Shinsuke Ninomiya

Autosomal dominant congenital cataract and microphthalmia associated with a familial t(2;16) translocation

SummaryWe describe a family in which autosomal dominant congenital cataract and microphthalmia were segregating together with a reciprocal translocation t(2; 16) (p22.3;p13.3) through three generations. This family included four individuals with balanced translocations, three with partial trisomy 2p derived from this translocation, and two with a normal karyotype. All of the subjects with balanced and unbalanced translocations had congenital cataract and microphthalmia, whereas the two individuals with normal karyotypes did not show any ocular anomalies. These observations suggest that the altered function of a gene that lies on the 16p13.3 band and that has an important role in the development of the eye is responsible for this disorder.

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.

A novel mutation (296 del G) of the SOX9 gene in a patient with campomelic syndrome and sex reversal

The human SOX9 gene is responsible for the campomelic syndrome (CMPS) and sex reversal. This gene encodes a transcription factor containing a DNA binding domain homologous to the SRY high mobility group (HMG) domain. A novel mutation of SOX9, i.e. a single G deletion in one allele at nt 296 from A of the first ATG in the open reading frame, was identified in a patient with CMPS with sex reversal. The deletion resulted in a frameshift mutation upstream of the HMG box and a stop codon 30 bp downstream of the HMG box. The predicted truncated SOX9 protein contained 108 amino acids instead of the 509 amino acids of the normal SOX9 protein, removing nearly 80% of the SOX9 protein, including the HMG and the C‐terminal transactivation domain. Most patients with CMPS reported previously died within the neonatal period. Our findings that the patient has survived, although has been in daily need of mechanical ventilation support for 5 years and 3 months despite a severely impaired SOX9 protein, do not support a linear relationship between the type of mutation and severity of the clinical outcome.

Maternal origin of a unique extra chromosome, der(9)(pter→q13::q13→q12:) in a girl with typical trisomy 9p syndrome

We report on a girl with the typical trisomy 9p syndrome who had an additional E-sized metacentric chromosome. On the basis of GTG- and CBG-banding, her karyotype was considered to be 47,XX,+der(9)(pter-->q13::q13-->q12:) de novo. Results of a fluorescence in situ hybridization study using a chromosome 9-specific painting probe were compatible with this cytogenetic interpretation. Molecular analyses of six highly polymorphic dinucleotide repeat loci on the short arm and the proximal long arm of chromosome 9 demonstrated that the girl inherited one allele from her father and two identical or different alleles from the mother. We speculated that the extra chromosome may have resulted from either nondisjunction of chromosome 9 followed by a U-type exchange and a crossing-over between different sister chromatids during maternal meiosis I and subsequent breakage and malsegregation during meiosis II, or nondisjunction during meiosis II followed by isochromosome formation in one of the two maternal chromosomes 9 and subsequent breakage.

Rapid screening method to detect mutations in CYP21, the gene for 21-hydroxylase

To facilitate a rapid and practical molecular diagnosis of 21-hydroxylase deficiency (21-OHD), we developed a polymerase chain reaction (PCR) test in which only the 21-OH gene (CYP21) is amplified. We applied the test to diagnose 23 patients with salt-wasting type of 21-OHD. The upstream and downstream sequences of CYP21 have been specifically amplified by using a primer set containing the 8-bp deletion sequence of exon 3, which is distinct from its pseudogene CYP21P. The amplified PCR products were further subjected to mutation detection by restriction analysis: E1PL by AciI, I2g by PstI, E63a by DraIII, E7VL by ApaLI, E8non by PstI, and E8RW by AciI. To detect delections and/or gene conversions occurring on exon 3, we used the method described by Rumsby and Honour [1990: J Med Genet 27:676-678]. Our method is able to elucidate 8 common CYP21 mutations by using only 3 primer pairs and 4 restriction enzymes. The overall detection ratio of abnormal haplotypes by this method was over 95%, indicating that our method is practical and useful, particularly for carrier detection.

Unique maternal deletion of 15q in a patient with some symptoms of Prader-Willi syndrome

Abstract Background : Human chromosome 15q11‐q13 is a critical region for Prader‐Willi syndrome (PWS) and Angelman syndrome (AS) and most of the genes are under the condition of imprinting mechanism. PWS results from the loss of expression of paternally expressed genes and AS of maternally expressed genes. In this study molecular studies about a patient with congenital anomalies and mental retardation are analyzed.

Interchange trisomy 9 due to maternal t(6;9) translocation.

The occurrence of interchange trisomy due to a 3:1 malsegregation has been documented in only a few cases with trisomy 21. We describe the first case of interchange trisomy 9 due to a maternal t(6; 9) translocation. The patient, a boy neonate who died immediately after birth, had intra‐uterine growth retardation, specific craniofacial features including microcephaly with a high forehead, low‐set ears, upslanting short palpebral fissures, microphthalmia, bulbous nose and micrognathia, cryptorchidism, cystic kidney and various skeletal anomalies. His phenotype was consistent with that of the trisomy 9 syndrome. Cytogenetic analysis showed his karyotype of 47,XY,‐6, + der(6), + der(9)t(6; 9)(q27;q21.1)mat. The present report indicates that a very rare interchange mode of a 3:1 segregation can give rise to a live birth with full trisomy 9 in female carriers with reciprocal translocations involving the proximal long arm of chromosome 9.