Kiyoshi Kikkawa

Probable assignment of soluble isocitrate dehydrogenase (IDH1) to 2q33.3

SummaryGene dosage effects for soluble isocitrate dehydrogenase (IDH1) were investigated in four unrelated cases with abnormalities involving the long arm of chromosome 2. Case 1 was trisomic for 2q33.3→qter, Case 2 monosomic for 2q33.3→q35, Case 3 trisomic for 2q11.2→q24.2, and Case 4 monosomic for 2q23→q24.2. These abnormalities were de novo except in Case 1, where trisomy 2q resulted from a maternal translocation. The red cell IDH1 levels were significantly reduced in Cases 1 (41.4% of normal value) and 2 (51.9%), while they were normal in Cases 3 and 4. The low IDH1 level also in the father of Case 1 (43.6%), together with the common electrophoretic phenotype of IDH1 in red cells as well as leukocytes, led us to suppose that Case 1 was really heterozygous for common and probable null alleles, and that the IDH1 gene locus could be excluded from 2q33.3→qter. On the other hand, normal IDH1 values in the parents of Case 2 were consistent with the hemizygosity for this locus in Case 2. The results suggested that the IDH1 locus could be assigned to the 2q33.3 band, especially the proximal portion of it.

Regional mapping of catalase and Wilms tumor--aniridia, genitourinary abnormalities, and mental retardation triad loci to the chromosome segment 11p1305----p1306.

SummaryGene dosage effects for catalase (CAT) were studied in two unrelated patients with an interstitial deletion involving 11p13 to determine precisely the sites of the genes for CAT and the Wilms tumor—aniridia, genitourinary abnormalities, and mental retardation triad (WAGR) in the 11p13 band. Case 1 had the aniridia-Wilms tumor association, and case 2 showed the AGR triad. The karyotypes identified by high resolution banding techniques were 46,XY,del(11)(pter→p13::p11.11→qter) for case 1 and 46,XY,t(2;17) (q23;q25), del(11) (pter→p13::p11.2 →qter) for case 2. In both cases, the distal breakpoints of the deleted chromosomes 11 appeared to have occurred on the middle portion of 11p13 (11p1305→p1306). The level of erythrocyte CAT activities in case 1 was reduced (47% of normal), while that in case 2 was normal. The results suggested not only that both the CAT and WAGR should be mapped to chromosome region 11p1305→p1306, but also that in this region the CAT locus is more distally placed than the WAGR locus. Because of the proximity of the two gene loci, assays of erythrocyte CAT may be useful to identify a submicroscopic deletion in some patients with sporadic aniridia and to predict a risk of developing Wilms tumor.

Assignment of ABO locus to 9q31.3----qter by study of a family in which an intrachromosomal shift involving chromosome 9 is segregating

SummaryA family in which an intrachromosomal shift, dir ins(9) (q22.1q31.3;q34.3), was segregating is described. A meiotic crossing over in the noninsertional loop of the carrier mother appeared to have resulted in the proband with a recombinant chromosome 9 duplicating the interstitial segment 9q22.1→q31.3. The study of ABO and AK1 phenotypes in the family showed that the proband was also a recombinant for the ABO locus. These results allowed us to assign the ABO locus to 9q31.3→qter on the cytogenetic basis.

Duplication of 2p25: confirmation of the assignment of soluble acid phosphatase (ACP1) locus to 2p25

SummaryThe regional localization of the gene coding for soluble acid phosphatase (ACP1) has been under debate in the two different chromosome regions, 2p23 or 2p25. Gene dosage studies in a case with a karyotype of 46,XX,dir dup(2) (p25.1→p25.3) showed that the ACP1 activity was increased to 1.4 times the mean value of normal individuals with the same ACP1 phenotype, while the level of soluble malate dehydrogenase (MDH1) was normal. These gene dosage effects indicated that the ACP1 gene locus can be mapped to 2p25.

45,X/46,X, idic(Yq) mosaicism : Clinical, cytogenetic, and molecular studies in four individuals

45,X/46,X,idic(Yq) mosaicism is associated with a variety of sex phenotypes, including Ullrich-Turner syndrome (UTS), intersexuality, and complete male. It remains unclear whether the phenotypic variability results from a dilutional effect by the 45,X cell line in the primordial gonad or an abnormality of the SRY gene (SRY). We conducted cytogenetic and molecular studies on four patients with such mosaicism, two of whom had a complete male phenotype and two who had UTS. Chromosome analyses showed that the frequency of cells carrying an idic(Yq) chromosome in peripheral blood lymphocytes and skin fibroblasts was not related to the given sex phenotype. The SRY, PABY, and ZFY genes were present in all four patients. A fluorescence in situ hybridization (FISH) study showed that both a patient with a complete male phenotype and another with UTS had duplicate copies of SRY in their idic(Yq) chromosomes, whereas a patient with UTS had a single copy of the gene. These findings suggested that the coexisting 45,X cell line is more influential on the determination of the sex phenotype in individuals with 45,X/ 46,X,idic(Yq) mosaicism.

The critical monosomic segment involved in 4p- syndrome: A high-resolution banding study on five inherited cases

SummaryIn an attempt to determine the critical monosomic segment involved in 4p- syndrome, we studied the precise breakpoints of five inherited cases with the syndrome using a high-resolution banding technique. The 5 patients ranged in age at diagnosis from newborn to 15 months, 4 of whom could be clinically diagnosed as having 4p- syndrome. Common clinical features included mental retardation, low birth weight, growth failure, hypotonia, microcephaly, peculiar facial dysmorphia and ear malformations. Karyotypes of the 5 were 46,XX,−4,+der(4),t(4;21) (p16.1;q22.3)pat; 46,XX,−4,+der(4), inv ins(4;9)(p15.32p16.3;q34.3)pat; 46,XX,rec(4),del p,inv(4)(p15.2q35)pat; and 46,XX,−4,+der(4),t(4;18) (p15.2;p11.21)mat (two cases, related). The results suggested that monosomy for the proximal half of the 4p16 band is sufficient to express 4p-syndrome.

Interstitial deletion of the long arm of chromosome 2: A case report and review of the literature

SummaryA girl with mental retardation and multiple anomalies was shown to have a de novo interstitial deletion of the long arm of chromosome 2(2q23.3→q24.2) by the use of high resolution banding technique. Review of the literature revealed that her clinical features resembled those of the previously reported cases with monosomy for the middle portion of 2q.

De novo complex chromosome rearrangement in identical twins with multiple congenital anomalies

SummaryA de novo and apparently balanced complex chromosome rearrangement (CCR) was found in monozygotic (MZ) twin infants with multiple congenital anomalies. The rearrangement involved 4 chromosomes with 6 breakpoints including 2p23, 2q13, 2q21.1, 3p23, 11q13.1, and 12q24.1. This seems to be the first report of a CCR in MZ twins. The relationship between this chromosome abnormality and MZ twinning is discussed.

Pallister-Killian syndrome: Cytogenetic and biochemical studies

SummaryPallister-Killian syndrome is characterized by specific dysmorphic features and tissue-limited mosaicism for tetrasomy 12p. We describe an additional case of a stillborn neonate, who had not only the specific craniofacial features seen in the syndrome but also various internal malformations. Cytogenetic study showed that an extra F-like chromosome was found in 43% of lymphocytes and in 90% of fibroblasts. The high resolution G-banded pattern of the extra chromosome was consistent with an interpretation of an i(12p). The diagnosis of tetrasomy 12p was further confirmed by four-fold gene dosage effects in fibroblasts for GAPD and LDH-B, whose locus was both assigned to the 12p. The proportion of tetrasomic cells in fibroblasts decreased remarkably during long-term cultures. These results suggest that the tissue specific mosaicism in the syndrome is not simply a result of preferential selection against lymphocytes carrying the marker but may be related to the time of mosaic formation as well as the somatic selection of different intensity in different tissues.

Reproductive risk of paracentric inversion carriers: Report of two unrelated cases with paracentric inversion of the long ARM of chromosome 3

SummaryTwo unrelated cases with a paracentric inversion involving the long arm of a chromosome 3 were described. One case was a 29-year-old female with habitual spontaneous abortions. The karyotype was 46,XX,inv(3)(q25q27). The other case was a two year one month-old girl with growth and psychomotor retardation and multiple minor anomalies. She was found to have a recombinant chromosome 3 resulting from a paternal paracentric inversion. The karyotype of the patient was 46,XX, rec(3),dup(q26.3),inv(3)(q12q29)pat. The review of previously reported cases showed a considerable risk for live-born recombinants derived from parental paracentric inversions and the analysis of reproductive histories of inversion carriers suggested a possible contribution of this type of chromosome abnormalities to the cause of spontaneous abortions.