Detection of an unbalanced t(4;15) by FISH in a child with multiple congenital anomalies

Detection of an unbalanced t(4;15) by FISH in a child with multiple congenital anomalies: In this report, we present the clinical history and findings in a 6-month-old male with multiple congenital anomalies, developmental delay, and an initial male karyotype with 4q+. The origin of the additional segment on 4q was unequivocally established by fluorescence in situ hybridization (FISH). Whole chromosome probe for chromosome 4 and chromosome 15-specific a-satellite probe were used. The karyotype was demonstrated to be 46,XY,der(4), t(4;15)(q35;?),inv(9)(p13q13). To the best of our knowledge the above cytogenetic abnormalities with these clinical findings have not been described previously. This case further demonstrates the advantage of FISH in the identification of anomalous chromosome regions and breakpoints.     

Additional chromosome in a child as a result of a balanced reciprocal translocation t(12;18)(p13;q12) in his mother's karyotype

In this case report we present a child with an additional chromosome in the karyotype. The karyotypes of the boy and his parents were analyzed by use of a conventional banding technique (GTG) and fluorescence in situ hybridization (FISH). Probes painting whole chromosomes 12 and 18 were used in FISH. Cytogenetic examination of the parents revealed that his mother was carrying balanced reciprocal translocation between chromosomes 12 and 18. Her karyotype was described as 46,XX,t(12;18)(p13;q12). Father's karyotype was normal, described as 46,XY. The boy's karyotype was defined as 47,XY,+der(18)t(12;18)(p13;q12). The additional chromosome appeared probably due to 3:1 meiotic disjunction of the maternal balanced translocation, known as tertiary trisomy. The mother displayed a normal phenotype and delivered earlier a healthy child. However, the boy with the unbalanced karyotype shows multiple congenital abnormalities.     

De novo inv del(4) in an infant with the Wolf-Hirschhorn syndrome

An infant was found to have a de novo complex rearrangement of one chromosome 4. Her karyotype was interpreted as 46,XX,inv del(4)(pter::p16.3::q31.2----p15.2::q31.2----qter). Clinically she showed the features of the Wolf-Hirschhorn syndrome.     

Langer-Giedion syndrome,in a child with complex structural aberration of chromosome 8

A patient with typical features of the Langer-Giedion syndrome (tricho-rhino-phalangeal syndrome, type II) is described. In the karyotype an interstitial deletion of the long arm of chromosome 8 (band 8q22) was observed as the result of a complex rearrangement of chromosomes 1 and 8: 46,XY inv(8)(q23 leads to q242), del(8)(q221 leads to q223), ins(8;1) (q221;p321 p341;q242). Previously reported cases of Langer-Giedion syndrome with deletion of 8q are compared with the present one.     

Partial trisomy 14q due to maternal t(4;14)(p16;q32) in a dysmorphic newborn

Partial Trisomy 14q is a rare chromosomal disorder that mostly results from a parental translocation. We report here a newborn boy with partial trisomy 14q and dysmorphic features that are compatible with previously reported cases. Conventional cytogenetic analysis revealed an extra chromosomal segment at the end of the short arm of chromosome 4. In order to determine the origin of this chromosome region we used subtelomeric FISH technique. Based on the results of these cytogenetic studies and the physical examination, this dysmorphic case was diagnosed as partial trisomy of 14q and his karyotype determined as 46 XY, der(4)t(4;14)(p16;q32) resulting from a balanced maternal translocation identified as 46,XX, t(4;14)(p16;q32).     

Recurrent proximal 18p monosomy and 18q trisomy in a family with a maternal pericentric inversion of chromosome 18

We report a recurrent partial monosomy of 18p10-->11.2 and proximal partial trisomy of 18q10-->21.3 caused by a maternal pericentric inversion of chromosome 18, involving breakpoints p11.2 and q21q21.3 Based on cytogenetics and FISH analysis, we speculate that the recurrent chromosome abnormality in the proband and in the fetus was the result of a translocation, possibly in a germ cell or germ cell precursor, between the maternal normal 18 and her inverted 18, resulting in maternal germinal mosaicism, i.e. 46,XX,inv(18)/46,XX,t[18;inv(18)][q10;q10]. The unbalanced karyotype of the proband and the fetus is 46,XY,+18,der[18;inv(18)][q10;q10]. To the best of our knowledge, there are no reports of this combination of proximal 18p monosomy and proximal 18q trisomy. The other interesting observation was association of Hirschsprung's disease in the proband.     

Two complementary recombinant chromosomes 5 in a healthy woman

We report a healthy woman with two abortions who is a carrier for a rare heterozygous double recombinant of an inv(5) chromosome, karyotype 46,XX,rec(5)dup(5p) inv(5)(p13q22),rec(5)dup(5q)inv(5)(p13q22). Her father had a 46,XY,inv(5)(p13q22) karyotype; his consanguineous wife had died. Molecular investigation of 11 highly polymorphic markers spanning chromosome 5 revealed biparental inheritance for two markers (D5S406, D5S681) on 5p15.3 and 5q13.1, and an allele constellation not compatible with paternal heterodisomy for marker D5S623 on 5q11.2. Eight markers were not informative. Three mechanisms of formation are proposed: First, fertilization of a normal oocyte by a sperm carrying the two recombinant chromosomes 5, followed by postzygotic recombination between the normal maternal homologue and the rec(5)dup(5p), and by loss of the mitotically recombined maternal homologue, leading to segmental paternal heterodisomy 5q13-->qter (trisomic rescue). Second, postzygotic recombination in a 46,XX,inv(5)(p13q22) zygote resulting in the 46,XX,rec(5)dup(5p)inv(5)(p13q22),rec(5) dup(5q)inv(5)(p13q22) karyotype, followed by absence of the original cell line in lymphocytes. Third and most likely, both parents were inv(5) carriers and complementary recombinations in maternal and paternal meiosis resulted in a zygote with two recombinant chromosomes 5. Our patient refused any further studies but later reported the birth of a phenotypically normal child. This is the first report known to us of complementation by two non-homologous recombinant chromosomes in a phenotypically normal woman, and the first example of a child born to a carrier of complementary recombinant chromosomes.     

16种罕见的人类染色体异常核型报告

通过对患有闭经、自发流产、死胎、死产等患者外周血淋巴细胞染色体检查,发现16种新的罕见人类染色体异常核型,它们是46,XY,t(6;11)(q25;p15);46,XY,inv(3)(p25;q29);46,XY,t(7;18)(q10;p10);46,X,t(X;13)(q24;q14);46,XY,t(4;7)(q33;q22);46,XY,t(8;15)(q24;q15);46,XY,t(2;17)(q33;q25);46,XX,t(4;7)(q34;q11);46,XX,t(1;3)(p36;p23);46,XX,t(4;6)(q35;p11);46,X,inv(X)(q22;q28);46,XX,t(7;10)(p11;q26);46,XX,t(3;6)(p21;q23);46,XX,t(8;16)(p21;p13);46,XX,t(8;9)(q21;q34);46,XY,t(17;22)(q21;q11)。描述了患者的临床表现,并对生殖异常患者染色体畸变与其表型效应关系进行探讨。Abstract：By examining the lymphocytic chromosomes of peripheral blood from patients with amenorrhea,spontaneous abortion and stillbirth history, .the 16 rare species of human chromosomal abnormal karyotypes were discovered. They wre 46,XY,t(6;11)(q25;p15);46,XY,inv(3)(p25;q29);46,XY,t(7;18)(q10;p10);46,X,t(X;13)(q24;q14);46,XY,t(4;7)(q33;q22);46,XY,t(8;15)(q24;q15);46,XY,t(2;17)(q33;q25);46,XX,t(4;7)(q34;q11);46,XX,t(1;3)(p36;p23);46,XX,t(4;6)(q35;p11);46,X,inv(X)(q22;q28);46,XX,t(7;10)(p11;q26);46,XX,t(3;6)(p21;q23);46,XX,t(8;16)(p21;p13);46,XX,t(8;9)(q21;q34);46,XY,t(17;22)(q21;q11). Their clinical situation were described. Discussion on the relationship between the chromosomal aberrations and phenotype effect indicates the importance of chromosome karyotyping in patients with abnormal reproductive history.     

Chromosome duplications and deletions and their mechanisms of origin.

Duplications and deletions of the same gene loci or chromosome regions are known to produce different clinical manifestations and are significant factors in human morbidity and mortality. Extensive cytogenetic and molecular cytogenetic studies with cosmid and YAC probes in two patients with unique mosaicism for reciprocal duplication-deletion allowed us to further understand the origin of these abnormalities. The first patient's mosaic karyotype was 46,XX, inv dup(11) (q23q13)/46,XX,del(11)(q13q23). The second patient had a 46,XY,dup(7)(p11.2p13)/46,XY,del(7)(p11.2p13)/46,XY karyotype. Fluorescence in situ hybridization studies on the first patient placed the two breakpoints near the folate-sensitive fragile sites FRA11A and FRA11B. The presence of repeated sequences responsible for these fragile sites may have been involved in the patient's duplication-deletion. Our investigation leads us to conclude that, in addition to known mechanisms (such as unequal crossovers between homologs, unequal sister chromatid exchanges, excision of intrachromatid loops, and meiotic recombination within a single chromatid), duplication-deletion can also arise by the formation of an overlying loop followed by an uneven crossover at the level of the DNA strand.     

9种新的人类染色体异常核型报告

发现９种新的人类染色体异常核型,分别为：４６,ＸＸ,ｔ（２;１０）（ｑ３３;ｑ１１）;４６,ＸＹ,ｔ（１０;１２）（ｑ２６;ｑ２２）;４６,ＸＹ,ｔ（６;１５）（ｐ２３;ｑ２３）;４６,ＸＹ,ｔ（１;６）（ｐ３６;ｑ２１）;４６,ＸＹ,ｔ（１;１９）（ｐ３２;ｐ１３）;４６,ＸＹ,ｔ（１６;１８）（ｑ２２;ｑ２１）;４６,ＸＹ,ｉｎｖ（１）（ｐ３６ｑ２５）;４６,ＸＹ,ｔ（１３;１７）（ｑ１２;ｑ２５）;４６,ＸＹ,ｔ（１５;２１）（ｑ２６;ｑ１１）。异常核型是导致自然流产和不育的原因。     

A dysmorphic newborn with 45,X,der(1)inv(1)(p13;qter)t(Y;1)(pter-->q11;p13),-Y de novo karyotype

A dysmorphic newborn with 45,x,der(1)inv(1)(p13;qter)t(y;1)(pter-->q11;p13),-Y de novo karyotype: Y/autosome translocations are very rare chromosomal rearrangements. In most cases, the long arm of the Y chromosome is translocated onto an autosome and most patients are referred because of male infertility. Y/1 translocations are very rare, and have been reported in seven patients so far. Pericentric inversions may be seen in all chromosomes and are not associated with phenotypic abnormalities. Here we report a 6-day old male baby with prenatal growth retardation, frontal bossing, hypertelorism, micrognathia, cleft soft palate, absent uvula, hypospadias, simian line in both hands and hammer toes. Cytogenetic analysis was performed with GTG-banding, C-banding and FISH analysis containing X centromeric probe, Yq12-qter locus specific probe and whole chromosome Y probe. An unbalanced Y/1 translocation was diagnosed: 45,X,der(1)inv(1)(p13;qter)t(Y;1)(pter-->q11;p13),-Y.     

"Cri-du-chat" syndrome in a patient born to a mother with a paracentric inversion of chromosome 5q

We report the case of a female child presented at birth with hypotonia, growth retardation and respiratory distress. Chromosome study from peripheral blood showed a 46,XX,del(5)(p14pter) karyotype. Parental chromosome studies revealed that the mother carried an apparently balanced paracentric inversion of long arms of one chromosome 5, giving the karyotype 46,XX,inv(5)(q12q32), whereas paternal karyotype was normal. The maternal abnormality was confirmed by fluorescence in situ hybridization (FISH) and was not present in the daughter's metaphases. Microsatellite analysis in the proposita and her parents permitted us to conclude that the deleted chromosome 5 was paternal in origin, as usually described. Therefore, as might have been expected, maternal paracentric inversion of chromosome 5q and "cri-du-chat syndrome" presented by the daughter were not related.     

A cytogenetic survey of 200 unclassifiable mentally retarded children with congenital anomalies and 200 normal controls

Summary A cytogenetic survey was carried out on 200 patients with mental retardation and multiple congenital anomalies, and on 200 normal adult controls. Patients with a known syndrome were excluded from the survey. Chromosome analyses were carried out on blind-coded slides using the ASG banding technique as the routine stain. After the initial analyses (at least 15 cells per person) the slides were decoded, destained and reused for C and Q band polymorphism studies.Five major chromosome abnormalities were detected in the patient group during the survey. They included three patients with de novo, apparently balanced, reciprocal translocations, karyotypes 46,XY,rcp(3;16)(q21;p12); 46,XX,rcp(5;8)(p15;q22); and 46,XX,rcp(5;12)(p11;q24); one with karyotype 47,XX,+mar and one with karyotype 46,XX,der(13),t(13;?)(q34;?). One additional patient whose karyotype in lymphocytes was 46,XX,inv(9)(p11;q13) was found to have a mosaic karyotype 46,XX,inv(9)(p11;q13)/46,XX,inv(9) (p11;q13),der(12),t(12;?)(p13;?) in cultured skin fibroblasts. None of the 200 controls had a major chromosome abnormality.From the combined results of this and previous surveys it is now apparent that about 6.2% of the unclassifiable mentally retarded patients with three or more congenital anomalies and about 0.7% of the controls reveal major chromosome abnormalities.     

Mapping breakpoints of a familial chromosome insertion (18,7) (q22.1; q36.2q21.11) to DPP6 and CACNA2D1 genes in an azoospermic male

It is widely accepted that the incidence of chromosomal aberration is 10–15.2% in the azoospermic male; however, the exact genetic damages are currently unknown for more than 40% of azoospermia. To elucidate the causative gene defects, we used the next generation sequencing (NGS) to map the breakpoints of a chromosome insertion from an azoospermic male who carries a balanced, maternally inherited karyotype 46, XY, inv ins (18,7) (q22.1; q36.2q21.11). The analysis revealed that the breakage in chromosome 7 disrupts two genes, dipeptidyl aminopeptidase-like protein 6 (DPP6) and contactin-associated protein-like 2 (CACNA2D1), the former participates in regulation of voltage-gated potassium channels, and the latter is one of the components in voltage-gated calcium channels. The deletion and duplication were not identified equal or beyond 100 kb, but 4 homologous DNA elements were verified proximal to the breakpoints. One of the proband's sisters inherited the same aberrant karyotype and experienced recurrent miscarriages and consecutive fetus death, while in contrast, another sister with a normal karyotype experienced normal labor and gave birth to healthy babies. The insertional translocation is confirmed with FISH and the Y-chromosome microdeletions were excluded by genetic testing. This is the first report describing chromosome insertion inv ins (18,7) and attributes DPP6 and CACNA2D1 to azoospermia.     

一例罕见的复杂易位携带者的染色体绘画研究

本文报道了一例罕见的复杂易位男性携带者,结婚８年,其妻连续７次流产、死胎和出生早夭的畸型儿。用染色体显微切割、ＰＣＲ技术构建的人类７号和８号染色体特异性探针地对其进行了染色体绘画研究,分析确定其核型为：４６,ＸＹ,－７,－８,－９,＋ｄｅｒ（７）、ｔ（７;９）（ｑ２２００;ｐ２４）,＋ｄｅｒ（８）ｉｎｖｉｎｓ（８;７）（ｑ２１００;ｑ３１．２ｑ２２００）,＋ｄｅｒ（９）ｔ（９;７）（ｐ２４;ｑ３１．２）．ｉｓｈｄｅｒ（７）ｔ（７;９）（ｗｃｐ７＋）,ｄｅｒ（８）ｉｎｖｉｎｓ（８;７）（ｗｃｐ７＋,ｗｃｐ８＋）,ｄｅｒ（９）ｔ（９;７）（ｗｃｐ７＋）。染色体绘画技术为研究染色体异常提供了一种有效的分子细胞遗传学技术,本文并对携带者复杂易位的发生机理进行了讨论。     

Molecular genetic and cytogenetic characterization of a partial Xp duplication and Xq deletion in a patient with premature ovarian failure

Background

The etiology of premature ovarian failure (POF) still remains undefined. Although the majority of clinical cases are idiopathic, there are possibilities of the underestimation of the most common etiologies, probably genetic causes. By reporting a case of POF with a partial Xp duplication and Xq deletion in spite of a cytogenetically 46,XX normal karyotype, we look forward that the genetic cause of POF will be investigated more methodically.

Methods

We performed a basic and clinical study at a university hospital-affiliated fertility center. The study population was a POF patient and her family. Cytogenetic analysis, FMR1 gene analysis, multiplex ligation-dependent probe amplification (MLPA), fluorescent in situ hybridization (FISH), and oligonucleotide-array based comparative genomic hybridization (array CGH) were performed.

Results

In spite of normal cytogenetic analysis in the proband and her mother and younger sister, FMR1 gene was not detected in the proband and her younger sister. In Southern blot analysis, the mother showed a normal female band pattern, but the proband and her younger sister showed no 5.2 kb methylated band. The abnormal X chromosome of the proband and her sister was generated from the recombination of an inverted X chromosome of the mother during maternal meiosis, and the karyotype of the proband was 46,XX,rec(X)dup(Xp)inv(X)(p22.1q27.3).

Conclusion

Array CGH followed by FISH allowed precise characterization of the der(X) chromosome and the initial karyotype of the proband had been changed to 46,XX,rec(X)dup(Xp)inv(X)(p22.3q27.3)mat.arr Xp22.33p22.31(216519–8923527)x3,Xq27.3q28(144986425–154881514)x1. This study suggests that further genetic investigation may be needed in the cases of POF with a cytogenetically 46,XX normal karyotype to find out the cause and solution for these disease entities.     

Sex reversal due to Xp disomy by t(X;Y)(p21;q11).

A 20-month-old infant exhibiting psychomotor retardation, dysmorphisms and ambiguous external genitalia was found to have a 46-chromosome karyotype including a normal X chromosome and a marker Y with most of Yq being replaced by an extra Xp21-->pter segment. The paternal karyotype (G and C bands) was 46,XY. The marker Y composition was verified by means of FISH with a chromosome X painting, an alphoid repeat and a DMD probe. Thus, the final diagnosis was 46,X,der(Y)t(X;Y)(p21;q11)de novo.ish der(Y)(wcpX+,DYZ3+,DMD+). The patient's phenotype is consistent with the spectrum documented in 13 patients with similar Xp duplications in whom sex reversal with female or ambiguous genitalia has occurred in spite of an intact Yp or SRY gene. A review of t(X;Y) identifies five distinct exchanges described two or more times: t(X;Y)(p21;q11), t(X;Y)(p22;p11), t(X;Y)(p22;q11-12), t(X;Y) (q22;q12), and t(X;Y)(q28;q12). These translocations probably result from a recombination secondary to DNA homologies within misaligned sex chromosomes in the paternal germline with the derivatives segregating at anaphase I.     

Severe psychomotor retardation in a boy with a small supernumerary marker chromosome 19p

We describe the clinical case of a nine-year-old boy with psychomotor retardation and a small supernumerary marker chromosome (sSMC) present in mosaic form. Fluorescence in situ hybridization (FISH) using centromere cross-hybridizing probes D1/5/19Z (pZ5.1), the whole chromosome paint probe 19, pool YACs19p (839B1, 872G3, 728C8), and pool YACs19q (767C4, 761C1, 786G6) demonstrated that the sSMC was derived from chromosome 19p. Based on GTG-banding and FISH analyses, the patient's karyotype was interpreted as: 47,XY,+mar.ish der(19) (:p13.3-->p11:)(839B1+, 872G3+,728C8+, D1/5/19Z+) de novo[52]/46,XY[48]. To our knowledge, only two other similar cases have been reported. This case helps to better delineate karyotype-phenotype correlations between sSMC 19p and associated clinical phenomena.     

A case of insertional translocation resulting in partial trisomy 16p

This report concerns the case of a boy with partial trisomy 16p resulting from the insertional translocation of the short arm of chromosome 16 into the long arm of chromosome 1 in his father. He was referred for genetic testing because of mental retardation, short stature, microcephaly, seizures and multiple dysmorphic features. Chromosome analysis performed in the child demonstrated the presence of additional material in the long arm of chromosome 1. Paternal high resolution chromosome analysis and fluorescence in situ hybridisation revealed the following karyotype: 46,XY,ins(1;16)(q42;p13.1p13.3), while the karyotype of the boy is 46,XY,der(1),ins(1;16)(q42;p13.1p13.3)pat. This is the first reported case of partial trisomy 16p due to paternal insertional translocation.     

Inherited ring chromosome 8 without loss of subtelomeric sequences

We report the first case of inherited ring chromosome 8 syndrome without loss of subtelomeric sequences. The proband is a 6 1/2-year-old boy with short stature, microcephaly, mild mental retardation, and behavioral problems including hyperactivity and attention deficit. His mother presented the same physical features but intelligence was normal. Family history also revealed an uncle and a grandmother, with short stature and microcephaly. Moderate mental retardation was reported in the uncle. Karyotypes and fluorescence in situ hybridization (FISH) analyses were performed on peripheral blood lymphocytes for both child and mother. The child's karyotype was reported as 46,XY,r(8)(p23q24.3)[24]/45,XY,-8[2] and the mother's karyotype 46,XX,r(8)(p23q24.3)[22]/45,XX,-8[2]/47,XX,r(8)(p23q24.3), +r(8)(p23q24.3)[1]. FISH studies showed no deletion of subtelomeric sequences for both child and mother indicating that no or little chromosomal euchromatic material has been deleted. These findings indicate that ring chromosome 8 without loss of subtelomeric sequences can be inherited and that carriers in a same family present with cognitive function ranging from mild mental retardation to normal intelligence.