Variability in the heterochromatin regions of the chromosomes and chromosomal anomalies in children with autism: Identification of genetic markers of autistic spectrum disorders

Cytogenetic and molecular cytogenetic analysis of children with autism (90 subjects) and their mothers (18 subjects) is presented. Anomalies and fragility were found in chromosome X in four cases of autism: mos 47,XXX[98]/46, XX[2]; 46,XY,r(22)(p11q13); 46,XY,inv(2)(p11.2q13),16qh-; and 46,Y,fra(X)(q27.3),16qh-. C staining and quantitative fluorescent in situ hybridization (FISH) were used to demonstrate a significant increase in the frequency of variations in the heterochromatin regions of chromosomes in children with autism as compared with a control group (48% and 16% respectively). Pericentric chromosome inversion 9phqh was not characteristic of patients with autism, while variation in heterochromatin regions 1phqh, 9qh+, and 16qh-were found significantly more frequently in children with autism. These data provide the basis for discussing the possible role of the gene position effect in the pathogenesis of autism and the possible search for biological markers of autistic disorders. __________ Translated from Zhurnal Nevrologii i Psikhiatrii imeni S. S. Korsakova, Vol. 106, No. 6, pp. 52–57, June, 2006.     

Chromosome abnormalities involving heterochromatic regions in monocytic leukemia

We report two cases of monocytic leukemia associated with cytogenetic changes involving the juxtacentromeric heterochromatin of different chromosomes. In a patient with chronic myelomonocytic leukemia (CMMoL) we describe a translocation t(1;9)(q12;q13) in which the duplicated derivative chromosome 9q + showed a huge centromeric C-band, derived by fusion of the heterochromatic regions of chromosomes 1 and 9. The constitutional karyotype showed two heterochromatin polymorphisms, 1qh + and inv(9qh). In the second case, an acute monoblastic leukemia was associated with an abnormally elongated juxtacentromeric heterochromatic region of chromosome 4 that was not constitutionally present.     

Heterochromatic variants and their association with neoplasias: III. Multiple myeloma

The incidence of heterochromatic variants was assessed in 26 patients with multiple myeloma (MM) and 55 control individuals. An enhanced frequency of heteromorphism was present in 92% of the MM population compared with 44% of the control group (p less than 0.001). Significant differences with regard to controls were observed in chromosome pairs #1, #9, and #16 due to 1qh-, inv(1),inv(9) and 16qh- variants. We suggest that MM would present an intermediate heterochromatic behavior between hematologic diseases and solid tumors.     

C-band polymorphism: Comparison between trisomy 21 cases and mentally retarded controls

C-banding was done prospectively on 50 Down syndrome (trisomy 21) cases and 50 mentally retarded controls. Heterochromatin was quantitated by measuring the lengths of heterochromatin blocks and comparing these segments to the length of the short arm of chromosome 16 for 1, 9 and 16 heterochromatin, and to the total length of the Y chromosome for the Y heterochromatin in the distal long arm. For the first 30 individuals in each group, there was no difference in the mean lengths of C-band blocks of the 1, 9, 16 and Y chromosomes. For the total sample, there also was no difference between the trisomy 21 cases and controls in the number or size of pericentric inversions involving the heterochromatin blocks of chromosomes 1 and 9. Assuming random segregation of the parental C-band polymorphisms, this study gives no evidence for an association between such polymorphisms of the 1, 9, 16 and Y chromosomes and nondisjunction of chromosome 21.     

9号染色体异染色质区的变异分析

目的分析疑有染色体异常个体的9号染色体异染色质区的变异。方法采集疑有染色体异常的3075名个体静脉血，其中男性1653例，女性1422例，以1515名正常人作对照，培养其淋巴细胞进行染色体核型分析。结果疑有染色体异常个体的9号染色体异染色质区的变异率为5．56％，而正常对照组9号染色体异染色质区的变异率仅为1．32％，9号染色体异染色质区的变异包括9qh＋、9qh-及inv（9）。结论疑有染色体异常个体的9号染色体异染色质区的变异率高于正常人4．2倍（P＜0．01），这说明9号染色体异染色质区的变异可能参与一些染色体病的发生。     

Heterochromatic variants and their association with neoplasias: IV. Colon adenomas and carcinomas

C-band polymorphisms in peripheral blood lymphocytes of 62 patients (33 with colon adenomas and 29 with colon carcinomas) were studied. A significant difference in the frequency of heterochromatic variants in chromosomes #1 in both colon adenoma (56%) and carcinoma (67%) with respect to controls (18%) was observed (p less than 0.001). The heterochromatic variants preferentially involved in both pathologies were inv(1), 1qh-, and inv(9), compared with controls. No differences were found between colon adenomas and carcinomas. We suggest that 1qh- and inv(1) variants are important heterochromatic changes in neoplasia.     

The karyotype of the glucocorticoid-sensitive, lymphoblastic human T-cell line CCRF-CEM shows a unique deleted and inverted chromosome 9

Chromosome karyotypes were prepared from the highly glucocorticoid-sensitive clone C7 of the human acute lymphoblastic leukemia T-cell line CCRF-CEM. The modal number of chromosomes is 47, and one chromosome #9 has a pericentric inversion of the heterochromatin region (9qh) plus a deletion of the short arm. In most cells, there is an extra chromosome #20. All other chromosomes appear to be normal. Examination of the uncloned line CCRF-CEM (ATCC CCL 119), which was frozen away shortly after the line was originated and has undergone fewer passages than CEM C7, also revealed the same abnormality of chromosome #9. Each of 10 other clones isolated from CCRF-CEM in this laboratory also contained the abnormal chromosome #9.     

9号染色体臂间倒位的遗传效应分析

目的探讨9号染色体臂间倒位的常见区带及其所产生的遗传效应.方法应用统计学方法对国内中文杂志从1994年以来报道的342例9号染色体臂间倒位进行分析.结果117例(34.2%)为次缢痕区(p11q12)的倒位,96例(28.1%)倒位区带为p11q13,由此可见,inv(9)主要发生于次缢痕区,而且大部分病例都有不同的临床病理表现.结论从目前的研究资料分析,许多研究者倾向于inv(9)(qh)并非仅是一种多态性,它可能在一定的诱因存在下会对减数分裂时同源染色体的分离产生一定的影响.     

A 46,X,inv(Y) young woman with gonadal dysgenesis and gonadoblastoma: cytogenetics, molecular, and methylation studies

Cytogenetic analysis of a young woman with gonadal dysgenesis and bilateral gonadoblastoma shared a male karyotype with a rearranged Y chromosome, interpreted as a pericentric inversion. The breakpoints, defined by fluorescent in situ hybridization (FISH), were located on the very distal short arm on band Yp11.31 and in the middle of the Yq12 long arm heterochromatic region. FISH analysis documented that the short arm breakpoint was 93 Kb distal to SRY and disrupted the CD99 gene, which was transposed to the distal portion of Yq12. The proposita's phenotype was similar to that of XY individuals with gonadal dysgenesis but without signs of Ullrich-Turner syndrome. There were no mutations in the SRY gene. Cytogenetic analysis in the proposita's father showed mosaicism of a normal Y chromosome and several different rearrangements, such as deletion of a heterochromatin portion at band Yq12.2, a fragile site at the same band, structural rearrangements between the Y-chromosome and other autosomes, Y-chromosome aneuploidies, and "Premature Centromere Division" (PCD) anomaly. The proposita's inverted Y chromosome appears to have originated from paternal Y chromosome instability. The patient's female phenotype could be due to SRY CpG methylation-mediated positional effects (PEV).     

Karyotypic evolution in acute myelomonocytic leukemia with pericentric inversion of chromosome 16

A 37-year-old Japanese male patient with acute myelomonocytic leukemia subtype M4 (according to FAB classification) associated with bone marrow eosinophilia and specific chromosome abnormalities: a pericentric inversion of chromosome 16, inv(16)(p13q22); a long arm deletion of chromosome #7, del(7)(q22q34); and a gain of chromosomes #8 and #22 is reported. In addition to the modal karyotype, 47,XY,7q-,inv(16),+22, there were three other clones whose karyotypes were 46,XY,inv(16); 47,XY,inv(16),+22; and 48,XY,+8,inv(16),+22. As these karyotypes were related to each other, the presence of multiple clones indicated that karyotypic evolution had occurred. The karyotypic evolution associated with 7q- has not been reported previously in patients with M4Eo with inv(16).     

闽南地区遗传咨询者染色体多态性与临床效应关系的分析

目的研究人类染色体多态性的遗传效应,分析染色体多态性与临床效应的关系。方法对5052例患者外周血进行培养获得淋巴细胞中期分裂相,常规制片G、C显带进行核型分析。结果从遗传咨询者5052例中检出染色体多态性438例,其中Y染色体长度变异246例,占多态性的56.17%;D、G组短臂增长57例,占多态性的13.01x%;9号染色体臂间倒位58例,占染色体多态性的13.24%;副缢痕增长71例,占染色体多态性的16.21%。结论染色体多态性与临床效应有一定的关系,临床医生应高度重视。     

Normal psychomotor development in a child with mosaic trisomy and pericentric inversion of chromosome 9.

A female infant with trisomy 9 in 58% of her cells is reported. Multiple congenital malformations were present, but she had normal psychomotor development. A pericentric inversion involving a portion of the centromeric heterochromatin of chromosome 9 was identified in the patient and her mother. This variant chromosome 9 was present in duplicate in the trisomic line. Since similar variants of 9qh have been found repeatedly in this syndrome, we feel that this association may be a non-random one.     

Pericentric inversion with a minute deletion of the Y chromosome in a severely oligozoospermic man

An apparent pericentric inversion of the Y chromosome in a severely oligozoospermic infertile patient is described. The karyotype was 46,X,inv (Y) (p11.2 q11.23). DNA analysis, however, revealed a deletion involving nine loci within the most distal part of the euchromatic region of the long arm.     

Frequency and segregation of 16qh+

The frequency of 16qhk among 2,548 individuals in various psychiatric institutions was 1.2 per 1,000, compared with 1.0 per 1,000 in 6,164 individuals found in the general population.
The enlargement of chromosome No. 16 appeared, in all cases, to be due to enlargement of the heterochromatic secondary constriction area in the long arm of chromosome No. 16.
The observed segregation rate of 16qhf (57 %) did not deviate significantly from that expected. There were no indications of an increase in mortality among the progeny of the 16qh+ carriers, and there was no increased frequency of abortions in carriers. No association was found between 16qh+ and any physical or mental disorders.     

401例染色体多态性引起生殖异常分析

目的分析染色体多态性与不孕不育患者之间临床效应关系。方法对4541例不孕不育患者进行常规外周血染色体核型分析。结果 4541例不孕不育患者检出染色体多态401例,检出率8.83%。其中inv(9)105例,inv(1)1例,inv(10)1例,1qh+8例,16qh+5例,大Y79例,小Y2例,Y长臂缺失1例,inv(Y)2例,13号大随体29例,14号大随体37例,15号大随体37例,21号大随体53例,22号大随体41例。患者临床表现为无精子症者5例,占1.25%,精子密度10×106/ml 50例,占12.47%;反复自发流产、胎儿停止发育275例,占68.58%;畸形儿分娩史43例,占10.72%;智力低下、发育异常5例,占1.25%;男性或女性生殖器发育不良12例,占2.99%;不孕11例,占2.74%。结论染色体多态性与生殖异常存在明显的关系,不能忽视其临床效应。     

Cytogenetic and dermatoglyphic studies on severely handicapped patients in an institution

Cytogenetic and dermatoglyphic studies were performed on a group of 197 institutionalized patients with severe mental and physical handicaps in order to evaluate the contribution of chromosomal aberrations on the etiology of the condition, and to determine whether any association exists between the dermatoglyphics and the severe handicaps. There were 4 patients with trisomy 21 and 2 patients with a de novo balanced reciprocal translocation. In addition, 9 patients were found to have a pericentric inversion of chromosome 9 (inv (9) (p11q13)). Other chromosome variations identified included inv (1) (p11q11) (one case), elongation of 1 qh (one case), and telocentric chromosome 13 (two cases). Dermatoglyphics from the patients excluding cases with Down syndrome were compared with those from 500 normal controls. Significant differences were observed in several dermatoglyphic characteristics, including simian crease, fingertip pattern, mean a-b ridge count, thenar/first interdigital pattern, hypothenar pattern, and hallucal pattern. The present study indicated that de novo balanced translocation as well as chromosome duplication or deficiency is causally related to the severe combined handicaps. This study also showed that the incidence of inv (9) (p11q13) in the patients was 4.2 times higher than that in the general Japanese population. If a real association exists between the inv (9) (p11q13) and severe handicaps, the increase of inv (9) (p11q13) in the patients may be explained by the concept of a risk factor. Moreover, the dermatoglyphic deviations found in patients may be evidence that pathological factors had been operating during early embryonic life in some of them.     

66例9号染色体臂间倒位临床分析

目的探讨9号染色体臂间倒位的临床意义,分析inv(9)与生育障碍的关系。方法患者抽取外周血进行淋巴细胞培养,按常规方法制备染色体,G显带行核型分析。结果 6962例外周血中检出inv(9)66例,检出率0.95%,将6962例受检者分为正常生育组和生育障碍组,比较其inv(9)检出率,差异无显著性,并就各组资料行临床分析。结论 inv(9)对生育无确切不良影响,无确切病理学意义。     

Heterochromatic variants and their association with neoplasias. II. Preleukemic states

A study of the heteromorphism of chromosomes #1, #9, and #16 was performed in the cells of 55 normal subjects and in those of 40 preleukemic patients including those with refractory anemia (RA) and sideroblastic anemia (SA), classified on the basis of the FAB nomenclature. Heteromorphism was present in 85% of the preleukemic patients, compared with 44% in normal controls (p less than 0.01). The patient population presented an increased incidence of C-band size variants in chromosome #1 (1qh+ and 1qh-), while chromosomes #9 and #16 showed no difference, compared with the findings in the control group.     

A child with a recombinant of chromosome 8 inherited from her carrier mother.

A female child with mental retardation and dysmorphic features was found to have a duplication deficiency of chromosome 8: rec(8)dup q,inv(8)(p23q24), a recombinant product derived from a familial pericentric inversion, inv(8)(p23q24)mat. Clinical features of this previously undescribed inversion product are compared with other reported cases of partial trisomy for the distal long arm of chromosome 8, since this segment is thought to be primarily responsible for the phenotypic features of the trisomy 8 syndrome.     

Heterochromatic variants and their association with neoplasias: V. Non-Hodgkin's lymphomas

A study of heterochromatic regions in chromosomes #1, #9, and #16 was performed on lymphocytes of peripheral blood from 55 normal individuals and 50 patients with non-Hodgkin's lymphoma (NHL). Heteromorphism was present in 90% of the NHL patients, compared with 44% in normal individuals (p less than 0.001). An increase of inv(1), 1qh-, and 9qh-variants was observed in malignant lymphoma patients with respect to controls.