Complex chromosomal rearrangement and associated counseling issues in a family with Pelizaeus-Merzbacher disease

We report cytogenetic and molecular findings in a family in which Pelizaeus-Merzbacher disease has arisen by a sub-microscopic duplication of the proteolipid protein (PLP1) gene involving the insertion of approximately 600 kb from Xq22 into Xq26.3. The duplication arose in an asymptomatic mother on a paternally derived X chromosome and was inherited by her son, the proband, who is affected with Pelizaeus-Merzbacher disease. The mother also carries a large interstitial deletion of approximately 70 Mb extending from Xq21.1 to Xq27.3, which is present in a mosaic form. In lymphocytes, the mother has no normal cells, having one population with three copies of the PLP1gene (one normal X and one duplication X chromosome) and the other population having only one copy of the PLP1 gene (one normal X and one deleted X chromosome). Her karyotype is 46,XX.ish dup (X) (Xpter --> Xq26.3::Xq22 --> Xq22::Xq26.3 --> Xqter)(PLP++)/46,X,del(X)(q21.1q27.3).ish del(X)(q21.1q27.3)(PLP-). Both ends of the deletion have been mapped by fluorescence in situ hybridization using selected DNA clones and neither involves the PLP1 gene or are in the vicinity of the duplication breakpoints. Prenatal diagnosis was carried out in a recent pregnancy and the complex counseling issues associated with these chromosomal rearrangements are discussed.     

PLP1 duplication at the breakpoint regions of an apparently balanced t(X;22) translocation causes Pelizaeus–Merzbacher disease in a girl

Fonseca ACS, Bonaldi A, Costa SS, Freitas MR, Kok F, Vianna‐Morgante AM. PLP1 duplication at the breakpoint regions of an apparently balanced t(X;22) translocation causes Pelizaeus–Merzbacher disease in a girl. PLP1 (proteolipid protein1 gene) mutations cause Pelizaeus–Merzbacher disease (PMD), characterized by hypomyelination of the central nervous system, and affecting almost exclusively males. We report on a girl with classical PMD who carries an apparently balanced translocation t(X;22)(q22;q13). By applying array‐based comparative genomic hybridization (a‐CGH), we detected duplications at 22q13 and Xq22, encompassing 487–546 kb and 543–611 kb, respectively. The additional copies were mapped by fluorescent in situ hybridization to the breakpoint regions, on the derivative X chromosome (22q13 duplicated segment) and on the derivative 22 chromosome (Xq22 duplicated segment). One of the 14 duplicated X‐chromosome genes was PLP1.The normal X chromosome was the inactive one in the majority of peripheral blood leukocytes, a pattern of inactivation that makes cells functionally balanced for the translocated segments. However, a copy of the PLP1 gene on the derivative chromosome 22, in addition to those on the X and der(X) chromosomes, resulted in two active copies of the gene, irrespective of the X‐inactivation pattern, thus causing PMD. This t(X;22) is the first constitutional human apparently balanced translocation with duplications from both involved chromosomes detected at the breakpoint regions.     

X;14 translocation:an exception to the critical region hypothesis on the human X-chromosome

We report on a family in which an X;14 translocation has been identified. A phenotypically normal female, carrier of an apparently balanced X-autosome translocation t(X;14)(q22;q24.3) in all her cells and a small interstitial deletion of band 15q112 in some of her cells had 2 offspring. She represents a fifth case of balanced X-autosome translocation with the break point inside the postulated critical region of Xq(q13 q26) associated with fertility. The break point in this case is located in Xq22, the same band as in four previously published exceptional cases. In most of her cells, the normal X was inactivated. Her daughter, the proposita, has an unbalanced karyotype 46,X,der(X), t(X;14)(q22;q24.3)mat, del(15)(q11.1q11.3)mat. She is mildly retarded and has some Prader-Willi syndrome manifestations. She has two normal 14 chromosomes, der(X), and deletion 15q11.2. Her clinical abnormalities probably could be attributed to the deletions 15q and Xq rather than 14q duplication. In most of cells, der(X) was inactivated. We assume that spreading of inactivation was extended to the 14q segment on the derivative X. Late replication and gene dose studies support this view. Another daughter, who inherited the balanced X;14 translocation and not deletion 15 chromosome, is phenotypically normal.     

Molecular cytogenetic studies of Xq critical regions in premature ovarian failure patients

BACKGROUND: Premature ovarian failure (POF) is defined as amenorrhoea for more than 6 months, occurring before the age of 40, with an FSH serum level higher than 40 mIU/ml. Cytogenetically visible rearrangements of the X chromosome are associated with POF. Our hypothesis was that cryptic Xq chromosomal rearrangements could be an important etiological contributor of POF. METHODS: Ninety POF women were recruited and compared to 20 control women. Peripheral blood samples were collected and metaphase chromosomes were prepared using standard cytogenetic methods. To detect Xq chromosomal micro-rearrangements, fluorescence in situ hybridization (FISH) analysis was performed using a selection of 30 bacterial artificial chromosome (BAC) and P1 artificial chromosome clones, spanning Xq13-q27. We further localized the translocation breakpoints by FISH with additional BAC clones. RESULTS: Chromosomal abnormalities were identified in 8.8% of our 90 patients [one triple X, three large Xq deletions 46,X,del(X)(q22.3), 46,X,del(X)(q21.2) and 46,X,del(X)(q21.32), two balanced X;autosome translocations 46,X,t(X;1) (q21.1;q32) and 46,X,t(X;9)(q21.31;q21.2) and two Robertsonian translocations 45,XX,der(15;22)(q10;q10) and 45,XX,der(14;21)(q10;q10)]. The two Xq translocation breakpoints were among a cluster of repetitive elements without any known genes. FISH analysis did not reveal any Xq chromosomal micro-rearrangement. CONCLUSIONS: Karyotyping is definitely helpful in the evaluation of POF patients. No submicroscopic chromosomal rearrangements affecting Xq region were identified. Further analysis using DNA microarrays should help delineate Xq regions involved in POF.     

Translocation (X;19) with involvement of the inactive X chromosome in oligoblastic granulocytic leukemia

A 72-year-old female with metastatic breast cancer developed oligoblastic granulocytic leukemia 6 months after initiation of chemotherapy. Cytogenetic examination of the bone marrow cells revealed a balanced t(X;19)(q12;q13.3) as the sole abnormality in 50% of the metaphases. The remaining cells showed a normal female karyotype. The der(19) chromosome displayed consistent folding in the Xq13-q23 region in all metaphases, indicating involvement of the inactive X chromosome in translocation.     

X;14 translocation: An exception to the critical region hypothesis on the human X-chromosome

We report on a family in which an X;14 translocation has been identified. A phenotypically normal female, carrier of an apparently balanced X-autosome translocation t(X;14) (q22;q24.3) in all her cells and a small interstitial deletion of band 15q 112 in some of her cells had 2 offspring. She represents a fifth case of balanced X-autosome translocation with the break point inside the postulated critical region of Xq(q13 q26) associated with fertility. The break point in this case is located in Xq22, the same band as in four previously published exceptional cases. In most of her cells, the normal X was inactivated. Her daughter, the proposita, has an unbalanced karyotype 46,X,der(X), t(X;14)(q22;q24.3)mat, del(15)(q11.1q11.3)mat. She is mildly retarded and has some Prader-Willi syndrome manifestations. She has two normal 14 chromosomes, der(X), and deletion 15q11.2. Her clinical abnormalities probably could be attributed to the deletions 15q and Xq rather than 14q duplication. In most of cells, der(X) was inactivated. We assume that spreading of inactivation was extended to the 14q segment on the derivative X. Late replication and gene dose studies support this view. Another daughter, who inherited the balanced X;14 translocation and not deletion 15 chromosome, is phenotypically normal.     

Multiple apparently unrelated clonal chromosome abnormalities in a squamous cell carcinoma of the tongue

We have cytogenetically examined short-term cultures from a squamous cell carcinoma of the tongue, a tumor type in which chromosome aberrations hitherto have not been reported. No less than 12 pseudodiploid clones were detected, giving the tumor karyotype 46,X,der(X)t(X;1)(q26;p32),der(1)(Xqter→Xq26::1p32→cen→1q42:),del(13)(q11q21),t(15;?) (q26;?)/46,XX,t(1;?)(p34;?),inv(2)(p21q11)/46,XX,t(1;10)(p32;q24)/46,XX,+der(1)(12pter→ 12p11::1p11→cen→1q32::11q13→11q32→1q42:),del(11)(q13q22), - 12, der(17)t(1:17) (q42;p13)/46,XX,inv(1)(p22q44)/47,XX,del(1)(q32),der(17)t(1:17)(p22;q25),der(1)inv(1) (q25q44)t(1;17)(p22;q25),ins(14;7)(q11;q22q36), + 14/46,XX,t(1;4)(q23;q35)/46,XX,t(1;21) (q25;q22),t(2;10)(q31;q26),t(22;?)(q12;?)/46,XX,del(1)(q32)/46,XX,t(1;8)(q44;q21)/46,XX, t(2;21)(q11;p11)/46,XX,t(9;11)(q34;q13). The large number of apparently unrelated abnormalities leads us to suggest that the carcinoma may have been of multiclonal origin.     

A de novo complex karyotype with two independent balanced translocations and a double inversion of chromosome 6 presenting with multiple congenital anomalies

We report a 4-year-old female with a de novo complex karyotype with multiple chromosomal rearrangements and a distinctive phenotype. Her medical history is significant for having been a twin born at 35 weeks gestation, breech presentation, with feeding problems and poor growth as an infant, gastroesophageal reflux disease, peripheral pulmonic stenosis, omphalocele, high myopia, and severe mental retardation. She is small for her age with microcephaly, posteriorly sloping forehead, shallow orbits, long palpebral fissures, prominent nose, wide mouth, absent uvula, kyphosis, brachydactyly, bridged palmar crease, and hypertonia. Peripheral blood lymphocytes revealed a karyotype of 46,XX,t(1;12)(p22.3;q21.3),inv(6)(p24q23),t(7;18)(q11.2;q21.2) in all cells. Parental karyotypes and that of her twin were normal. Spectral Karyotyping (SKY) and fluorescence in situ hybridization (FISH) with whole chromosome paints for chromosomes 1, 6, 7, 12, and 18 did not reveal additional rearrangements. Prometaphase G-banding analysis suggested that the "inverted" chromosome 6 might contain a cryptic rearrangement. Although no deletion nor duplication was detected using metaphase comparative genomic hybridization (CGH), multicolor high resolution banding (mBAND) demonstrated a double inversion of chromosome 6, resulting in a final karyotype as above but including der(6)(pter --> p23::q21 --> q22.3::q21 --> p23::q22.3 --> qter).     

Unbalanced mosaic karyotypes with different structural abnormalities involving a common chromosome region: Report of two cases

We report on 2 cases with different de novo unbalanced mosaic karyotypes in which each cell line had a different structural abnormality involving a common chromosome region: 46,XX,del(11)(q23.3)/46,XX,?11,+der(11)t(11;?)(q23.3;?) and 46,X,idic(Xq)/46,X,idic(Xq),?12,+der(12)t(X;12)(p11.2;p13.3). Molecular-cytogenetic analysis confirmed the origin of the derivative 12 chromosome in the latter. We present a literature review of reports with mosaic cell lines of structural chromosome abnormalities that share the same chromosome breakpoint. © 1993 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.     

Dominant X linked subcortical laminar heterotopia and lissencephaly syndrome (XSCLH/LIS): evidence for the occurrence of mutation in males and mapping of a potential locus in Xq22.

X linked subcortical laminar heterotopia and lissencephaly syndrome (XSCLH/ LIS) is an intriguing disorder of cortical development, which causes classical lissencephaly with severe mental retardation and epilepsy in hemizygous males, and subcortical laminar heterotopia (SCLH) associated with milder mental retardation and epilepsy in heterozygous females. Here we report an exclusion mapping study carried out in three unrelated previously described families in which males are affected with lissencephaly and females with SCLH, using 38 microsatellite markers evenly distributed on the X chromosome. Most of the X chromosome was excluded and potential intervals of assignment in Xq22.3-q23 or in Xq27 are reported. Although the number of informative meioses did not allow a decision between these two loci, it is worth noting that the former interval is compatible with the mapping of a breakpoint involved in a de novo X;autosomal balanced translocation 46,XX,t(X;2)(q22;p25) previously described in a female with classical lissencephaly. In addition, haplotype inheritance in two families showed a grandpaternal origin of the mutation and suggested in one family the presence of mosaicism in germline cells of normal transmitting males.     

A novel case of unilateral blepharophimosis syndrome and mental retardation associated with de novo trisomy for chromosome 3q.

We have evaluated a 3 2/12 year old girl who presented with unilateral blepharophimosis, ptosis of the eyelid, and mental retardation. Additional dysmorphic features include microcephaly, high, narrow forehead, short stubby fingers, and adduction of the right first toe. Cytogenetic analysis showed an unbalanced karyotype consisting of 46,XX,add(7)(q+) that was de novo in origin. Fluorescence in situ hybridisation (FISH) using microdissected library probe pools from chromosomes 1,2,3,7, and 3q26-qter showed that the additional material on 7q was derived from the distal end of the long arm of chromosome 3. Our results indicate that the patient had an unbalanced translocation, 46,XX,der(7)t(3;7)(q26-qter;q+) which resulted in trisomy for distal 3q. All currently reported cases of BPES (blepharophimosis-ptosis-epicanthus inversus syndrome) with associated cytogenetic abnormalities show interstitial deletions or balanced translocations involving 3q22-q23 or 3p25.3. Our patient shares similar features to BPES, except for the unilateral ptosis and absence of epicanthus inversus. It is possible that our patient has a contiguous gene defect including at least one locus for a type of blepharophimosis, further suggesting that multiple loci exist for eyelid development.     

Consistent breakpoints in region 14q22-q24 in uterine leiomyoma

The chromosomes of nine consecutive human benign leiomyomas of the uterus were studied with banding methods following short-term culture. All of the tumors had a typical benign histology. Five exhibited clonal chromosome changes including three with consistent involvement of chromosomes 12 and 14 in a translocation, t(12;14)(q14-15;q23-q24), a direct insertion, dir ins(12;14)(p11.2;q22q24.1), and a direct insertion, dir ins(14;12)(q22-q23;q14-q15q23-q24.1). Thus, this study demonstrated the presence of consistent chromosome changes in another benign proliferation. Strikingly, the breakpoint observed at 12q14-q15 in two specimens is also involved nonrandomly in other benign proliferations such as mixed salivary gland tumors and lipomas. However, region 14q22-q24, which was involved in three specimens, may contain a DNA sequence critical for the genesis of uterine leiomyoma.     

Functional disomy of the Xq28 chromosome region

We report on two patients, a boy and a girl, with an additional Xq28 chromosome segment translocated onto the long arm of an autosome. The karyotypes were 46,XY,der(10)t(X;10)(q28;qter) and 46,XX,der(4)t(X;4)(q28;q34), respectively. In both cases, the de novo cryptic unbalanced X-autosome translocation resulted in a Xq28 chromosome functional disomy. To our knowledge, at least 17 patients with a distal Xq chromosome functional disomy have been described in the literature. This is the third report of a girl with an unbalanced translocation yielding such a disomy. When the clinical features of both patients are compared to those observed in patients reported in the literature, a distinct phenotype emerges including severe mental retardation, facial dysmorphic features with a wide face, a small mouth and a thin pointed nose, major axial hypotonia, severe feeding problems and proneness to infections. A clinically oriented FISH study using subtelomeric probes is necessary to detect such a cryptic rearrangement.     

Combined trisomy 9 and Ullrich-Turner syndrome in a girl with a 46,X,der(9)t(X;9)(q12;q32) karyotype

Total trisomy 9 is a rare disorder with most patients dying before age 4 months. Herein, we report a 9-year-old girl with mental retardation, short stature, a peculiar face and other minor defects, who was diagnosed as having an unbalanced de novo X-autosome translocation with a 46,X,der(9)t(X;9) (q12;q32) karyotype resulting in almost a full trisomy 9(pter→q32) and a partial monosomy X(q12→pter). The clinical findings of our patient, almost exclusively resemble those of trisomy 9p and the Ullrich-Turner syndromes and has few manifestations of 9q trisomy. BrdU replication studies by Giemsa staining showed an earlier replication of 9p in the translocated chromosome, but a marked late-replication pattern for almost the complete 9q arm involved in the translocation. FISH studies confirmed the presence of three 9 centromeres, excluded the presence of the X centromere signal in the rearranged chromosome, and showed that both Xq telomeric sequences were present. BrdU replication studies by FISH showed an usual pattern of striking late-replication around the XIC of the derivative chromosome, but early replication of the chromosome 9p segment and distal Xq. Am. J. Med. Genet. 80:199–203, 1998. © 1998 Wiley-Liss, Inc.     

Molecular cytogenetic analysis of leukemic mantle cell lymphoma with a cryptic t(11;14)

We report a case of leukemic mantle cell lymphoma of the blastoid variant with complex chromosomal rearrangements leading to the recombination of BCL1 from 11q13 and IGH from 14q32. G-banding analysis showed, in addition to multiple other chromosome abnormalities, a del(11)(q13) and addition of unknown material to chromosome arms 13p and 21p. The two latter rearrangements were revealed, by use of multicolor in situ hybridization (M-FISH) analysis, to be a der(13)(qter-->p11::14q32::11q13-->11q22::14q32-->14q11::11q22-->11qter) and a similar der(21)(qter-->p11::14q32::11q13-->11q23::14q32-->14q11::11q22-->11qter). FISH with locus-specific probes for BCL1 and IGH showed a fusion signal on both derivative chromosomes.     

Interstitial deletion of chromosome 1q [del(1)(q24q25.3)] identified by fluorescence in situ hybridization and gene dosage analysis of apolipoprotein A-II,coagulation factor V,and antithrombin III

We report on a 12-month-old Japanese boy with an interstitial deletion of the long-arm of chromosome 1 and meningomyelocele, hydrocephalus, anal atresia, atrial septal defect, left renal agenesis, bilateral cryptorchidism, talipes equinovarus, low birth weight, growth/developmental retardation, and many minor anomalies. By conventional GTG-banding, his karyotype was first interpreted as 46,XY,del(1)(q23q24), but it was corrected as 46,XY.ish del(1)(q24q25.3) by fluorescence in situ hybridization using 11 known cosmid clones as probes. His serum levels of apolipoprotein A-II (gene symbol: APOA2, previously assigned to 1q21-q23) and coagulation factor V (F5, 1q21-q25) were normal, while serum concentration and activity of antithrombin III (AT3, 1q23-q25.1) was low. The results indicated that localization of APOA2 and F5 are proximal to the deleted region and AT3 is located within the deletion extent in the patient. Am. J. Med. Genet. 68:207–210, 1997 © 1997 Wiley-Liss, Inc.     

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。     

A father and son with mental retardation, a characteristic face, inv(12), and insertion trisomy 12p12.3-p11.2

A male patient with mental retardation (MR) and mild facial features was shown by high-resolution G-banding to have pericentric inversion of chromosome 12 with an unknown segment inserted into the long arm of the inverted chromosome [46,XY,inv(12)(pter-->p11.2::q14.1-->p11.2::?::q14.1-->qter)]. Both the inverted chromosome 12 and clinical manifestations were transmitted to his son. Karyotypes of the propositus' parents were normal. Studies with fluorescence in situ hybridization (FISH) in both the propositus and his son revealed that the extra segment was derived from 12p. Further FISH mapping and the genome-wide copy number detection by GeneChip Mapping 100K Array showed that an 11-Mb segment of 12p between two BAC clones, RP11-22H10 and RP11-977P2, was inserted at one of the reunion points in the long arm of the inv(12) chromosome. Analysis of parent-child transmissions of duplicated alleles using microsatellite markers defined the maternal origin of the chromosomal anomaly in the propositus and suggested a mechanism of its formation through a sister-chromatid rearrangement (SCR), that is, mismatched pairing and unequal crossover between sister chromatids as well as three break rearrangements including a U type rearrangement. Karyotypes of the propositus and his son were thus inv(12)(pter-->p11.22::q14.1-->p12.3::q14.1-->qter). This is the first report of "pure" proximal 12p-trisomy including p12.3-p11.22 region.