Angelman syndrome caused by an identical familial 1,487-kb deletion.
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Adult↗
Biomedical subjects
Naoki Harada
Publications and source records attributed to Naoki Harada.
Primary hepatic lymphoma 1 year after resection of hepatocellular carcinoma.
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Aged↗
Array comparative genomic hybridization analysis in first-trimester spontaneous abortions with 'normal' karyotypes.
Array comparative genomic hybridization (array CGH) analysis was conducted in chorionic villous samples from 20 first-trimester spontaneous abortions with G-banding normal chromosomes. A microarray, containing 2,173 BAC clones and covering the whole genome with a 1.5-Mb resolution, was constructed and used in the analysis. Two deletions were identified: a 1.4-Mb deletion at 3p26.2-p26.3 and a 13.7-Mb deletion at 13q32.3-qter. Reexamination of chromosome preparations from the sample with the 13.7-Mb deletion documented a mixture of cells with the 13q- chromosome and those with 46,XX chromosomes, the latter of which are likely to have been derived from contaminating decidual cells. This left the 1.4-Mb 3p deletion as the only instance with submicroscopic imbalance detected, giving a frequency of 1 in 19 (5%) G-banding normal abortions.
Abortion, Spontaneous↗
Clinical outcome of infants with confined placental mosaicism and intrauterine growth restriction of unknown cause.
The purpose of this study was to know a role of confined placental mosaicism (CPM) in perinatal outcome and postnatal growth and development of infants with intrauterine growth restriction (IUGR). We selected 50 infants with IUGR (<-2.0 SD) from 3,257 deliveries in a regional medical center during the past 10-year period, and carried out cytogenetic and molecular analyses in their placenta and cord blood. Of the 50 infants, 8 had CPM (CPM group) and were composed of five single (CPM2, 7, 13, 22, and 22), one double (CPM7/13), and one quadruple trisomy (CPM2/7/15/20), and one partial monosomy [del(2)(p16)]. The origin of an extra chromosome of trisomy was maternal in six cases of CPM, paternal in one, and undetermined in one. Uniparental disomy in disomic cell lines was ruled out in all these mosaics. We also compared clinical parameters for perinatal outcome between CPM group and infants without evidence of CPM (non-CPM group), such as maternal and gestational age, birth weight, Apgar score, cord blood pH, gender, and uterine artery patterns by Doppler ultrasonography, as well as weight, height, and developmental quotient (DQ) by Denver Developmental Screening Test at age 12 months. Phenotypic abnormalities were noted in two infants with CPM and three infants of non-CPM group: One with CPM22 had ASD and hypospadias, one with CPM7/13 had Russell-Silver syndrome (RSS), and one without CPM had polydactyly, and two without CPM had RSS. All but one infant with CPM are alive at age 12 months. Among the clinical parameters, the detection rate of a notch waveform pattern of the uterine artery was significantly higher in the CPM group (P < 0.05). However, no significant difference was noted in perinatal outcome of pregnancy and in DQ at age 12 months between the two groups. Interestingly, short stature (<-2 SD) at age 12 months was more frequently seen in CPM group (7/8 infants with CPM vs. 8/15 infants without CPM), although no statistically significant difference was obtained. The information obtained will be useful for perinatal care and genetic counseling for infants with IUGR and CPM.
Adult↗
Comprehensive genetic analysis of relevant four genes in 49 patients with Marfan syndrome or Marfan-related phenotypes.
In order to evaluate the contribution of FBN1, FBN2, TGFBR1, and TGFBR2 mutations to the Marfan syndrome (MFS) phenotype, the four genes were analyzed by direct sequencing in 49 patients with MFS or suspected MFS as a cohort study. A total of 27 FBN1 mutations (22 novel) in 27 patients (55%, 27/49), 1 novel TGFBR1 mutation in 1 (2%, 1/49), and 2 recurrent TGFBR2 mutations in 2 (4%, 2/49) were identified. No FBN2 mutation was found. Three patients with either TGFBR1 or TGFBR2 abnormality did not fulfill the Ghent criteria, but expressed some overlapping features of MFS and Loeys-Dietz syndrome (LDS). In the remaining 19 patients, either of the genes did not show any abnormalities. This study indicated that FBN1 mutations were predominant in MFS but TGFBRs defects may account for approximately 5-10% of patients with the syndrome.
Activin Receptors, Type I↗
Origin and mechanisms of formation of fetus-in-fetu: two cases with genotype and methylation analyses.
Fetus-in-fetu (FIF) is a condition in which a host infant has a fetus-like mass(es) within its body. We describe here results of molecular genetic analysis in two cases of FIF. In FIF-1, a male host had two retroperitoneal fetiform masses each with a vertebral column, and in FIF-2, a fetiform mass with vertebral column was present in the cranial cavity of a male host. Genotyping of each case using microsatellite markers showed that the host infant and its fetus(es) inherited one copy each of parental alleles and shared identical genotypes. These findings were confirmed by single nucleotide polymorphism (SNP) analysis using Affymetrix GeneChip Human Mapping 50K Array, and supported a monozygotic twin theory of FIF. Analysis of the methylation status was done in both cases at the differentially methylated region (DMR) within the human IGF2-H19 locus after bisulfite treatment, methylation-specific PCR, and cloning of PCR products. Normally, only the paternal allele is methylated and the maternal allele unmethylated in DMR. However, in FIF-1, 7 (46.7%) of 15 clones from a fetiform mass and 6 (66.7%) of 9 clones from the other mass showed an unmethylated paternal allele, while the methylation status of a host infant and its fetiform mass in FIF-2 was the same in all clones examined with normal patterns. These data suggest that in FIF-1, two isolated blastocysts originated from one zygote, one of the two was implanted into (or included by) the other blastocyst during the process of methylation, and such abnormal implantation may have occurred in FIF-2 after the establishment of methylation. This is the first case of FIF showing different methylation patterns between a host infant and fetiform mass.
Adult↗
Mild craniosynostosis with 1p36.3 trisomy and 1p36.3 deletion syndrome caused by familial translocation t(Y;1).
We report on a 20-year-old man and a 16-year-old woman with a chromosomal imbalance derived from a balanced translocation, t(Y;1)(q12;p36.3) of the father. The man had a partial trisomy for 1p36.3-pter [46,X,der(Y)t(Y:1)(q12;p36.3)] and mild craniosynostosis of metopic and sagittal sutures as well as a borderline mental impairment, while the woman with a deletion for 1p36.3-pter [46,XX,der(1)t(Y;1)(q12;p36.3)] showed dysmorphic face with large anterior fontanel and severe developmental delay. Fluorescence in situ hybridization (FISH) showed that his trisomy spanned the 5.3-Mb region from 1p telomere harboring the critical region for craniosynostosis. To our knowledge, the man is the first case of a pure type of simple 1p36.3 trisomy as the effect of heterochromatic Yq12-qter deletion likely does not affect phenotype.
Adult↗
Microarray comparative genomic hybridization (CGH)-based prenatal diagnosis for chromosome abnormalities using cell-free fetal DNA in amniotic fluid.
Cell-free fetal DNA (cffDNA) in the supernatant of amniotic fluid, which is usually discarded, can be used as a sample for prenatal diagnosis. For rapid prenatal diagnosis of frequent chromosome abnormalities, for example trisomies 13, 18, and 21, and monosomy X, using cffDNA, we have developed a targeted microarray-based comparative genomic hybridization (CGH) panel on which BAC clones from chromosomes 13, 18, 21, X, and Y were spotted. Microarray-CGH analysis was performed for a total of 13 fetuses with congenital anomalies using cffDNA from their uncultured amniotic fluid. Microarray CGH with cffDNA led to successful molecular karyotyping for 12 of 13 fetuses within 5 days. Karyotypes of the 12 fetuses (one case of trisomy 13, two of trisomy 18, two of trisomy 21, one of monosomy X, and six of normal karyotype) were later confirmed by conventional chromosome analysis using cultured amniocytes. The one fetus whose molecular-karyotype was indicated as normal by microarray CGH actually had a balanced translocation, 45,XY,der(14;21)(q10;q10). The results indicated that microarray CGH with cffDNA is a useful rapid prenatal diagnostic method at late gestation for chromosome abnormalities with copy-number changes, especially when combined with conventional karyotyping of cultured amniocytes.
Amniotic Fluid↗
Complete hydatidiform mole and normal live birth following intracytoplasmic sperm injection.
A twin pregnancy with complete hydatidiform mole (HM) and preterm birth of a normal female infant after intracytoplasmic sperm injection (ICSI) conception was experienced. ICSI due to severe oligozoospermia was performed on three ova, and three embryos with confirmed two proneclei (2PN) were subsequently transferred to the uterus. At 7 weeks of gestation, molar pregnancy as well as a viable fetus was recognized. At 33 weeks, the pregnancy was terminated due to preterm labor. Dichorionic pregnancy consisting of a normal fetus and placenta in one chorionic membrane and complete HM in the other was recognized. Cytomolecular analysis indicated that the complete HM genome was derived from duplication of a single sperm, and a normal neonate was from biparental genomes. It should be noted that ICSI can avoid incomplete HM (mostly triploid) due to multi-sperm fertilization but might not be able to avoid complete HM (paternal diploid) although such a risk is very low. This is the second report of this condition and is accompanied by the first well-described molecular analysis.
Adult↗
Narrowing candidate region for monosomy 9p syndrome to a 4.7-Mb segment at 9p22.2-p23.
A 2-year-old boy with clinical manifestations of monosomy 9p syndrome and brown hair is described. G-banding and chromosome FISH studies demonstrated complex rearrangements involving seven breakpoints in chromosomes 2 and 9, which included a 6.6-Mb deletion at 9p22.2-p23. This, together with previous studies in the literature, narrowed the shortest region of overlap (SRO) for the syndrome to a 4.7-Mb interval. Candidate genes for trigonocephaly, mental retardation, and brown hair are discussed.
Abnormalities, Multiple↗
No detectable genomic aberrations by BAC array CGH in Kabuki make-up syndrome patients.
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Abnormalities, Multiple↗
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.
Abnormalities, Multiple↗
BAC array CGH reveals genomic aberrations in idiopathic mental retardation.
Array using 2,173 BAC clones covering the whole human genome has been constructed. All clones spotted were confirmed to show a unique signal at the predicted chromosomal location by FISH analysis in our laboratory. A total of 30 individuals with idiopathic mental retardation (MR) were analyzed by comparative genomic hybridization using this array. Three deletions, one duplication, and one unbalanced translocation could be detected in five patients, which are likely to contribute to MR. The constructed array was shown to be an efficient tool for the detection of pathogenic genomic rearrangements in MR patients as well as copy number polymorphisms (CPNs).
Chromosome Aberrations↗
A large interstitial deletion of 17p13.1p11.2 involving the Smith-Magenis chromosome region in a girl with multiple congenital anomalies.
A 6-month-old girl had multiple congenital anomalies, including dysmorphic face; tetralogy of Fallot, pulmonary atresia and patent ductus arteriosus; congenital cystic adenomatoid malformation of the right upper lung, and hemilateral kidney defect. Chromosome analysis as well as fluorescence in situ hybridization (FISH) and polymorphic marker analyses in the girl and her parents revealed a de novo large interstitial deletion of 17p13.1-p11.2 of the paternally derived chromosome 17. The deletion involved the Smith-Magenis chromosome region (SMCR). Lack of involvement of the Miller-Dieker syndrome region at 17p13.3 was confirmed by both FISH analysis and radiological examinations that showed no migrational abnormality. The girl died at age 7 months. This is the first report of a patient with a large interstitial deletion of 17p.
Abnormalities, Multiple↗
Congenital neuroblastoma in a patient with partial trisomy of 2p.
We report the fourth example of a patient with germline partial trisomy of 2p21-pter and congenital neuroblastoma. The male infant had a dysmorphic facial expression and presented with congenital heart disease, supernumerary nipples, hypospadias, shawl scrotum, hemilateral persistent hyperplastic primary vitreous, and neuroblastoma. His germline karyotype of 46,XY,der(8)t(2;8)(p21;p23.2) was inherited from a maternal-balanced translocation, which indicates that the proto-oncogene MYCN region of 2p24.3 is tripicated in germline cells. A cytogenetic study of the biopsied tumor cells did not show MYCN amplification, but the DNA index was 2.4 and histologic fluorescent in situ hybridization analysis indicated somatic mutation with near-pentaploidy of the tumor cells. This could be an alternative mechanism of MYCN activation in the process of the tumorigenesis of neuroblastoma.
Abnormalities, Multiple↗
[Acute lymphoblastic leukemia presenting with calcineurin-inhibitor induced pain syndrome after a second allogeneic bone marrow transplantation].
A 42-year-old woman was referred to us for the treatment of relapsed Philadelphia-positive acute lymphoblastic leukemia (Ph+ALL), which had been maintained in complete remission for seven years after an allogeneic bone marrow transplantation (allo-BMT) from an unrelated donor. She received remission-reinduction chemotherapy combined with imatinib mesylate. After the documentation of the molecular remission of Ph+ALL, she underwent the second allo-BMT from another unrelated donor. GVHD prophylaxis consisted of tacrolimus (TAC) and short-term methotrexate. On day 21, she suddenly suffered from an intermittent severe, cramp-like pain in the right lower limb. The typical pain profile and exclusion of other causative diseases suggested calcineurin-inhibitor induced pain syndrome (CIPS) as a possible cause of pain. The pain was gradually relieved after discontinuation of TAC and administration of several analgesic drugs. CIPS is rarely seen following allogeneic stem cell transplantation (allo-SCT); only three cases have been so far reported to our knowledge. Thus, physicians should be alert to this complication in patients receiving allo-SCT.
Adult↗
Klippel-Feil anomaly in a boy and Dubowitz syndrome with vertebral fusion in his brother: a new variant of Dubowitz syndrome?
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Child↗
Glyceraldehyde-3-phosphate dehydrogenase in the extracellular space inhibits cell spreading.
The occurrence and the novel function of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in the extracellular space were studied. The extracellular GAPDH with the same molecular mass as the intracellular GAPDH was detected in the conditioned medium of mammalian cultured cell lines such as COS-7, HEK293, MCF-7, HepG2, PC-12, and Neuro-2a cells. Western blot analysis represented the occurrence of GAPDH, but not alpha-tubulin (an intracellular marker protein), in the conditioned medium of COS-7 cells. Furthermore, GAPDH was found in rat serum. These results indicate that GAPDH was secreted outside of the cells. Addition of GAPDH to the cultured medium of COS-7, HEK293, and HepG2 cells allowed cells to undergo morphological changes. In COS-7 cells, the extracellular GAPDH inhibited cell spreading without influencing the cell growth. Western blot and immunofluorescent microscopy analyses revealed that the extracellular GAPDH bound to COS-7 cells in time- and dose-dependent manners. However, a mutant substituting Ser for Cys at position 151 of GAPDH resulted in no binding to the cells, no decreased cell-spreading efficiency and no cell morphological changes. These results indicate that the Cys151 was involved in the binding of GAPDH to cells and the GAPDH-inhibited cell spreading.
Animals↗