Telomere-telomere (end to end) fusion of chromosomes 7 and 22 with an interstitial deletion of chromosome 7p11.2-->p15.1: phenotypic consequences and possible mechanisms

We report a rare case of a de novo end to end fusion of chromosomes 7 and 22 in conjunction with an interstitial deletion of chromosome 7p11.2p15.1 in a newborn with congenital anomalies. The proband presented for chromosome analysis with bilateral cataracts, dysmorphic facies and distal limb abnormalities. Chromosome analysis showed a 45,XY,der(22)psu dic(22;7)(p13;p22.3)del(7)(p11.2p15.1) karyotype. This short arm to short arm fusion of chromosomes 7 and 22 resulted in a pseudodicentric chromosome. The interstitial deletion in the short arm of chromosome 7 was likely a result of breakage and reunion related to instability of the dicentric chromosome. Loss of genetic material in this region of chromosome 7p has been implicated in the pathophysiology of craniosynostosis and cephalopolysyndactyly syndromes.     

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.     

Duplication of distal 19q: clinical report and review.

We report on a 20-month-old boy with duplication of the distal part of 19q. His karyotype is 46,XY, -22, + der(22),t(19;22)(q13.3;p11.2)mat. The propositus has multiple minor anomalies, congenital heart defects, seizures, profound psychomotor retardation, and growth impairment. These characteristics are similar to those in the other 10 reported cases of distal 19q duplication and help delineate the phenotype. A review of the literature is presented.     

XY sex reversal and gonadal dysgenesis due to 9p24 monosomy

We describe a case of XY sex reversal, gonadal dysgenesis, and gonadoblastoma in a patient with a deletion of 9p24 due to a familial translocation. The rearranged chromosome 9 was inherited from the father; the patient's karyotype was 46,XY,der(9)t(8;9)(p21;p24)pat. A review shows that 6 additional patients with 46,XY sex reversal associated with monosomy of the distal short arm of chromosome 9 have been observed. The observation that all 7 patients with sex reversal share a deletion of the distal short arm of chromosme 9 is consistent with the hypothesis that the region 9p24 contains a gene or genes necessary for male sex determination. This present case narrows the chromosome interval containing a critical sex determination gene to the relatively small region 9p24. A molecular analysis of this region will provide a means to identify a gene invoved in male sex determination. Am. J. Med. Genet. 73:321–326, 1997. © 1997 Wiley-Liss, Inc.     

Chromosomal microarray analysis of functional Xq27-qter disomy and deletion 3p26.3 in a boy with Prader-Willi like features and hypotonia

Duplications of the long arm of the X chromosome are rare. The infantile phenotype shares some resemblance with the Prader-Willi syndrome, presenting severe psychomotor retardation, facial dysmorphic features with a broad face, a small mouth and a thin pointed nose, hypotonia, urogenital malformation and proneness to infections. We report a boy with an additional Xq27-qter chromosome segment translocated onto the short arm of chromosome 3. The karyotype was 46,XY,der(3)t(X;3)(q27.3; p26.3)mat. This cryptic unbalanced X-autosome translocation resulted in Xq27-qter functional disomy and a deletion 3p26.3. A detailed analysis of the constitutional chromosomal changes in the patient was performed using array-CGH, FISH and PCR. The aim was to characterize the size and the location of the duplication Xq27-qter (8.18 Mb) and of the deletion 3p26.3 (1.05 Mb), to establish phenotype-genotype correlations and to offer genetic counselling.     

47,XX,+der(18),t(9;18)(p24;q21) mat: a distinct partial trisomy 18q--syndrome?

A moderately retarded girl had a 47,XX,+der(18),t(9;18)(p24;q21)mat abnormality that was inherited from her mother, who had a 46,XX,t(9;18)(p24;q21) karyotype in most cells, and a minor cell line of 47,XX,+der(18),-t(9;18)(p24;q21). Her dysmorphic features--bilateral epicanthic folds, low-set, abnormal ears, low posterior hairline, clinodactyly of the 5th fingers, and broad great toes--were similar to those of other patients with an additional number 18 chromosome in which all or most of the long arm was missing, thus raising the possibility of a distinct syndrome.     

Duplication of part of 9q due to maternal 12;9 inverted insertion associated with pyloric stenosis

We report on a 9-month-old boy who had duplication of the long arm of chromosome 9 [46,XY, -12, +der(12) inv ins (12;9)(p13;q32q13)mat.]. The clinical manifestations of the patient were different from those seen in distal 9q duplication. Pyloric stenosis appears to be common in cases with proximal 9q duplications.     

Ebstein anomaly associated with rearrangements of chromosomal region 11q

Ebstein anomaly (EA) is a relatively uncommon congenital heart defect and it is very rarely associated with a chromosomal anomaly. We report two distinct rearrangements of the chromosomal region 11q arm in two unrelated patients with Ebstein anomaly, renal malformation, minor anomalies, and the Pierre Robin sequence. The first patient had an interstitial deletion of chromosome 11 [46,XY,del(11)(11q21q23), and the other had a tertiary trisomy of chromosome 11qter (47,XX,+der(22)t(11;22)(q23; q11.2) Its association with either a chromosome 11q deletion or a duplication in some individuals suggests that a rearrangement of the 11q region is likely to cause a shift of the individuals' underlying liability to develop EA above a certain threshold. Am. J. Med. Gen. 80:157–159, 1998. © 1998 Wiley-Liss, Inc.     

Duplication of distal 19q: Clinical report and review

We report on a 20-month-old boy with duplication of the distal part of 19q. His karyotype is 46, XY, ?22, + der(22), t(19;22) (q13.3; p11.2)mat. The propositus has multiple minor anomalies, congenital heart defects, seizures, profound psychomotor retardation, and growth impairment. These characteristics are similar to those in the other 10 reported cases of distal 19q duplication and help delineate the phenotype. A review of the literature is presented.     

An unbalanced autosomal translocation (7;9) associated with feminization

A newborn girl presented with generalized mild dysmorphic features. She later developed heart failure and hydrocephalus, and died aged 5 months. Chromosome analysis revealed an unbalanced reciprocal translocation (with partial trisomy for half of the long arm of 7 and partial monosomy for the short arm of chromosome 9) and normal but inappropriate sex chromosomes (XY). The karyotype (46,XY,-9, +der(9),t(7;9)(q31.1;p23)pat) was inferred from her father who was a balanced carrier: 46, XY,(7;9)(q31.1;p23). The evidence of the present case, when considered with that of previous reports, suggests that deletion of genes on the 9p may have caused the feminization and therefore that the 9p region may contain genes which are important in the normal process of testis formation.     

一例母源性46,Y,der(X)t(X;Y)(p22;q11)染色体非平衡易位患儿的遗传学分析

目的对1例临床表征为身材矮小、鼻根部内陷、双侧隐睾、智力低下患儿进行遗传学分析,探讨该染色体结构异常与临床表征之间的关系。方法应用G显带染色体核型分析及染色体微阵列分析(chromosomal microarray analysis,CMA)技术对患儿进行遗传学检测,并对其父母进行外周血染色体核型分析。结果G显带分析结果显示患儿染色体核型为46,Y,der(X)t(X;Y)(p22;q11),mat。CMA检测结果提示患儿X染色体短臂Xp22.33p22.31存在约8.3 Mb片段缺失,Y染色体长臂Yq11.221qter存在约43.3 Mb片段重复。其父亲染色体核型正常,母亲染色体核型结果为46,X,der(X)t(X;Y)(p22;q11)。结论患儿携带母源性der(X)t(X;Y)(p22;q11)染色体非平衡易位,携带者的表型与其性别以及X染色体缺失片段的大小和位置密切相关。男性携带者智力障碍、生长发育落后等异常表型较女性更为严重。     

Familial complex chromosome rearrangement giving rise to balanced and unbalanced recombination products

We report on a family ascertained through a 14-month-old girl with a terminal deletion of chromosome 8p23.1. Analysis of the karyotype of other relatives showed that the mother is the carrier of a balanced complex 4-break chromosome rearrangement, which she and her brother inherited from their father following recombination. This complex chromosome rearrangement (CCR) was confirmed by fluorescence in-situ hybridization (FISH) using libraries for chromosomes 1, 8, and 9, and telomeric probes for the long arm of chromosome 9. The karyotype of the maternal grandfather was 46,XY,t(1;8) (p31;q21.1),t(8;9)(p23.1;q34). The karyotype of his daughter is 46,XX,rec(8)t(1;8) (p31;q21.1)t(8;9)(p23.1;q34)pat. The karyotype of the proposita is 46,XX,rec(8)t(8;9) (p23.1;q34)mat, and that of her abnormal elder sister is 46,XX,t(1;8)(p31;q21.1)rec(8) t(8;9)(p23.1;q34)mat,der(9)t(8;9)(p23.1;q34) mat. Unbalanced segregation and/or recombination during maternal meiosis gave rise to the two abnormal sisters, one effectively with 8p trisomy and the other with monosomy for that same 8p segment. To our knowledge, this is the first case of a familial CCR giving rise to unbalanced recombination products. Am. J. Med. Genet. 79:30–34, 1998. © 1998 Wiley-Liss, Inc.     

Familial reciprocal translocation, t(2;10)(p24;q26), resulting in duplication 2p and deletion 10q

We describe a familial reciprocal translocation between the distal part of the short arm of chromosome 2 and the long arm of chromosome 10. Five individuals in two generations had multiple congenital anomalies. Their karyotypes were 46, XX or XY,−10, + der(10), t(2;10)(p24;q26). Seven persons were balanced translocation carriers whose karyotypes were 46, XX or XY, t(2;10)(p24;q26). Common manifestations included mental retardation, strabismus, narrow high-arched palate, wide alveolar ridges, other facial abnormalities, genital abnormalities and mutism. The phenotype of the unbalanced individuals is compared to that of previously published cases of the syndrome of partial duplication 2p and to reported patients with partial deletion of 10q.     

Different clones of t(1;12)/t(12;12) involving the ETV6 gene in a case of acute myeloid leukemia

We report a boy with Down syndrome and leukemia who acquired uniparental isodisomy of chromosome 7q as a secondary chromosomal change during recurrence of the disease. His karyotype before therapy was 46,XY,der(1)t(1;1)(p36;q32),-7,+21c/46,idem,del(9)(p22), whereas at recurrence it was 46,XY,der(1)t(1;1)(p36;q32,-7,der(7)(qter-->p22 through pter::q10-->qter),del(9)(p22),+21c/47,XY,+21c. By using polymerase chain reaction amplification of D7S493 and D7S527 markers, we identified the loss of the maternal chromosome 7 with a consequent paternal isodisomy in the clone with dup7q. This rearrangement could be implicated in the progression of the disease by causing (1) nullisomy for a gene or genes located on 7p22-->pter, (2) functional double doses of exclusively paternal expressed genes, and (3) restoration of the effects produced by haploinsufficiency of biparental expressed genes.     

Submicroscopic terminal deletion of 1p36.3 and Xp23 hidden in complex chromosome rearrangements: independent mechanism of telomere restitution on the two chromatids

In this study, we report two cases each with a complex chromosome rearrangement concealing a submicroscopic terminal deletion. The first case had a mos 46,XX,der(1)t(1;9)(p36.3;p13). ish der(1)(wcp9 +, 1ptel-, 9ptel +, pan tel +)[88]/46,XX. ish del(1)(1ptel -, 9ptel -, pan tel +)[12] karyotype. Scrutiny by FISH using wcp 9, 1ptel, 9ptel, and pan telomeric probes found a subtelomeric 1ptel deletion on the der(1) in the abnormal cell line and on a chromosome 1 in the apparently normal cell line. The telomere (TTAGGG)n, however, was present on the terminal ends of both copies of chromosome 1 in the apparently normal and abnormal cell lines. The second case had a de novo mos 46,X,der(X)t(X;22)(p22.3;q11.2),inv dup(22)(q11.2).ish der(X)(wcpX +,wcp22 +,KAL +, STS -,Xptel -,BCR +),inv dup(22)(wcp22 +,TUPLE ++,BCR -)[85]/45,X,der(X)t(X;22)(p22.3;q11.2),- 22[15].ish der(X)(wcpX +,wcp22 +, KAL +,STS -,Xptel -,BCR +) karyotype. FISH probes identified a terminal Xpter deletion, distal to the KAL gene. The two rearrangements are hypothesized to have been initiated by a terminal deletion. We propose a model for the formation of the rearrangement in Case 1, which invokes independent telomere stabilization of the sister chromatids. A terminal deletion 1pter in meiosis, was followed by acquiring or regenerating a telomere (TTAGGG)n cap on one chromatid and the other chromatid was involved in a translocation with a chromosome 9 chromatid. Following segregation of this chromosome the viable cell line survives to form the mosaic karyotype. Our findings suggest that subtelomeric deletions should be ruled out in cases with complex and simple rearrangements involving the terminal regions.     

Clinical outcomes of adjacent 1 segregation in a familial translocation t(8;18)(p21.3;p11.23).

We report a reciprocal translocation t(8;18)(p21.3;p11.23) in which both unbalanced products of adjacent 1 segregation were observed within a family. The proband was originally referred because of short stature and a webbed neck, but further investigations showed that she had mental retardation and a congenital heart defect, and had inherited an unbalanced form of the maternal translocation, 46, XX,der(8)t(8;18)mat. The proband's sister spontaneously aborted an 11 week fetus with multiple major system malformations, which was found to have a 46,XY, der(18)t(8;18)mat karyotype. The phenotypic findings of the affected subjects are discussed.     

两例分别由父源性平衡易位和母源性插入易位导致8p部分三体智力低下患儿的临床表型和遗传学分析

目的 明确两例智力低下患儿8号染色体短臂异常性质和来源,分析其染色体改变与表型的相关性.方法 首先应用常规G显带分析2例患儿及父母外周血染色体改变,然后应用比较基因组杂交芯片(array comparative genomic hybridization,array CGH)对其中1例常规核型分析的结果进行精确定位.结果 例1母亲的染色体改变为8p和3q的平衡插入易位,该患儿继承了母亲的1条衍生3号染色体,核型为46,XX,der(3) inv ins (3;8)(q25.3;p23.1p11.2)mat,导致8p部分三体.Array CGH分析显示重复区域为8p11.21-8p22,片段大小为26.9 Mb,该患儿主要表现为智力低下,未见其他8p三体的典型临床特征.例2父亲的核型为8p和11q的平衡易位,该患儿继承了父亲的1条衍生11号染色体,核型为46,XX,der(11)t(8;11)(p11.2;q25)pat,临床表现为智力低下,特殊面容,同时伴有先天性心脏病和骨骼异常,与典型8p三体表型相似,但面容特征不典型.结论 8p部分三体是2例患儿异常表型的主要原因,但与典型的8p三体相比,表型存在异质性;父母染色体分析可以帮助明确易位的性质从而有利于再发风险评估;与传统的细胞遗传学分析方法相比,arrayCGH在染色体异常分析中具有更高的分辨率和准确性.

Abstract：

Objective To determine the origin of aberrant chromosomes involving the short arm of chromosome 8 in two mentally retarded children, and to correlate the karyotype with abnormal phenotype. Methods Routine G-banding was performed to analyze the karyotypes of the two patients and their parents, and array comparative genomic hybridization (array CGH) was used for the first patient for fine mapping of the aberrant region. Results The first patient presented with only mental retardation. The father had normal karyotype. The mother had an apparent insertion translocation involving chromosomes 8 and 3 [46,XX, inv ins (3;8) (q25.3;p23.1p11.2)], the karyotype of the child was ascertained as 46,XX,der(3) inv ins (3;8)(q25.3;p23.1p11.2). Array CGH finely mapped the duplication to 8p11.21-8p22, a 26.9Mb region. The other patient presented with mental retardation, craniofacial defects, congenital heart disease and minor skeletal abnormality. The mother had normal karyotype. The father had an apparently balanced translocation involving chromosome 8p and 11q, the karyotype was 46,XY, t(8;11)(p11.2;q25). The karyotype of the child was then ascertained as 46,XX,der(11)t(8;11)(p11.2;q25). Conclusion These results suggested that partial trisomy 8p was primary cause for the phenotypic abnormalities of the two patients, whereas a mild phenotypic effect was observed in patient 1. Parental karyotype analysis could help define the aberrant type and recurrent risk evaluation. In contract to routine karyotype analysis, aberrant regions could be mapped by array CGH with higher resolution and accuracy.     

Duplication of distal 17q from a maternal translocation: an additional case with some unique features.

A female with multiple dysmorphic features was found to have an unbalanced karyotype with duplication of the distal long arm of chromosome 17 and deletion of the terminal region of the short arm of chromosome 12. This was derived from a reciprocal translocation in the mother, 46,XX,t(12;17)(p13.3;q23). Clinical findings are presented and comparison with other reported cases of distal 17q duplication shows several unique features in our case.     

Confirmation of centromeric fusion in 7p/1q translocation associated with myelodysplastic syndrome.

Fluorescence in situ hybridization (FISH) using chromosome 1- and chromosome 7-specific centromeric alpha-satellite probes was performed on the bone marrow (BM) cells of a patient with myelodysplastic syndrome (MDS) who had been treated for lymphoma and whose BM karyotype was initially considered to be 46,XY,-7,+der(1)t(1;7)(p11;p11). FISH results suggested the presence of both chromosome 1 and chromosome 7 centromeres in the rearranged chromosome. Thus, the correct karyotype should be written as 46,XY,-7,+der(1;7)(q10;p10).