Search

A Japanese boy aged 7 years with Bainbridge-Ropers syndrome (BRPS) had a prominent domed forehead without metric ridge, mild prominence of the Sylvian fissure with bitemporal hollowing, and a heterozygous de novo novel variant "p.P1010Lfs*14" in ASXL3 gene in addition to typical findings of BRPS., 論文

Kabuki syndrome is a rare, multiple malformation disorder characterized by a distinctive facial appearance, cardiac anomalies, skeletal abnormalities, and mild to moderate intellectual disability. Simplex cases make up the vast majority of the reported cases with Kabuki syndrome, but parent-to-child transmission in more than a half-dozen instances indicates that it is an autosomal dominant disorder. We recently reported that Kabuki syndrome is caused by mutations in MLL2, a gene that encodes a Trithorax-group histone methyltransferase, a protein important in the epigenetic control of active chromatin states. Here, we report on the screening of 110 families with Kabuki syndrome. MLL2 mutations were found in 81/110 (74%) of families. In simplex cases for which DNA was available from both parents, 25 mutations were confirmed to be de novo, while a transmitted MLL2 mutation was found in two of three familial cases. The majority of variants found to cause Kabuki syndrome were novel nonsense or frameshift mutations that are predicted to result in haploinsufficiency. The clinical characteristics of MLL2 mutation-positive cases did not differ significantly from MLL2 mutation-negative cases with the exception that renal anomalies were more common in MLL2 mutation-positive cases. These results are important for understanding the phenotypic consequences of MLL2 mutations for individuals and their families as well as for providing a basis for the identification of additional genes for Kabuki syndrome.

A girl with partial trisomy 9q is reported. She was characterized by dolichomorphism, abnormalities of the digits, a cardiac defect and craniofacial dysmorphism. A high-resolution analysis revealed the karyotype to be: 46,XX,-3,+ der(3)t(3;9)(q29;q13) de novo. A phenotype-karyotype correlation study in 22 cases of partial trisomies 9q supported the delineation of a trisomy 9q3 syndrome. The smallest region of overlap was confined to 9q32.

Lenz microphthalmia syndrome comprises microphthalmia-anophthalmia with mental retardation, malformed ears and skeletal anomalies, and is inherited in an X-linked recessive pattern. In 2004, it was reported that the missense mutation (BCL-6 co-repressor gene [BCOR] c.254C>T, p.P85L) in a single family with Lenz microphthalmia syndrome co-segregated with the disease phenotype. We report a case of prenatal diagnosis for X-linked recessive Lenz microphthalmia syndrome with the mutation. A 32-year-old gravida 5, para 2 Japanese woman was referred to Nagoya City University Hospital at 15 weeks of gestation. After genetic counseling and informed consent, amniocentesis was performed for fetal karyotyping, which was 46,XY. Using the extracted DNA from cultured amniotic cells, fetal search for BCOR c.254C>T mutation was undertaken. The couple requested medical termination of pregnancy, and the postabortion examination confirmed the diagnosis. This is the third report of a BCOR mutation, associated with X-linked syndromic microphthalmia, and most importantly, it is always the same mutation. The prenatal genetic diagnosis of the Lenz microphthalmia syndrome allowed time for parental counseling and delivery planning.

Silver-Russell syndrome (SRS) is characterized by prenatal and postnatal growth retardation with morphologic anomalies. Maternal uniparental disomy 7 has been reported in some SRS patients. PEG1/MEST is an imprinted gene on chromosome 7q32 that is expressed only from the paternal allele and is a candidate gene for SRS. To clarify its biological function and role in SRS, we screened PEG1/MEST abnormalities in 15 SRS patients from various standpoints. In the lymphocytes of SRS patients, no aberrant expression patterns of two splice variants (α and β) of PEG1/MEST were detected when they were compared with normal samples. Direct sequence analysis failed to detect any mutations in the PEG1/MEST α coding region, and there were no significant mutations in the 5′-flanking upstream region containing the predicted promoter and the highly conserved human/mouse genomic region. Differential methylation patterns of the CpG island for PEG1/MEST α were normally maintained and resulted in the same pattern as in the normal control, suggesting that there was no loss of imprinting. These findings suggest that PEG1/MEST can be excluded as a major determinant of SRS. © 2001 Wiley-Liss, Inc.

“University of the Ryukyus-Database for Malformation Syndromes (UR-DBMS)” is a computerized database available as a diagnostic aid for malformation syndromes, chromosomal aberrations and other genetic diseases. This UR-DBMS had been originally programmed by the author since 1989. The first version was established and opened to Japanese dysmorphologists in 1991. The newest version 5, started to be opened since 1998 in the form of a CD-ROM disk, composed of four major data files and three other supporting files with a total volume about 400 MB. The main UR-DBMS file includes clinical findings and notes of about 6,300 diseases/genes as well as 1,200 photographic data quoted from two major publishers in USA. Reference file includes almost all titles of the papers concerned. Abstract file has about 30,000 abstracts. Mutation file includes information for about 800 allelic variants identified so far, updated daily through Online MIM. These data were summarized and combined from several leading English textbooks and refined through Online MIM. UR-DBMS uses an original systematized code to obtain quick and complete results in referring the database. UR-DBMS was applied in the diagnosis of 51 newly visited patients with malformations and mental retardation from 1996 to 1997. As a result, clinical diagnoses were obtained or highly suspected in about 75% of the patients. It is confirmed that UR-DBMS is a useful aid for clinical geneticists to obtain correct or near correct diagnoses, especially when they must check further examinations to rule out and refine the diagnoses.

Deletion 22q11.2 syndrome is a well-known contiguous gene syndrome, for which the list of findings is extensive and varies from patient to patient. We encountered a unique patient who had a familial 3-Mb deletion 22q11.2 associated with trigonocephaly derived from craniosynostosis of the metopic suture. Almost all the symptoms of the patient, including polymicrogyria, microcephaly, facial abnormalities, internal anomalies, seizures, and mental retardation, were compatible with deletion 22q11.2 syndrome, except for synostosis of the metopic suture. This is the first report of a relationship between deletion 22q11.2 syndrome and trigonocephaly. Craniosynostosis of the metopic suture might be a minor complication of deletion 22q11.2, although coincidental occurrence cannot be ruled out. © 2006 Wiley-Liss, Inc.

Opitz trigonocephaly C syndrome (OTCS) is a multiple congenital anomaly syndrome characterized by trigonocephaly, mental retardation, a typical facial appearance, redundant skin, joint and limb abnormalities, and visceral anomalies. We describe a patient with the manifestations of OTCS who also had a de novo balanced reciprocal translocation t(3;18)(q13.13q12.1). His phenotype is a mild form with mild developmental delay and no severe visceral anomalies. Our findings suggest the possible existence of a new locus responsible for OTCS either on 3q13.13 or 18q12.1.

Chromosomes were studied in 9 individuals with pigmentary dysplasias of the skin and other abnormalities. Of the 9 individuals, 5 were chromosomal mosaics in both blood lymphocytes and skin fibroblasts (46,XY/47,XY, + 13;46,XX/47,XX, + 14;46,XY/47,XY, + 18;46,XX/47,XX, + 18;46, XX/47,XX, + mar), while the other 4 individuals were chromosomally normal in both tissues studied. The pigmentary dysplasias involved hypo- or hyperpigmented patches/flecks or lines/whorls. The latter ran along Blachko lines on the back, abdomen and the limbs. These patterns varied not only between individuals but also between different regions of an individual. The possibility of chimerism was studied but ruled out (1/32 to 1/256) in 7 individuals, using chromosomal heteromorphisms in the patients and their parents as markers.

Toriello-Carey syndrome comprises agenesis of the corpus callosum, telecanthus, short palpebral fissures, small nose with anteverted nares, Robin sequence, abnormally shaped ears, cardiac defect, and hypotonia. We describe two Japanese sisters with a Toriello-Carey syndrome whose phenotypes were as severe as reported male cases. The younger sister died suddenly at age 4 months. Our patients with a severe phenotype and possible parental consanguinity suggest autosomal recessive inheritance of Toriello-Carey syndrome.

Six patients, including two sibs, with Angelman syndrome (AS; three females and three males, aged 11 to 18 years) were studied cytogenetically. Molecular analysis was also performed. Using high-resolution banding technique, we detected a microdeletion in the proximal region of chromosome 15q in four cases. The deleted segment was heterogenous between these patients, and the common deleted region appeared to be 15q11.2. Four patients with deleted 15q were all sporadic cases, whereas in the sib cases we could not detect a visible deletion in the long arm of chromosome 15. However, there was no clinical difference between sporadic cases and sib cases. Densitometric analysis of autoradiographic bands of Southern hybridization using two DNA segments, pML34 and pTD3-21, as probes demonstrated that two patients had only one copy for each of the probes. In the remaining four patients, including the sibs, two copies of each sequence were retained. The probes used here detect a molecular deletion in most Prader-Willi syndrome patients. Thus the segment causing AS is localized adjacent to the critical segment of Prader-Willi syndrome. There seemed to be heterogeneity for the molecular deletion within AS individuals.

The etiologies of 866 patients with mental retardation who visited the outpatient clinic were studied, being classified by the period when the causes were estimated to have occurred. The results revealed that a majority, 657 patients (75.9%), were in the prenatal group. Among the patients who belonged to the prenatal group, 260 patients (30%) exhibited chromosomal aberrations. Chromosomal aberrations were sporadically noted in 248 patients (96.9%), and the number of patients originating from balanced translocation of either parent was 8 (3.1%). Hereditary diseases were recognized in 53 patients (6.1%), among whom 2 patients with fragile X-linked mental retardation were detected. The number of patients who belonged to the perinatal and postnatal groups was markedly few.

These 62 patients with the Kabuki make-up syndrome (KMS) were collected in a collaborative study among 33 institutions and analyzed clinically, cytogenetically, and epidemiologically to delineate the phenotypic spectrum of KMS and to learn about its cause. Among various manifestations observed, most patients had the following five cardinal manifestations: 1) a peculiar face (100%) characterized by eversion of the lower lateral eyelid; arched eyebrows, with sparse or dispersed lateral one-third; a depressed nasal tip; and prominent ears; 2) skeletal anomalies (92%), including brachydactyly V and a deformed spinal column, with or without sagittal cleft vertebrae; 3) dermatoglyphic abnormalities (93%), including increased digital ulnar loop and hypothenar loop patterns, absence of the digital triradius c and/or d, and presence of fingertip pads; 4) mild to moderate mental retardation (92%); and 5) postnatal growth deficiency (83%). Thus the core of the phenotypic spectrum of KMS is rather narrow and clearly defined. Many other inconsistent anomalies were observed. Important among them were early breast development in infant girls (23%), and congenital heart defects (31%), such as a single ventricle with a common atrium, ventricular septal defect, atrial septal defect, tetralogy of Fallot, coarctation of aorta, patent ductus arteriosus, aneurysm of aorta, transposition of great vessels, and right bundle branch block. Of the 62 KMS patients, 58 were Japanese, an indication that the syndrome is fairly common in Japan. It was estimated that its prevalence in Japanese newborn infants is 1/32,000. All the KMS cases in this study were sporadic, the sex ratio was even, there was no correlation with birth order, the consanguinity rate among the parents was not high, and no incriminated agent was found that was taken by the mothers during early pregnancy. Three of the 62 patients had a Y chromosome abnormality involving a possible common breakpoint (Yp11.2). This could indicate another possibility, i.e., that the KMS gene is on Yp11.2 and that the disease is pseudoautosomal dominant. These findings are compatible with an autosomal dominant disorder in which every patient represents a fresh mutation. The mutation rate was calculated at 15.6 X 10(6).

A boy with severe growth and psychomotor retardation, facial dysmorphism, a large atrial septal defect, limitation of joint movement and hearing impairment is described. High-resolution banding chromosome analysis showed interstitial deletion of the proximal segment of chromosome 3: 46, XY, del(3)(p12p14.2) de novo. The deleted chromosome 3 was of paternal origin as judged from Q-banding polymorphisms. Delineation of proximal 3p deletion syndrome is proposed by summarizing the clinical and cytogenetical findings of the present and previously reported five patients.

A case of 4p trisomy syndrome originated from familial rep (4; 14) is reported. The rearrangement was characterized by a breakpoint at the centromeric region of chromosome 14 and by a reciprocal translocation between chromosomes 4 and 14. The translocation was observed in three generations. As a result of CBG banding analysis in prometaphase cells, the breakpoint of der(14) was considered to be located at 14p11.1, and a part of 14p11.1 was translocated to chromosome 4p. It was unknown whether a part of the centromere was involved in it or not.