A case of de novo i(12p) with 12q whole-arm translocation mosaicism

We report a dup(12p) due to a de novo i(12p) in a girl with mosaicism for 12q whole-arm translocations onto 7p, 7q, and 11q terminal regions. The dup(12p) syndrome was confirmed by clinical, cytogenetic, and LDH-dosage studies.     

Unique t(Y;1)(q12;q12) reciprocal translocation with loss of the heterochromatic region of chromosome 1 in a male with azoospermia due to meiotic arrest: a case report

A de novo reciprocal translocation 46,X,t(Y;1)(q12;q12) was found in an azoospermic male with meiotic arrest. Cytogenetics and fluorescent in situ hybridization (FISH) were used to define the karyotype, translocation breakpoints and homologue pairing. SRY (Yp), Yq11.2-AZF regions, DAZ gene copies and the distal Yq12 heterochromatin were studied by PCR and restriction analysis using sequence-tagged sites and single nucleotide variants. High resolution GTL, CBL and DA-DAPI staining revealed a (Y;1) translocation in all metaphases and a normal karyotype in the patient's father. FISH showed the presence of the distal Yq12 heterochromatic region in der(1) and loss of the heterochromatic region of chromosome 1. PCR demonstrated the intactness of the Y chromosome, including the SRY locus, AZF regions, DAZ genes and distal heterochromatin. A significant decrease (P = 0.005) of Xp/Yp pairing (18.6%), as compared with controls (65.7%), was found in arrested primary spermatocytes, and cell culture and mRNA expression studies confirmed an irreversible arrest at meiosis I, with induction of apoptosis and removal of germ cells by Sertoli cells. We characterized a de novo t(Y;1)(q12;q12) balanced reciprocal translocation with loss of the heterochromatic region of chromosome 1, that caused unpairing of sex chromosomes followed by meiosis I arrest, apoptotic degeneration of germ cells and azoospermia.     

Fish mapping of a translocation breakpoint at 6q21 (or q22) in a patient with heterotaxia

Summary Heterotaxia is a congenital lateralization defect of visceral organs. As several single-genes that act on the formation of left-right asymmetry during embryogenesis have been identified in animals, a defect in the similar system may play a role in heterotaxia in man. We previously reported a Japanese girl with heterotaxia associated with ade novo balanced translocation (6;18)(q21 or q22;q21.3 or q22). In the present study, based on a hypothesis that one of the putative situs-determining genes is disrupted at a breakpoint of the translocation, we first isolated a yeast artificial chromosome (YAC) clone covering a breakpoint, 6q21 (or q22) of the translocation. Then, using STSs mapped on the YAC, we isolated bacterial artificial chromosome (BAC) clones spanning the breakpoint. FISH analysis using the BAC clones as probes revealed that the breakpoint is confined to a segment between two STS loci, WI-4066 and the CHLC.GATA6B06.192, within a genetic distance of 1.4 cM. The human connexin43 gene was not disrupted in our patient, although mutations of this gene have been reported in patients with complex heart disease and heterotaxia. The molecular localization of the translocation breakpoint in our patient may contribute to the positional cloning of a putative heterotaxia gene.     

Boy with a chromosome del (3)(q12q23) and Blepharophimosis syndrome

We report on a 6-year-old boy with de novo 46, XY, del(3)(q12q23) and bilateral blepharo-phimosis, ptosis, epicanthus inversus, in addition to multiple other anomalies. Since 4 previously reported cases of interstitial deletion of 3q involving 3q23 band are clinically similar, we propose this blepharophimosis sequence due to 3q23 deletion as a further “contiguous gene syndrome”.     

Identification and molecular characterization of a small 11q23.3 de novo duplication in a patient with Rett syndrome manifestations

We report on an interstitial duplication of the long arm of chromosome 11 [46,XX,dup(11)(q23.3)] in a girl with atypical Rett syndrome (RS). This case was discovered during a systematic cytogenetic study of RS. Fluorescent in situ hybridization including total chromosome painting and use of regional specific YAC, cosmid and plasmid probes, was used to confirm the chromosome 11q involvement and to identify the landmarks of the smallest 11q duplication reported to date. The findings are compared to cases of trisomy 11q reported previously, all of which have a larger duplication and different clinical manifestations. Surprisingly, mental retardation and behavior disorders are less severe in these cases. Am. J. Med. Genet. 80:273–280, 1998. © 1998 Wiley-Liss, Inc.     

Duplication 6q24 → 6qter in an infant from a balanced paternal translocation

Duplication of 6q24 → 6qter was identified by GTG banding in an infant girl whose father was a balanced translocation carrier 46,XY,t(3;6)(p26 → q2402). At birth and at 4 mo she had proportionate short stature, microcephaly, asymmetric micrognathia, bow-shaped upper vermilion, long upper lip, submucous cleft palate, antimongoloid slant of palpebral fissures, telecanthus, prominant eyes, short neck with anterior and lateral webbing, short sternum, overlapping toes, wrist contractures, and hypertonicity. Later she was noted to have psychomotor retardation. Eleven previously published cases and our patient suggest that duplication of 6q (involving at least 6q25 → 6qter) produces a highly characteristic syndrome.     

Partial trisomy 3q due to a de novo translocation t(X;3) (p21;q12)

A patient with several congenital malformations, principally in the face, cardiovascular system and genitalia, was found to have the karyotype 46 ,X,der(X),t,X;3)(Xqter← p21::3ql2-←3qter). A comparison of the clinical and cytogenetical findings with similar cases in the literature led to the conclusion that a partial trisomy 3q is the most likely cause for the symptoms in this patient.     

Beckwith-Wiedemann syndrome due to 11p15.5 paternal duplication associated with Klinefelter syndrome and a "de novo" pericentric inversion of chromosome Y

We report on an infant who had been prenatally diagnosed with Klinefelter syndrome associated with a "de novo" pericentric inversion of the Y chromosome. A re-evaluation at 3 years of age suggested that he was also affected by Beckwith-Wiedemann syndrome (BWS). Karyotype was repeated and fluorescence in situ hybridisation (FISH) analysis revealed trisomy for 11p15.5-->11pter and a distal monosomy 18q (18q23-->qter). Parental cytogenetic studies showed that the father carried a balanced cryptic translocation between chromosomes 11p and 18q. Furthermore, the child had an extra X chromosome and a "de novo" structural abnormality of chromosome Y. Thus, his karyotype was 47,XX, inv (Y) (p11.2 q11.23), der(18) t (11;18) (p15.5;q23) pat. ish der(18) (D11S2071+, D18S1390-). Two markers on the X chromosome showed that the extra X of the child was paternally inherited. No deletions were observed on the structurally abnormal Y chromosome from any of the microsatellites studied. Clinical findings of patients with BWS due to partial trisomy 11p reveal that there is a distinct pattern of dysmorphic features associated with an increased incidence of mental retardation when comparing patients with normal chromosomes. This fact reinforces that FISH study have to be performed in all BWS patients, specially in those with mental retardation since small rearrangements cannot be detected by conventional cytogenetic techniques.     

Reassessment of a chromosome 12q + marker by fluorescent in situ hybridization (FISH)

We present a case previously described by Jenkins et al. (1983) as atypical Down syndrome (DS). The initial diagnosis was first made on the basis of phenotypic and cytogenetic data. This analysis was supported by studies of superoxide dismutase (SOD1) activity that maps to band 21q22.1. Results from phenotypic, chromosome banding and SODI studies suggested a karyotype of 46,XX,—12, + t(12pter to 12qter::21q21 to 21q22.?2). Using fluorescent in situ hybridization (FISH) for chromosome painting with DNA libraries derived from sorted human chromosomes to stain selectively the chromosomes No. 21 and No. 12, we demonstrate that the marker chromosome 12q+ has no chromosome 21 content but it is derived from chromosome 12.     

EEC syndrome (ectrodactyly, ectodermal dysplasia and cleft lip/palate) with a balanced reciprocal translocation between 7q11.21 and 9p12 (or 7p11.2 and 9q12) in three generations

Familial cases (a grandfather, a father and a daughter) of the EEC syndrome (ectrodactyly, ectodermal dysplasia and cleft lip/palate) are reported. All of them have a balanced reciprocal translocation (46,XY or XX, t(7;9) (q11.21;p12) or (46,XY or XX, t(7;9) (p11.2;q12)), but no other members of the family have either the EEC syndrome or chromosome abnormalities. This indicates that one of the chromosome sites 7q11.21, 9p12, 7p11.2 and 9q12 is a candidate for gene locus of the EEC syndrome.     

Craniosynostosis and hemizygosity for D7S135 caused by a de novo and apparently balanced t(6;7) translocation

Craniosynostosis (CRS) is frequently seen in the del(7p) syndrome, and the gene for this cranial anomaly (CRS1) has been assigned to 7p21. We present a 3-year-old boy with CRS involving the sagittal and coronal sutures, who had a de novo and apparently balanced translocation, t(6;7)(q16.2;p15.3). Southern blot analysis of several loci on 7p14 → pter showed that the patient was heterozygous for HOX1I and IL6, possibly homozygous for D7S149, but hemizygous for D7S135 with a loss of the paternal allele. These findings suggest the localization of a candidate gene for CRS1 to be on 7p15.3 in the close proximity to the D7S135 locus. © 1994 Wiley-Liss, Inc.     

Analysis of sperm chromosome complements from a man heterozygous for a Robertsonian translocation 45,XY,t(15q;22q)

Chromosome complements were studied in 118 sperm from a man heterozygous for a 15;22 Robertsonian trnaslocation using the human sperm/hamster oocyte fusion technique. Alternate segregation occurred in most spreads (89.6%) and the proportion of normal (42.6%) and balanced complements (47%) was approximately equal. The frequency of sperm that were unbalanced with respect to the translocation was 10.4% and all categories of unbalanced sperm were observed (?15, ?22, +15, +22). The frequency of chromosome abnormalities unrelated to the translocation was 7.6%. Since the frequencies of both numerical (3.4%) and structural abnormalities (3.4%) were within the normal range of control donors, there was no evidence for an interchromosomal effect. The frequencies of X-chromosome bearing (48%) and Y-chromsome bearing (52%) sperm were not significantly different from 50%. Data on this translocation were compared to the 4 other reports of cytogenetic analysis in sperm of Robertsonian translocation carriers. © 1992 Wiley-Liss, Inc.     

FG syndrome: Report of three new families with linkage to xq12-q22.1

FG syndrome is a rare X-linked recessive form of mental retardation, first described by Opitz and Kaveggia in 1974 in five related males with mental retardation, disproportionately large heads, imperforate anus, and congenital hypotonia. Partial agenesis of the corpus callosum was noted in at least one of the initial cases and has been seen in a number of subsequently-reported cases. The associated congenital hypotonia with joint hyperlaxity tends to progress to contractures with spasticity and unsteady gait in later life. The presence of subtle facial abnormalities and the characteristic behavior in midchildhood facilitate diagnosis at this age, particularly when there are other affected male relatives in the maternal family. Recently, Briault et al. [1997[ mapped a gene for FG syndrome to the Xq12-q21.31 region. We describe three additional families (six additional patients) with FG syndrome on whom we have conducted linkage analysis. Our findings support the localization of a gene for the FG syndrome in Xq12-q21. In addition, we have noted skewed X-inactivation in carrier females, as well as new associated findings in affected males of sagittal craniosynostosis and split hand malformation. Am. J. Med. Genet. 80:145–156, 1998. © 1998 Wiley-Liss, Inc.     

Molecular characterization of complex chromosomal rearrangement: First report of novel t(7;12) (q11;q22) as part of a complex karyotype in de novo AML-M2 case

The strong association of diagnostic karyotype with clinical outcome has made cytogenetics one of the most valuable diagnostic and prognostic tools for acute myeloid leukemia (AML) till today. Complex chromosomal findings are reported to be seen in nearly 10–15% of adult AMLs and are generally associated with poor outcome. In the current report, we present the results of hematologic, immunophenotypic, cytogenetic, chromosomal microarray and molecular analyses of a 60-year-old female patient diagnosed with AML-M2. Cytogenetic analysis revealed complex chromosomal findings involving seven different chromosomes. However, cytogenetic analyses were not able to precisely unveil all karyotypic changes, hence chromosomal microarray was used for further characterization. The most interesting observation was identification of a t(7;12) (q11;q22) as part of this complex karyotype. To the best of our knowledge, this is the first report of identification of novel t(7;12) (q11;q22) as part of a complex karyotype in de novo AML-M2.     

一例由 KCNJ6基因新发变异导致的Keppen-Lubinsky综合征患儿的临床及遗传学分析

目的:探讨1例由 KCNJ6基因新发变异导致的Keppen-Lubinsky综合征患儿的临床及遗传学特点。 方法:应用全外显子组测序对患儿及其父母进行基因检测,并用生物信息学软件预测其危害性,并通过蛋白质结构模拟分析其影响。结果:患儿具有特殊面容,表现为大眼、鼻翼发育不全、小后缩下颌及早衰模样,同...     

Tetrasomy for the short arm of chromosome 12 with accessory isochromosome (+i(12p)) and a marked LDH-B gene dosage effect

A fetus with tetrasomy for the short arm of chromosome 12 due to a de novo accessory isochromosome i(12p) is described. Involvement of the 12p in this chromosome aberration was suggested by banding analysis and substantiated by detection of a marked increase of LDH-B in the fetal fibroblasts. The syndrome shown by this fetus includes many of the minor anomalies described for live-born patients with partial trisomy 12p, and in addition malformations including brachymelia, anal atresia and double kidneys.     

Maternal uniparental isodisomy and heterodisomy on chromosome 6 encompassing a CUL7 gene mutation causing 3M syndrome

We report a case of segmental uniparental maternal hetero- and isodisomy involving the whole of chromosome 6 (mat-hUPD6 and mat-iUPD6) and a cullin 7 (CUL7) gene mutation in a Japanese patient with 3M syndrome. 3M syndrome is a rare autosomal recessive disorder characterized by severe pre- and postnatal growth retardation that was recently reported to involve mutations in the CUL7 or obscurin-like 1 (OBSL1) genes. We encountered a patient with severe growth retardation, an inverted triangular gloomy face, an inverted triangle-shaped head, slender long bones, inguinal hernia, hydrocele testis, mild ventricular enlargement, and mild mental retardation. Sequence analysis of the CUL7 gene of the patient revealed a homozygous missense mutation, c.2975G>C. Genotype analysis using a single nucleotide polymorphism array revealed two mat-hUPD and two mat-iUPD regions involving the whole of chromosome 6 and encompassing CUL7. 3M syndrome caused by complete paternal iUPD of chromosome 6 involving a CUL7 mutation has been reported, but there have been no reports describing 3M syndrome with maternal UPD of chromosome 6. Our results represent a combination of iUPDs and hUPDs from maternal chromosome 6 involving a CUL7 mutation causing 3M syndrome.     

A retrospective CISS hybridization analysis of a case with de novo translocation t(18;22) resulting in an 18p—syndrome*

Voiculescu I, Toder R, Back E, Osswald P, Schempp W. A retrospective CISS hybridization analysis of a case with de novo translocation t(18;22) resulting in an 18p—syndrome. Clin Genet 1993: 43: 318–320. © Munksgaard, 1993 An unbalanced de novo translocation t(18;22) leading to a severely malformed liveborn girl with 18p—syndrome is described. Using the chromosomal in situ suppression (CISS) hybridization technique on 4-year-old G-banded chromosome preparations, it could be demonstrated that the translocation chromosome is composed of the long arm including the centromere of a chromosome 22 and the long arm of a chromosome 18. Consequently, the patient described here has lost the short arm including the centromere of chromosome 18. The possibility of restudying cytogen-etically unsolved cases in clinical cytogenetics using older G-banded chromosome preparations with the fluorescence in situ hybridization techniques is pointed out.