Allospecific Helper T-Lymphocyte Repertoire in Monozygotic Twins

In the course of maturation in the thymus there is a selection of T lymphocytes based on the avidity between their T-cell receptors and HLA/peptide complexes expressed on stromal thymic cells. The repertoire of mature T lymphocytes is further modulated by encounters with foreign antigens. Thus, the antigen specific repertoire of the peripheral T-lymphocyte pool is determined by genetic and environmental factors. We recently reported that pairs of monozygotic twins often display significant differences in their allospecific cytotoxic T-cell repertoire, suggesting an important role of confrontation with foreign antigens on the CD8⁺ T-cell repertoire. We have now performed similar studies on the repertoire of allospecific CD4⁺ T lymphocytes. Using positively selected CD4⁺ T cells in limiting dilution analyses we compared the differences in the allospecific helper T-lymphocyte precursor frequencies (HTLpf) between pairs of genetically identical monozygotic twins and pairs of unrelated, HLA disparate individuals. We found that all monozygotic twin pairs and most unrelated pairs had similar HTLpf to the same stimulator, i.e. the 95% confidence intervals were overlapping. However, when studied in greater detail, the differences in HTLpf within monozygotic twin pairs were found to be significantly smaller than the differences within pairs of unrelated responders. Thus, we find evidence of an influence by environmental antigens also on the repertoire of allospecific CD4⁺ T cells, but polymorphic genetic factors seem to be more important here than for the repertoire of allospecific CD8⁺ T cells.     

Adolescent Drinking and Motivated Decision-Making: A Cotwin-Control Investigation with Monozygotic Twins

The present study used a monozygotic (MZ) cotwin-control (CTC) design to investigate associations between alcohol use and performance on the Iowa gambling task (IGT) in a sample of 96 adolescents (half female). The MZ CTC design is well suited to shed light on whether poor decision-making, as reflected on IGT performance, predisposes individuals to abuse substances or is a consequence of use. Participants completed structural MRI scans as well, from which we derived gray matter volumes for cortical and subcortical regions involved in IGT performance and reduced in adolescents with problematic alcohol use. Drinking was associated with poorer task performance and with reduced volume of the left lateral orbital-frontal cortex. CTC analyses indicated that the former was due to differences between members of twin pairs in alcohol use (suggesting a causal effect of alcohol), whereas the latter was due to factors shared by twins (consistent with a pre-existing vulnerability for use). Although these preliminary findings warrant replication, they suggest that normative levels of alcohol use may diminish the quality of adolescent decision-making and thus have potentially important public health implications.     

March 1997-4 Year Old Girl with Ring Chromosome 22 and Brain Tumor

A four year old Caucasian girl with a constitutional ring chromosome 22 abnormality and developmental delay presented with increasing ataxia and a six week history of non-specific symptoms. Imaging studies demonstrated a large third ventricular tumor with apparent involvement of the septum. Microscopic and immunohistochemical studies demonstrated an atypical teratoid/rhabdoid tumor. This tumor is compared and contrasted to peripheral malignant rhabdoid tumors and central primitive neuroectodermal tumors. The role of a putative tumor suppressor gene on the long arm of chromosome 22 in the pathogenesis of these tumors is also discussed.     

Monozygotic Twins Display Differences in Their Allospecific Cytotoxic T-Cell Repertoire

The antigen-specific repertoire of peripheral blood T lymphocytes is generated by selection in the thymus followed by peripheral immunological events. While thymic selection is predominantly under genetic control, i.e. self-HLA molecules + self-peptides, confrontation with foreign antigens will lead to expansion of given T-cells, thus modifying the T-cell repertoire. To evaluate the relative importance of such modifying events the precursor frequencies (pf) of cytotoxic T lymphocytes (CTL) against given allogeneic HLA molecules were compared in six pairs of monozygotic twins. Using limiting dilution analyses, experiments with several different allogeneic stimulator/target cell donors were performed for each twin pair. In 12 out of 17 experiments, when the twins were tested against the same stimulator/target cell donor, the CTL pf differed and the 95% confidence intervals were non-overlapping. This suggests that modifying effects by confrontation with foreign antigens play an important role in shaping the allospecific T-cell repertoire.     

Mitochondrial DNA Variation and Heteroplasmy in Monozygotic Twins Clinically Discordant for Multiple Sclerosis

We examined the debated link between mitochondrial DNA (mtDNA) variation and multiple sclerosis (MS) using 49 monozygotic (MZ) twin pairs clinically discordant for MS, which enables to associate de novo mtDNA variants, skewed heteroplasmy, and mtDNA copy number with MS manifestation. Ultra‐deep sequencing of blood‐derived mtDNA revealed 25 heteroplasmic variants with potentially pathogenic features in 18 pairs. All variants were pair‐specific and had low and/or similar heteroplasmy levels in both cotwins. In one pair, a confirmed pathogenic variant (m.11778G>A, heteroplasmy ～50%) associated with Leber hereditary optic neuropathy was detected. Detailed diagnostic investigation revealed subclinical MS signs in the prior nondiseased cotwin. Moreover, neither mtDNA deletions nor copy‐number variations were involved. Furthermore, the majority of heteroplasmic variants were shared among MZ twins and exhibited more similar heteroplasmy levels in the same tissue of MZ twins as compared with different tissues of the same individual. Heteroplasmy levels were also more similar within MZ twins compared with nonidentical siblings. Our analysis excludes mtDNA variation as a major driver of the discordant clinical manifestation of MS in MZ twins, and provides valuable insights into the occurrence and distribution of heteroplasmic variants within MZ twins and nonidentical siblings, and across different tissues.     

Environmental Factors in Obsessive-Compulsive Behavior: Evidence from Discordant and Concordant Monozygotic Twins

To investigate environmental factors that protect against or exacerbate obsessive-compulsive (OC) symptoms, we selected 25 monozygotic (MZ) twin pairs discordant, 17 MZ twin pairs concordant high and 34 MZ pairs concordant low on OC symptoms from a large longitudinal Dutch sample of adult twin pairs and their family members, applying stringent criteria for OC symptomatology. Data were collected on psychopathology, family structure, health, lifestyle, birth complications and life events. Unique environmental factors were studied using within-discordant MZ pair comparisons, whereas between-concordant MZ pair comparisons were used to study environmental factors that are shared by the twins of an MZ pair. The high-scoring MZ twins of the discordant group reported more life events (especially sexual abuse) than their low-scoring twin-siblings. The between-pair comparisons showed lower birth weight in the discordant MZ pairs than in the concordant MZ pairs. Further, the concordant high MZ pairs as well as their spouses had a lower educational level than the two other groups. On scale scores of anxious-depression, neuroticism, and somatic complaints, concordant high MZ pairs showed highest scores, and the discordant MZ pairs scored intermediate, except for neuroticism, on which the high-scoring twins of discordant MZ pairs were equal to the concordant high pairs. Discordance on psychological scale scores between the concordant MZ pairs was evident from 1991 onward, and within the discordant MZ pairs from 1997 onward, confirming previous reports of an association of early-onset OC symptoms with higher genetic load. Parent scores of OC symptoms and anxious-depression suggested intermediate genetic load in the discordant MZ group. In conclusion, this study reports on both unique and shared environmental factors associated with OC symptomatology. Whether these factors operate in addition to or in interaction with genetic disposition is to be elucidated in future studies. Edited by Tatiana Foroud.     

Monozygotic twins with chromosome 22q11 deletion and discordant phenotype.

We report monozygotic twins concordant for 22q11.2 deletion but discordant for clinical phenotype. Both boys show the typical dysmorphic features with short palpebral fissures, square nasal tip, small mouth, and both have nasal speech, but only one twin had a heart defect. They show that the phenotypic variability seen in this microdeletion syndrome cannot be explained on the basis of genotypic differences alone.     

Developmental Abnormalities Associated with a Ring Chromosome 6

A clinical and cytogenetic report is made of a patient with microcephaly, peculiar facies, and retardation of physical and mental development, who possesses a karyotype containing a ring chromosome No. 6 identified by Q-staining with quinacrine mustard. This is the first report of a ring autosome in the C group to be identified. Comparison with other patients reported as having C-group autosomal rings failed to reveal many common phenotypic characteristics.     

Chromosome 22 workshop report

The chromosome 22 workshop took place at the Sixth World Congress on Psychiatric Genetics from October 6th–10th, 1998 in Bonn, Germany. Aim of the workshop was to summarize the findings in psychiatric genetics on chromosome 22. Four reports concerning a susceptibility locus for schizophrenia and one report on bipolar disorder were given. A potential locus for nocturnal enuresis has been suggested to reside on chromosome 22. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:276–278, 1999. © 1999 Wiley-Liss, Inc.     

21号环状染色体的细胞遗传学分析

目的通过对1例21号环状染色体嵌合体患者的细胞遗传学分析,探讨21号环状染色体的形成原因,临床表型与染色体区带及嵌合比例的关系。方法应用染色体常规标本、G显带、C显带技术对21号环状染色体进行识别与区带定位。结果患者核型为mos46,XX,r（21）（pllq22）[91]／45,XX,-21[5]／46,XX,dicr（21;21）（pllq22;p11q22）[4]。结论环状染色体断裂位点在21pll和q22,21号环状染色体综合征的临床表现与核型嵌合比例及21q末端缺失的多少相关,女性不孕可能与21q22片段的缺失相关。     

A Note on Including Phenotypic Information from Monozygotic Twins in Variance Components Qtl Linkage Analysis

Williams & Blangero (1999) derived closed form expressions for the power of a univariate variance components test of linkage for a variety of pedigree structures. We have extended their results by investigating the effect of including monozygotic twins in the design on the power to detect linkage. Specifically, we determined the power associated with a pedigree of size three, where individuals one and two were monozygotic twins and individual three was a full sibling to the twins. The power of this sampling unit was uniformly greater than the power obtained from a sib‐pair under the same genetic model. The reason for this was that addition of a second monozygotic twin provided another estimate of the sibling correlation for the particular IBD class. In addition, when the total heritability of the trait was <50%, the number of individuals that needed to be phenotyped was less than that with sib‐pairs alone. However, a pedigree consisting of a monozygotic pair and sibling was never as informative as a sib‐trio, presumably because the sib‐trio provided information about allele sharing between three individuals, whereas the monozygotic twins and sibling unit only provided one such relationship. We conclude that including a monozygotic twin in the analysis is an economical strategy, since only one twin needs to be genotyped.     

15号环状染色体综合征的产前诊断

目的探讨15号环状染色体综合征产前诊断的进展。方法对1例15号环状染色体综合征胎儿超声检查,脐带血染色体G带分析。结果胎儿脐带血染色体G显带分析为15号环状染色体,伴有单脐动脉,膈疝等。胎儿双亲染色体未见异常。结论本例支持15号环状染色体综合征胎儿伴随膈疝,宫内发育迟缓等症状。     

Chromosome 22 workshop report.

The chromosome 22 workshop took place at the Sixth World Congress on Psychiatric Genetics from October 6th-10th, 1998 in Bonn, Germany. Aim of the workshop was to summarize the findings in psychiatric genetics on chromosome 22. Four reports concerning a susceptibility locus for schizophrenia and one report on bipolar disorder were given. A potential locus for nocturnal enuresis has been suggested to reside on chromosome 22.     

Ring chromosome 22 and neurofibromatosis

Variable constitutional mosaicism, mos45,XY,-22/46,XY,-22,+mar/46,XY,-22,+r(22)/47,XY,-22,+r(22)+mar/ 47, XY,-22,+r(22)*2, was found in PHA-stimulated peripheral blood, in a lymphoblastoid cell line and in cultured skin fibroblasts from a mentally retarded patient with neurofibromatosis. Both the ring chromosome and the small extra marker chromosome stained positively by in situ hybridization with a chromosome 14/22-specific alphoid repeat probe. DNA dosage analysis showed constitutional loss of one copy of the arylsulfatase A gene (ARSA), consistent with its terminal location on 22q. There was no evidence of constitutional loss of D22S1 or D22S28 which flank the neurofibromatosis type 2 (NF2) locus. Analysis of two DNA samples from a skin neurofibroma indicated retainment of two copies of D22S1, whereas the results were ambiguous with respect to tumor-specific loss of one copy of D22S28. It is suggested that the development of neurofibromatosis of unclear type in two r(22) carriers might be associated with somatic mutation of the NF2 locus due to instability of the ring chromosome(s), and in analogy, that somatic mutation of either NF1 or NF2 may account for some cases of neurofibromatosis which do not meet the criteria of either NF1 or NF2. The occurrence of seminoma in the proband may be fortuitous, but could also be due to the presence of a seminoma-associated locus on chromosome 22.     

1例13号环状染色体合并6号染色体末端重排核型的确定及遗传咨询

目的 确定1例13号环状染色体合并6号染色体末端重排核型，并为其生育提供指导。方法　1例有生育畸胎史的病例，染色体检测发现携带环状染色体，6号染色体短臂增加，选用6号和13号染色体特异性涂染探针进行荧光原位杂交分析。结果　确定其核型为环状13号染色体合并13号染色体长臂远端部分与6号染色体短臂的末端重排。结论 这是一例罕见的可能起源于三断裂的结构重排。根据减数分裂形成配子的规律，她仍有生育正常孩子的可能性，但必须进行产前诊断确保正常小孩的出生。