Balanced translocations involving chromosome 12: report of a case and possible evidence for position effect.

A girl with mental retardation, a convulsive disorder and clinical findings resembling cerebral palsy had an apparently balanced 12/18 translocation. Three additional cases reported in the literature had an abnormal phenotype associated with the positioning of segments from other autosomes adjacent to the band 12q21. Penotype abnormalities were not present in 14 individuals in which the translocation involved breaks at other sites on chromosome no. 12. These findings suggest the possibility of a position effect on chromosome segments translocated adjacent to the region 12q21.     

Pure 4p trisomy due to a de novo 4q;22p dicentric translocated chromosome karyotype 46,XX,-22,+t(4;22)(q1200;p13).

A de novo t(4;22)(q1200;p13) is reported in a girl with a florid 4p trisomy phenotype. The abnormal chromosome was identified by high resolution, C-bands and confirmed by 5-BrdU as de novo dicentric translocated chromosome.     

X-inactivation patterns in lymphocytes and skin fibroblasts of three cases of X-autosome translocations with abnormal phenotypes

Summary X-inactivation patterns were studied by replication analyses both in lymphocytes and skin fibroblasts of two patients carrying balanced X-autosome translocations, t(X;10)-(pter;q11) and t(X;17)(q11;q11), and one patient with an unbalanced translocation t(X;22)(p21;q11). Preferential late replication of the normal X chromosome was found in lymphocytes of both patients carrying balanced translocations and in skin fibroblasts of the patient carrying the translocation t(X;17). However, skin fibroblasts of the patient with a translocation t(X;10) showed preferential late replication of the abnormal der(X) chromosome with no spreading of late replication to the autosomal segment. In the case of unbalanced translocation t(X;22) there was preferential late replication of the der(X) chromosome both in lymphocytes and skin fibroblasts. The abnormal phenotype of the patients is discussed in relation to the observed X-inactivation patterns and the variability of the patterns in different tissues.     

De novo 13q paracentric inversion in a boy with cleft palate and mental retardation

Summary A paracentric inversion in chromosome 13, inv(13)(q12q22), is described in a boy with mild mental retardation and multiple minor anomalies. Bromodeoxyuridine-late replication studies showed no changes in the replication pattern of bands in the abnormal chromosome 13. The relation between the proband's phenotype and his inv(13) is unclear.Supported in part by the General Clinical Research Center, Texas Children's Hospital, Houston, TX and an NIH grant (GM 23905) to G.H.     

Partial trisomy of chromosome 21 by maternal translocation t(15;21) (q26.2; q21)]

A balanced reciprocal translocation, t(15;21) (q262;q21) was observed in the mother and maternal grandfather of two patients. The propositus, who received the abnormal chromosome 15 from his mother, is trisomic for the distal part of chromosome 21, and his phenotype is that of classical trisomy 21. His sister, who is trisomic for the proximal part of 21q, is slightly retarded but developmentally normal otherwise.     

SOD-A and chromosome 21

Summary A balanced maternal chromosome translocation (9p24;21q214) resulted in two offspring with unbalanced karyotypes. One of these, a girl trisomic for both segment 9pter9p24 and segment 21pter21q214, was found to have a SOD-A activity not significantly different from those found in a group of five cases with trisomy 21. However, clinical evaluation of this girl revealed no symptoms of the Down syndrome. These findings suggest that, providing the gene dosage theory is correct, the gene for SOD-A is probably localized on chromosome 21 proximal to, or in, band q21.     

Array-CGH characterization of a de novo t(X;Y)(p22;q11) in a female with short stature and mental retardation

We report the clinical and molecular investigations in a girl with 46,X,-X,+der(X)t(X;Y)(p22;q11) de novo karyotype who presented an intricate phenotype characterized by mental retardation and facial dysmorphisms in combination with short stature. The structure of the derivative X chromosome was studied using BAC array-CGH which disclosed the Xp22 breakpoint between the STS and the VCX3A gene and the presence of the Yq11.1qter chromosome. It is common that females with Xp;Yq translocations present only short stature and are normal in every other aspect. Thus, this would be the first case in which a girl with Xp;Yq translocation presents an unusual phenotype with intermediate male clinical features with Xp;Yq translocations. The risk of developing gonadoblastoma in females with Y chromosome material is also discussed and, to this effect, different explanations related to this apparent variation are also presented.     

X chromosomes attached by their long arm: replication autonomy of the short arm adjacent to the inactive centromere.

A 16 years old girl with Turner syndrome was found to have a 45,X/46,X,t(XqXq)?(q27q23) constitution. The two X chromosomes are attached by their long arms with loss of chromosome material and have one active and one inactive centromere. Analysis of replication patterns with autoradiography and BrdU treatment showed that the abnormal X is always the late replicating one and that the short arm of the second X which is adjacent to the inactive centromere maintains a degree of replication autonomy from the rest of the long arm.     

A patient with Down syndrome with a de novo derivative chromosome 21

Pure partial trisomy of chromosome 21 is a rare event. The patients with this aberration are very important for setting up precise karyotype-phenotype correlations particularly in Down syndrome phenotype. We present here a patient with Down syndrome with a de novo derivative chromosome 21. Karyotype of the patient was designated as 46,XY,der(21)(p13)dup(21)(q11.2q21.3)dup(21)(q22.2q22.3) with regard to cytogenetic, FISH and array-CGH analyses. Non-continuous monosomic, disomic and trisomic chromosomal segments through the derivative chromosome 21 were detected by array-CGH analysis. STR analyses revealed maternal origin of the de novo derivative chromosome 21. The dual-specificity tyrosine (Y)-phosphorylation regulated kinase 1A (DYRK1A) and Down Syndrome Critical Region 1 (DSCR1) genes that are located in Down syndrome critical region, are supposed to be responsible for most of the clinical findings of Down syndrome. However, our patient is the first patient with Down syndrome whose clinical findings were provided in detail, with a de novo derivative chromosome 21 resulting from multiple chromosome breaks excluding DYRK1A and DSCR1 gene regions.     

Genomic analysis of human chromosome 10q and 4q telomeres suggests a common origin

The subtelomeric region of human chromosome 4q contains the locus for facioscapulohumeral muscular dystrophy (FSHD). The FSHD mutation is a deletion within an array of 3.3-kb tandem repeats (D4Z4). The disease mechanism is unknown but is postulated to involve position effect. A closely related 3.3-kb array on chromosome 10qter, in contrast, is not associated with a disease phenotype. We show here that the 4q homology on chromosome 10 is not confined to the 3.3-kb repeats but extends both proximally (42 kb) and distally to include the telomere. We have also identified the most distal expressed gene on 10q known so far, mapping only 96 kb from the 3.3-kb repeat array. A 4q variant has also been identified; there is 92%nucleotide identity between the two 4q forms, 4qA and 4qB. The 4qter and 10qter forms show homology to other chromosome ends, including 4p, 21q, and 22q, and these regions may represent a relatively common subtelomeric domain.     

Identification of a locus for progressive familial intrahepatic cholestasis PFIC2 on chromosome 2q24.

Progressive familial intrahepatic cholestasis (PFIC; OMIM 211600) is the second most common familial cholestatic syndrome presenting in infancy. A locus has previously been mapped to chromosome 18q21-22 in the original Byler pedigree. This chromosomal region also harbors the locus for benign recurrent intrahepatic cholestasis (BRIC) a related phenotype. Linkage analysis in six consanguineous PFIC pedigrees from the Middle East has previously excluded linkage to chromosome 18q21-22, indicating the existence of locus heterogeneity within the PFIC phenotype. By use of homozygosity mapping and a genome scan in these pedigrees, a locus designated "PFIC2" has been mapped to chromosome 2q24. A maximum LOD score of 8.5 was obtained in the interval between marker loci D2S306 and D2S124, with all families linked.     

Kinetics of DNA replication in a dicentric X chromosome formed by long arm to long arm fusion

Summary Utilizing the 5-bromo-deoxyuridine (BrdU) incorporation technique, we have recently studied the DNA replication kinetics in a dicentric X chromosome, formed by long arm-to-long arm fusion at band q23, from a 16-year-old black female with primary amenorrhea. The patient has a karyotype 45,X/46,X,dic(X)(q23).In the buccal smear the presence of X chromatin was found in 33% of the cells examined. The Barr bodies are large and 21% of them are bipartite. DNA replication studies were performed on the patient's lymphocytes by the thymidine pulse (T-pulse) method and confirmed comparatively by the BrdU pulse (B-pulse) method. The results indicate that the dicentric X chromosome is always late-replicating. The replication pattern is symmetric on both sides of the breakpoint and the replication sequence is, in order, p11, p22, q1(1–3), q22, q23, p21, and q21. This finding is comparable to those of other investigators and supports the theory that there exist two inactivation centers in the dicentric X chromosome, located on or near the q21 band.     

Pure interstitial duplication of chromosome 7q (7q31.2-->q33) in a 4-year-old girl with growth restriction, short stature, speech delay and intellectual disability

We report the cytogenetic and molecular characterization of a 22.3-Mb pure interstitial duplication of chromosome 7q, dup(7)(q31.2-->q33) in a 4-year-old girl with growth restriction, short stature, speech delay, inguinal hernia, strabismus and intellectual disability. We speculate that the gene dosage increase effect of the ING3 and LEP genes may be partially responsible for the phenotype of growth restriction and short stature in this patient.     

A case report of a patient with retinoblastoma and chromosome 13q deletion: assignment of a new gene (gene for LCP1) on human chromosome 13

Summary Retinoblastoma (Rb) occurs in hereditary, non-hereditary, and chromosomal deletion forms and the locus for the Rb gene (Rb-1) is closely linked to the locus for esterase D (ESD) assigned to the chromosome 13q14.11. We describe a patient who was predicted to have Rb from the genetic analysis of the chromosome and ESD phenotype. Furthermore, the gene for lymphocyte cytosol polypeptide with molecular weight of 64,000 (LCP1: McKusick catalogue No. 15343, 1983) was assigned to chromosome 13 by deletion mapping. A 3-month-old female had many characteristics of chromosome 13q-syndrome, including dolichocephaly, epicanthus, ptosis, depressed nasal bridge, micrognathia, short webbed neck, and short fifth fingers with clinodactyly and single crease. The karyotype of the patient was 46,XX,del(13) (q14.1–q32), though both the parents had normal karyotypes. As expected, the phenotype of ESD derived from one of the parents, the father in this case, was not detected in peripheral blood lymphocytes by two-dimensional gel electrophoresis (two-DE), indicating that ESD from the father was deleted in the abnormal chromosome 13. The possibility of paternity was calculated to be 0.996 based on the data using 22 genetic markers. Bilateral retinoblastomas could be diagnosed by ophthalmologic examinations before the manifestation of any clinical signs of the tumor and immediately intensive care was taken. In addition, the phenotype of LCP1 derived from the father was not expressed in the lymphocyte proteins from the patient. These data indicate that the gene for LCP1 (LCP1) is located in the region q14.1–q32 of chromosome 13 and may be a useful genetic marker for preclinical diagnosis of Rb.     

Partial trisomy 21 (21q21 - 21q22.2)]

An abnormal chromosome 21 is reported in a child with a phenotype strongly reminiscent of trisomy 21 syndrome. It is shown to result from duplication of the segment 21q21 leads to 21q22.2. Comparison of the phenotype with that of other partial and total trisomics shows that the characteristic features of the trisomy 21 syndrome (mongolism), the mental retardation in particular - is due to trisomy 21q22.2 and perhaps 21q22.2.     

Partial trisomy 21

Summary Cytogenetic analysis of a 6-year-old girl with moderate mental retardation revealed 46 chromosomes with a tandem translocation (21;21) resulting in a partial trisomy 21. Only the terminal band 21q22 was not in triplicate. G-, Q-, R-, and C-banding techniques and silver nitrate staining of the nucleolus organizer regions (NORs) were used to identify this chromosome fully.The phenotype of the patient was not typical for Down's syndrome, providing additional evidence that trisomy of band 21q22 is pathogenetic for the phenotype of Down's syndrome. This is also a new example in human pathology of a stable dicentric chromosome in which one of the centromeric constrictions appears to be nonfunctional.     

Acute promyelocytic leukemia with unusual karyotype

Acute myeloid leukemia (AML-M3) is associated with the translocation t(15;17)(q22;q12-21) which disrupts the retinoic acid receptor alpha (RARA) gene on chromosome 17 and the PML gene on chromosome 15. We report a two-year-old patient with AML-M3 without the usual translocation t(15;17). Cytogenetic studies demonstrated normal appearance of chromosome 15 while the abnormal 17 homologue was apparently a derivative 17, der(17)(17qter-cen-q21:), the rearrangement distinctly shows deletion at 17q21 band and the morphology corresponding to an iso chromosome i(17q-). This case report is a rare cytogenetic presentation of acute promyelocytic leukemia (APML).     

Genetic counselling in carriers of reciprocal chromosomal translocations involving short arm of chromosome X

A central concept in genetic counselling is the estimation of the probability of occurrence of unbalanced progeny at birth and other unfavourable outcomes of pregnancy (miscarriages, stillbirths and early death). The estimation of the occurrence probability for individual carriers of four different X-autosome translocations with breakpoints at Xp, namely t(X;5)(p22.2;q32), t(X;6)(p11.2;q21), t(X;7)(p22.2;p11.1), and t(X;22)(p22.1;p11.1), is presented. The breakpoint positions of chromosomal translocations were interpreted using GTG, RBG and FISH-wcp. Most of these translocations were detected in women with normal phenotype, karyotyped because of repeated miscarriages and/or malformed progeny. A girl with very rare pure trisomy Xp22.1-->pter and a functional Xp disomy was ascertained in one family and her clinical picture has been described in details. It has been suggested that not fully skewed X chromosome inactivation of X-autosome translocation with breakpoint positions at Xp22 (critical segment) could influence the phenotype and risk value. Therefore, the X inactivation status was additionally evaluated by analysis of replication banding patterns using RBG technique after incorporation of BrdU. In two carriers of translocations: t(X;5)(p22.2;q32) and t(X;7)(p22.2;p11.1), late replication state of der(X) was observed in 5/100 and 10/180 analysed cells, respectively. In these both cases the breakpoint positions were clustered at the critical segment Xp22.2. In two other cases, one with the breakpoint position within [t(X;22)(p22.1;p11.1)] and one outside the critical region [t(X;6)(p11.2;q21)], fully skewed inactivation was seen. Therefore, we suggest that neither the distribution of the breakpoint positions nor fully skewed inactivation influenced the phenotype of observed t(X;A) carriers. The occurrence probabilities of the unbalanced progeny were calculated according to Stene and Stengel-Rutkowski along with application of updated available empirical data. In the studied group the values of occurrence probability for unbalanced offspring at birth ranged from 2.1% to 17%. Information on the magnitude of the individual figures may be important for women carrying a reciprocal X;A translocation when deciding upon further family planning.     

Partial 4q duplication due to Inherited der(13),t(4;13)(q26;q34)mat in a girl with a deficiency of Factor X

A girl with mental retardation had a partial trisomy 4q. The chromosome aberration originated from a maternal balanced translocation t(4;13)(q26;q34). The value for Factor X was half the normal value, raising the question of the location of a gene related to the production of Factor X on chromosome 4.