical phenotype is described in a patient with duplication of 13q32-->qter and a small deletion of 18p11.32-->pter. The 8 year old white male presented with psychomotor retardation, tethered cord, soft, fleshy ears, and normal facial features except for thin lips. The karyotype was found to be 46, XY, der(18)t(13;18) (q32;p11.32) pat confirmed by fluorescence in situ hybridisation (FISH). A review of earlier studies showed that features of trisomy 13 are found in cases of duplication of bands 13q14 to qter. None of the cardinal features of trisomy 13 was seen in this patient. The absence of polydactyly, hernias, urogenital abnormalities, and haemangiomas contrast this condition with both trisomy 13 and duplication of 13q14-22-->qter. Possible explanations for lack of Patau syndrome in this patient could include restriction of the critical region for Patau syndrome to duplication 13q14-->13q32 with variable expression, gene interactions, or interchromosomal effects.     

Origin of a paternal (13q; 15q) translocation leading to dup(13q) in two half sibs

We report on two half-sibs, a male and a female with dup(13)(q1405 → qter) that resulted from a der(15),t(13;15)(15qter → 15q25::13q1405 → 13qter), h +, pat. Their manifestations were similar to those with duplication of the distal half 13q. The father was a balanced de novo translocation carrier. Since the der(15) had a long secondary constriction, it was possible to trace the site of the mutation to the germ cell of the patients paternal grandmother who had this distinctive long secondary constriction in one of her normal 15 chromosomes.     

Origin of a paternal (13q;15q) translocation leading to dup(13q) in two half sibs

We report on two half-sibs, a male and a female with dup(13)(q1405 leads to qter) that resulted from a der(15),t(13;15)(15qter leads to 15q25::13q1405 leads to 13qter), h+, pat. Their manifestations were similar to those with duplication of the distal half 13q. The father was a balanced de novo translocation carrier. Since the der(15) had a long secondary constriction, it was possible to trace the site of the mutation to the germ cell of the patients paternal grandmother who had this distinctive long secondary constriction in one of her normal 15 chromosomes.     

Cryptic subtelomeric translocations in the 22q13 deletion syndrome

Cryptic subtelomeric rearrangements are suspected to underlie a substantial portion of terminal chromosomal deletions. We have previously described two children, one with an unbalanced subtelomeric rearrangement resulting in deletion of 22q13→qter and duplication of 1qter, and a second with an apparently simple 22q13→qter deletion. We have examined two additional patients with deletions of 22q13→qter. In one of the new patients presented here, clinical findings were suggestive of the 22q13 deletion syndrome and FISH for 22qter was requested. Chromosome studies suggested an abnormality involving the telomere of one 22q (46,XX,?add(22)(q13.3)). FISH using Oncor D22S39 and Vysis ARSA probes confirmed a terminal deletion. A multi-telomere FISH assay showed a signal from 19qter on the deleted chromosome 22. Results were confirmed with 19qtel and 22qtel specific probes. The patient is therefore trisomic for 19qter and monosomic for 22qter. The patient''s mother was found to have a translocation (19;22)(q13.42;q13.31). We also re-examined chromosomes from two patients previously diagnosed with 22q deletions who were not known to have a rearrangement using the multi-telomere assay. One of these patients was found to have a derivative chromosome 22 (der(22)t(6;22)(p25;q13)). No evidence of rearrangement was detected in the other patient. Thus we have found the 22q13 deletion to be associated with a translocation in three of four patients. This report illustrates the usefulness of examining patients with hypotonia, severe language delay, and mild facial dysmorphism for this syndrome and suggests that most of these deletions may be unbalanced subtelomeric rearrangements.     

Partial deletion of 14q and partial duplication of 14q in sibs: Testicular mosaicism for t(14q;14q) as a common mechanism

The propositus and a subsequently born sister presented with multiple congenital anomalies. Chromosome analyses were performed initially on peripheral blood lymphocytes from the propositus and his parents: the propositus was found to have a deletion of chromosome 14 (q32.11->qter); the parents' chromosomes were normal. When the sister of the propositus was born, she was determined to have a duplication of an equivalent segment of 14qter. Chromosome studies on the parents' fibroblasts demonstrated no structural abnormality or mosaicism. The parents have an older, phenotypically normal, healthy daughter, which supports mosaicism for intragonadal t(14;14)(q32.11;q32.33) in one parent. Chromosome polymorphism comparisons show that the normal number 14 chromosome in the propositus and his sister was inherited from the mother, thus indicating paternal testicular mosaicism. Clinical findings are compared to those of other reported cases of deletion 14q and duplication 14q.     

Tetrasomy 13q31.1qter due to an inverted duplicated neocentric marker chromosome in a fetus with multiple malformations

Small supernumerary marker chromosome (sSMC) lacking alpha satellite DNA or endogenous centromere regions are rare and contain fully functional centromeres, called neocentromeres. We report on a woman with a 14-week gestation pregnancy with a cystic hygroma and cerebellar hypoplasia at ultrasound examination. Cytogenetic studies showed a karyotype 47,XY,+mar dn. This sSMC was observed in chorionic villi, lung, and muscle tissue. Array Comparative Genomic Hybridization showed a gain from 13q31.1 to 13qter region. Fluorescent in situ hybridization with pan alpha satellite probe and probes specific for chromosome 13 showed a marker corresponding to an inversion duplication of the 13q distal chromosomal region without alpha satellite DNA sequence, suggesting the presence of a neocentromere. Examination of the fetus showed dysmorphic features, cystic cervical hygroma, postaxial polydactyly of the right hand and left foot with short fingers, malrotation of the gut, and a micropenis with hypospadias. Genotype-phenotype correlation in tetrasomy 13q is discussed according to the four 13q chromosomal breakpoints reported (13q32, 13q31, 13q21, 13q14) for chromosome 13 supernumerary markers.     

Neuroblastoma in a boy with MCA/MR syndrome,deletion 11q,and duplication 12q

Deletion 11q23→qter and duplication 12q23→qter are described in a boy with neuroblastoma, multiple congenital anomalies, and mental retardation. The patient has clinical manifestations of 11q deletion and 12q duplication syndromes. The possible involvement of the segment 11q23→24 in the cause of the neuroblastoma is discussed. © 1995 Wiley-Liss, Inc.     

Trisomy 20q13 --> 20qter in a girl with multiple congenital malformations and a recombinant chromosome 20 inherited from a paternal inversion (20)(p13q13.1): clinical report and review of the trisomy 20q phenotype

We report on a patient with a rec(20)dup(20q) chromosome abnormality derived from a paternal chromosome 20 inversion [inv(20)(p13q13.1)]. The rearrangement results in a duplication of 20q13.1 to 20qter and a deletion of 20p13 to 20pter. The patient is a girl with craniofacial features and multiple congenital malformations that overlap with the abnormalities previously described in trisomy 20q syndrome. To our knowledge this is the first report of a patient with rec(20)dup 20q.     

Boy with bilateral retinoblastoma due to an unusual ring chromosome 13 with activation of a latent centromere

We present a patient with bilateral retinoblastoma and developmental delay who has an abnormal male karyotype containing 47 chromosomes, including an acentric derivative chromosome 13. We postulate that the derivative 13 occurred after a break at 13q14, with the proximal portion of the chromosome forming a ring and the distal portion undergoing duplication. Thus, this patient is trisomic for 13q14-->qter. The derivative chromosome with duplicated distal portion (13q14-->qter) lacked the 13 centromere and was negative for chromosome 13 alpha-satellite DNA by low stringency FISH. Nevertheless, this chromosome is stably transmitted in lymphocytes and fibroblasts. A single primary constriction was observed at band 13q21, consistent with activation of a latent centromere (neocentromere) at this band. The neocentromere on der(13) was positive for multiple centromeric proteins, suggesting that it acts as the functional centromere. By FISH, the Rb gene was present on the normal 13, the proximally derived ring chromosome, but not on the derivative chromosome. Although there was no evidence for disruption of the Rb gene, this chromosome rearrangement most likely results in abnormal expression of the Rb gene product. Copyright Wiley-Liss. Inc.     

Cryptic duplication of the distal segment of 22q due to a translocation (21;22): three case reports and a review of the literature

Duplications of the proximal segment of chromosome 22q are not uncommon, like Cat-eye syndrome and duplications due to familial (11;22) translocations. However, duplications of the distal long arm of chromosome 22 (22qter) seem to be exceedingly rare. So far, duplications of 22q12 or 22q13 to 22qter have been described in 21 patients, of whom 13 had a pure duplication 22qter. Here we report on three new cases with a pure duplication of the distal part of 22q. The first patient carries a duplication of terminal 22q due to a de novo unbalanced translocation, 46,XX,der(21)t(21;22) (p13;q13.2), detected by NOR-staining, while the other patients have a familial cryptic duplication of terminal 22q due to an unbalanced translocation, 46,XY,der(21)t(21;22)(p10;q13.3). The last two patients were initially thought to have a polymorphic variant of 21p, but additional subtelomeric screening using FISH showed the extra material was derived from chromosome 22. Terminal duplications of 22qter may be more common than generally assumed, but due to its small size, especially when located on an acrocentric chromosome and/or possibly relatively mild phenotype remain undetected thus far.     

Clinical and genomic characterization of siblings with a distal duplication of chromosome 9q (9q34.1-qter)

We report herein on two female siblings exhibiting mild intellectual disability, hypotonia in infancy, postnatal growth retardation, characteristic appearance of the face, fingers, and toes. Their healthy mother had a translocation between 9q34.1 and the 13pter. FISH and array CGH analysis demonstrated that the two children had an additional 8.5 Mb segment of the 9q34.1‐qter at 13pter. The clinical features of the present cases were similar to those of previously reported 9q34 duplication cases; however, the present cases did not exhibit other abnormal behaviors, such as autistic features or attention deficit disorders, those are reportedly associated with 9q34 duplications. A 3.0 Mb region (9q34.1‐q34.3) within 9q34 duplication in our patients are overlapped with duplication region of previously reported cases and is proposed to be critical for the presentation of several phenotypes associated with 9q34 duplications. © 2011 Wiley‐Liss, Inc.     

De novo 13q partial duplication identified by cytogenetic, biochemical and molecular approaches

A 3.5-month-old female infant manifesting dysmorphic facies, developmental delay and failure to thrive was referred for cytogenetic evaluation. Peripheral lymphocytes revealed three chromosomally distinct cell lines: 46,XX/46,XX,10p+/47,XX,10p+,+mar. Dermal fibroblasts revealed only the 46,XX,10p+cell line. High resolution G-, R-, and Q-banding suggested that the extra chromosomal material (10p+) represented a duplication of the segment 13q14----13qter. Parental karyotypes were normal. As absolute identification of de novo chromosomal abnormalities, based solely on cytogenetic studies, is sometimes difficult, both biochemical and molecular approaches were undertaken to elucidate this abnormality in more detail. Dosage effects were examined using esterase D (localized to 13q14.1) and the DNA probes p1E8 and p9A7 (localized to 13q22 and 13q31/32, respectively). These studies suggested the presence of only 2 copies of esterase D, but 3 copies of both DNA probes, allowing identification of the breakpoint at 13q14.2.     

Cryptic duplication and deletion of 9q34.3 --> qter in a family with a t(9;22)(q34.3;p11.2)

A newborn male was referred for genetic evaluation because of multiple congenital abnormalities. Physical findings included a round face, telecanthus, hypertelorism, a short upturned nose with anteverted nares, small ears, micrognathia, short toes, and congenital heart disease. Chromosome analysis detected a possible deletion of 9qter because of satellite material on 9qter. Delineation by FISH and microarray CGH studies showed 46,XY,der(9)t(9;22)(q34.3;p11.2). The mother and maternal grandfather had a balanced t(9;22)(q34.3;p11.2) rearrangement. Also, the maternal great-aunt of the propositus was found to have a duplication of 9q34.3 --> qter. FISH was required to delineate her karyotype, which was 46,XX.ish der(22)t(9;22)(q34.3;p11.2). This maternal great-aunt and one of her daughters (cytogenetics not done) have a relatively normal phenotype, only reporting mild learning disabilities in school. Since the 22p material involved in this rearrangement is clinically irrelevant, this report describes an individual with a pure deletion of 9q34.3 --> qter and another with a pure duplication of 9q34.3 --> qter.     

Neocentromere at 13q32 in one of two stable markers derived from a 13q21 break

A 10-month-old girl with psychomotor retardation, microcephaly, bilateral microphthalmia, and postaxial polydactyly of the feet was karyotyped using banding techniques and (single or dual color) fluorescent in situ hybridization (FISH) with four probes: D13Z1/D21Z1, pancentromeric, pantelomeric, and a mix of 13q subtelomeric and 13/21 alphoid repeats. She was found to have a 47-chromosome karyotype in which a normal 13 was replaced by two stable markers derived from a breakpoint at 13q21.1, namely a del(13)(q21.1) and an isofragment(13) (qter→q21.1::q21.1→qter). The latter had a single C-negative but Cd-positive primary constriction at 13q32 which, however, was not obvious in about 12% of the cells. FISH studies showed that the small 13q- had the 13-centromere and a 13q telomere (as shown for a specific 13q subtelomeric signal) onto the broken end whereas the isofragment lacked alphoid signals but had 13q subtelomeric sequences on both ends. Parental karyotypes were normal. The patient's rearrangement represents the eighth chromosome-13–derived marker with a nonalphoid neocentromere located at 13q. All in all, such neocentromeres have been described in 29 markers derived from chromosomes 2, 3, 8–11, 13–15, 20, and Y, and plausibly result from the epigenetic activation of a latent centromere, which may even be a telomere with neocentric activity. The 13q telomere found in the del(13q) was probably captured from the homologous chromosome. Am. J. Med. Genet. 85:385–388, 1999. © 1999 Wiley-Liss, Inc.     

Patient with terminal duplication 3q and terminal deletion 5q: comparison with the 3q duplication syndrome and distal 5q deletion syndrome

Partial duplication of chromosome 3q is a well-described condition of multiple congenital anomalies and developmental delay that resembles the Brachmann-de Lange syndrome. Similarly, an emerging phenotype of a distal 5q deletion syndrome has recently been described. The combination of both chromosome abnormalities has not been previously described. We report on a child with both a de novo duplication of distal 3q (q27 --> qter) and terminal deletion of 5q (q35.2 --> qter). The patient had facial anomalies, hypoplastic toenails, lymphedema of the dorsum of the feet, type I Chiari malformation, a seizure disorder, and moderate developmental delays. The phenotype is compared and contrasted to the few reports of patients with similar terminal 3q duplications and 5q deletions. Our patient did not have the characteristic phenotype of the 3q duplication syndrome, suggesting that the chromosome region responsible for this phenotype is more proximal than the terminal 3q27 region. In addition, comparison with three other reported cases of terminal 5q35 deletions suggests a possible association of terminal 5q deletions with central nervous system (CNS) structural abnormalities.     

Partial triplication and deletion of 13q: study of a family presenting with bilateral retinoblastomas

This report compares the pathogenetic influences of selective deletion and triplicaton of chromosome 13 derived from a familial 12;13 insertional translocation. In the proband a heritable chromosomal basis for his bilateral retinoblastomas is established [46,XY,del (13) (pter leads to q12.5: :q22.1 leads to qter)mat], and in his sister the relatively modest effects of triplication of the mid-portions of 13q are demonstrated [46,XX,ins(12;13) (12pter leads to 12p11.2: :13q22.1 leads to 13q12.5: :12p11.2 leads to 12qter)mat]. Qualitative and quantitative gene marker studies and chromosomal staining techniques to differentiate timing of DNA replication failed to indicate functional gene changes about the breakpoints.     

Clinical delineation of proximal and distal partial 13q trisomy

The most relevant phenotypic features seen in both proximal and distal partial trisomy 13 have been identified from a review of 35 cases. Clinical delineation of either proximal or distal partial trisomy 13 has been demonstrated through the use of conspicuous phenotypic differences. The findings of persistent foetal Hb and increased number of nuclear projections on neutrophils are consistent findings associated with partial trisomy of a proximal segment of chromosome 13 and are diagnostic for trisomy of a partial segment of chromosome 13 that contains bands 13q12 and 13q14. The physical features of polydactyly and hemangioma have been mapped to bands 13q31 and 13q32----13qter and provide a differential diagnosis for a distal trisomic segment of chromosome 13 that may include bands 13q22----13qter. A segment of chromosome 13 has been identified that does not produce any detectable phenotypes in the triplicated state. The possible role of a triplicated 13q segment in altering expression of structural and regulatory systems elsewhere in the genome has been examined. Distinct clinical syndromes involving either a partial proximal or partial distal trisomic segment of chromosome 13 may be phenotypically defined.     

Familial t(11;13)(q21;q14) and the duplication 11q, 13q phenotype

Cases of duplication of distal 11q or proximal 13q have been reported independently. A specific translocation resulting in duplication of distal 11q, [der(22)t(11;22)(q23;q11)], has been documented in over 40 cases. We report on a male fetus with chromosomal excess of both distal 11q and proximal 13q resulting from a familial translocation. This case supports the causal association of duplication 11q with neural tube defects. © 1993 Wiley-Liss, Inc.     

Intrachromosomal triplication of 15q11-q13.

A 7 year old girl with intrachromosomal triplication 46,XX,-15,+der(15)(pter-->q13::q13-->q11::q11-->qter) resulting in tetrasomy of 15q11-q13 is reported. Fluorescence in situ hybridisation confirmed that the tetrasomic region included the entire segment normally deleted in Prader-Willi and Angelman syndrome patients, and breakpoints were similar to those reported in two tandem duplications of 15q11-q13. The middle repeat was inverted, suggesting a possible origin through an inverted duplication intermediate. Microsatellite analysis showed that the rearrangement was of maternal origin and involved both maternal homologues. Clinical findings included multiple minor anomalies (a fistula over the glabella, epicanthic folds, downward slanting palpebral fissures, ptosis of the upper lids, strabismus, a broad and bulbous tip of the nose, and small hands and feet), motor and mental retardation, a seizure disorder, and limited verbal abilities. In addition, immunological examination disclosed a selective immunodeficiency. The overall phenotype did not clearly resemble that of cases with tetrasomy 15pter-q13 associated with an extra inv dup(15)(pter-->q13:q13-->pter) chromosome. The latter aberration causes more severe mental deficit and intractable seizures, but less marked phenotypic alterations, although some overlap in mild facial dysmorphic features is present. A number of features common to Angelman syndrome were also observed in the patient.     

Trisomy 20q caused by interstitial duplication 20q13.2: clinical report and literature review

We report on a 3-year-old boy with moderate developmental delay, abnormal craniofacial features and ventricular septal defect resulting from trisomy of the long arm of chromosome 20. The cytogenetic defect consists of a de novo isolated interstitial duplication in distal 20q [dup(20)(q13.2q13.2)]. The duplication was detected by comparative genomic hybridization (CGH) and confirmed by array CGH. Other cases of comparable trisomies are reviewed. This new case further delineates the recognizable phenotype of trisomy 20q13 --> 20qter and highlights the relevance of CGH for the detection of such rearrangements.