Mutations at the PAX6 locus are found in heterogeneous anterior segment malformations including Peters' anomaly.

Mutation or deletion of the PAX6 gene underlies many cases of aniridia. Three lines of evidence now converge to implicate PAX6 more widely in anterior segment malformations including Peters' anomaly. First, a child with Peters' anomaly is deleted for one copy of PAX6. Second, affected members of a family with dominantly inherited anterior segment malformations, including Peters' anomaly are heterozygous for an R26G mutation in the PAX6 paired box. Third, a proportion of Sey/+ Smalleye mice, heterozygous for a nonsense mutation in murine Pax-6, have an ocular phenotype resembling Peters' anomaly. We therefore propose that a variety of anterior segment anomalies may be associated with PAX6 mutations.

Maternal uniparental disomy of chromosome 21 in a normal child.

Maternal uniparental disomy of chromosome 21 [upd(21)mat] was found previously in a normal female and in 2 cases of early embryonic failure. We present a phenotypically normal child with upd(21)mat due to a de novo der(21;21)(q10;10). This finding suggests that chromosome 21 is not imprinted in the maternal germline.

Reproductive risks for carriers of complex chromosome rearrangements: analysis of 25 families.

We have determined the empirical reproductive risks for heterozygous carriers of complex chromosome rearrangements (CCRs). CCRs are structural rearrangements involving at least three chromosomes and three or more chromosomal breakpoints. Pregnancy outcome, the frequency and type of chromosomal imbalance in the offspring, and the localization and distribution of chromosome breakpoints were analyzed in 25 CCR families ascertained by the birth of a malformed child or repeated spontaneous abortions. This study included two newly ascertained familial CCRs and a total of 67 informative pregnancies. Analysis of the data, after correction for ascertainment bias, showed that the incidence of spontaneous abortions in CCR families was 48.3%. Approximately one in ten pregnancies and 18.4% of all live births to CCR carriers resulted in phenotypically abnormal offspring. One-half of all CCR carrier liveborn offspring were also CCR carriers. There was a 53.7% incidence of an abnormal pregnancy outcome to CCR carriers. We failed to detect any evidence for a non-random involvement of specific chromosomes in CCRs. However, we did observe a non-random distribution of specific breakpoints at sites 1q25, 4q13, 6q27, 7p14, 9q12, 11p11, 11p15, 12q21, 13q31, and 18q21.

Truncus arteriosus and other lethal internal anomalies in Goltz syndrome.

An infant girl of 36 weeks gestational age was found to have cardiovascular and other lethal internal anomalies in addition to characteristic external abnormalities of focal dermal hypoplasia (Goltz syndrome). The internal anomalies included truncus arteriosus type II with truncal origin of hypoplastic pulmonary arteries, cardiac ventricular septal defect, severe hypoplasia of lungs and pulmonary veins, massive diaphragmatic hernia, and absence of the right kidney. Such a combination of severe anomalies has not been reported previously in Goltz syndrome.

Simpson-Golabi-Behmel syndrome: genotype/phenotype analysis of 18 affected males from 7 unrelated families.

Simpson-Golabi-Behmel syndrome (SGBS) is an X-linked overgrowth disorder recently shown to be caused by mutations in the heparan sulfate proteoglycan GPC3 [Pilia et al., Nat Genet; 12:241-247 1996]. We have used Southern blot analysis and polymerase chain reaction amplification of intra-exonic sequences to identify four new GPC3 mutations and further characterize three previously reported SGBS mutations. De novo GPC3 mutations were identified in 2 families. In general, the mutations were unique deletions ranging from less than 0.1 kb to more than 300 kb in length with no evidence of a mutational hot spot discerned. The lack of correlation between the phenotype of 18 affected males from these 7 families and the location and size of the GPC3 gene mutations suggest that SGBS is caused by a nonfunctional GPC3 protein.

Hyperdiploidy and trisomy 12 in the cystic partially differentiated nephroblastoma.

The karyotype of a cystic partially differentiated nephroblastoma (CPDN) was found to be 51, XY, +7, +8, +12, +13, +17. A review of the literature disclosed three other cytogenetically analyzed CPDNs. As in this case, they were all hyperdiploid. The only chromosomal anomaly common to all four cases was trisomy 12, suggesting this chromosome might have a pathogenetic role. Earlier reports had tentatively attributed this role to chromosome 8.

Translocation 10;17 in clear cell sarcoma of the kidney. A first report.

This is the first report of a t(10;17) as the unique cytogenetic finding in one case of a rare childhood tumor, clear cell sarcoma of the kidney (CCSK). This observation is discussed in relation to the cytogenetics of Wilms' tumors, of which CCSK is a variant.

Old syndromes and new cytogenetics.

This annotation has been confined to well-established clinical syndromes with recently discovered chromosomal etiologies. It deliberately omits retinoblastoma, the oft-cited paradigm of a contiguous gene syndrome, since it is usually inherited as a Mendelian single gene disorder. However, it was recognition of both the deletion of band q14 of chromosome 13 in mentally retarded children with retinoblastoma, and the linkage of retinoblastoma with the genetic marker esterase D, which resulted in the eventual cloning of the gene. Also omitted are microdeletions of the X chromosome. These disorders are seen primarily in males, who manifest the phenotypic effects of the deletion of the loci of various combinations of adjacent genes: Duchenne muscular dystrophy, glycerol kinase deficiency, adrenal hypoplasia, optic albinism, hypogonadotropic hypogonadism and anosmia (Kallman syndrome), chondrodysplasia punctata and ichthyosis. Many are also mentally retarded. The third group omitted are Mendelian disorders occurring with atypical mental retardation (not usually part of the disorder), the presumption being that they include small deletions. It is expected that other contiguous gene syndromes will be recognized eventually; Rubinstein-Taybi and Cornelia de Lange syndromes are prime candidates. Why do deletions have such dramatic consequences when a normal homologue of the region is present? If their effects were due to the uncovering of recessive genes, we would expect to see greater variations in phenotype among carriers, including normal individuals whose deletions were masked by the protective effects of dominant alleles in the homologous regions. Imprinting--the 'stamping' of a gene as it passes through the germ line--provides a more satisfactory explanation.(ABSTRACT TRUNCATED AT 250 WORDS)

Carrier detection in cystic fibrosis.

We evaluated four methods purported to distinguish between individuals homozygous or heterozygous for cystic fibrosis (CF) and normal controls: (1) detection of a protein in the serum by isoelectric focusing at pH 8.5, (2) detection of a lectinlike factor in the serum by hemagglutination, (3) isolation of CF-lectin from the serum by affinity chromatography, and (4) measurement of MUGB-reactive proteases in the plasma. The results were disappointing. The detection of CF protein by isoelectric focusing was unreliable; it could be identified in only 46% of heterozygotes and 66% of homozygotes, with a false positive rate of 17%. Detection of a lectinlike factor by hemagglutination was also found to be unreliable and irreproducible. The lectin isolated by affinity chromatography was not specific for the CF gene. No significant differences were found in the MUGB titers of the three populations tested. However, low titers (MU less than 200 nmol/ml) were found in 33% of homozygotes and heterozygotes and in 17% of normal controls. We conclude that none of these methods is suitable for carrier detection in cystic fibrosis.

Prenatal diagnosis of the 22q11 deletion syndrome.

A 27 weeks gestation fetus, evaluated because of polyhydramnios, was found by echocardiography to have an interrupted aortic arch type B. Because of the known association between this malformation and DiGeorge syndrome, an amniocentesis was performed. Fluorescence in situ hybridization revealed a 22q11 deletion. This is, to our knowledge, the first report of prenatal detection of a fetus with 22q11 deletion in the absence of a family history.

A new point mutation in the beta-hexosaminidase alpha subunit gene responsible for infantile Tay-Sachs disease in a non-Jewish Caucasian patient (a Kpn mutant).

The abnormality in the gene coding for the beta-hexosaminidase alpha subunit was analyzed in a non-Jewish patient with clinically typical infantile Tay-Sachs disease. The family was Catholic, and the father and the mother were of Irish and German descent, respectively. A hitherto undescribed single nucleotide transversion was found within exon 11 (G1260----C; Trp420----Cys). The coding sequence was otherwise entirely normal. Expression in the COS I cell system confirmed that the mutant gene does not produce functional enzyme protein. The mutation can be identified rapidly and reliably because it abolishes one of the two KpnI sites in the coding sequence. The patient was a compound heterozygote with one allele carrying this mutation. The nature of the abnormality in the other allele remains unidentified. Examination of genomic DNA from the parents demonstrated that this "Kpn mutation" was inherited from the maternal side of the family.

5p14 deletion associated with microcephaly and seizures.

We report on a father and son who have an interstitial deletion of 5p14. The father is clinically and mentally normal while the son has significant clinical involvement including microcephaly, seizures, and global developmental delay. The extent of the 5p14 deletion was determined using fluorescence in situ hybridisation (FISH). The deletion in this present family is smaller than a deletion previously described in a multigenerational family that lacks any clinical phenotype. This report shows that a 5p14 deletion does not always lead to a normal phenotype.

Clinical manifestations of familial 13;18 translocation.

Female first cousins, aged 21 and 2 1/2 years, with many of the characteristic features of trisomy 18, were found to have identical unbalanced translocations, 46,XX,--13, + der(13)t(13;18) (p13;q12)mat. Clinical features of another cousin, two uncles, and an aunt suggested that they, too, had a partial trisomy 18 phenotype. The long survival and normal menstrual and secondary sexual development in one case are remarkable. A heritable balanced translocation, 46,XX or XY, t(13;18) (p13;q12), was detected in the mothers of the cases, a sib, an aunt, and two uncles. Translocation carriers had abnormalities in gonadal structure or function, with aspermia in males and polycystic ovaries with infertility in several females, suggesting that some gene controlling reproductive development occurs on the long arm of chromosome 18, with normal function interrupted at the breakpoint. Balanced translocation carriers may also be at greater risk for both benign and malignant neoplasms, which included acute leukaemia in an uncle and adenocarcinoma of the stomach at an early age in the grandmother. Although aetiological laboratory studies identified no premalignant state, the clinical findings suggest a defect that may predispose to cytogenetic abnormalities and malignancy.

Cytogenetic analysis of a choroid plexus papilloma.

We report the cytogenetic analysis of a choroid plexus papilloma, a benign tumor, with a modal number of 56 chromosomes. In our review of the few reported karyotypes of choroid plexus tumors, we found no predictive relationship between the karyotype and the pathologic diagnosis or outcome.

Focal dermal hypoplasia symdrome in a male.

Focal dermal hypoplasia (Goltz syndrome) is characterized by a pathognomonic abnormality of the skin in association with other congenital defects. There are only seven males among the 52 reported cases. We report the eighth case in a male and evaluate the possible genetic origin of the syndrome. A critical review of the literature provides no evidence for the previously accepted single gene mode of inheritance.

Quinacrine fluorescence and Giemsa banding in trisomy 22.

Using quinacrine fluorescence and Giemsa banding techniques we have identified an extra chromosome 22 in three non-mongoloid children with similar phenotypes and 47 chromosomes. In one of the children, the long arm of the extra 22 was shorter than usual. This 22q-chrcmcscme was observed in 4 normal family members with 46 chromosomes. In a fourth child, with similar physical findings, the extra G chromosome was shown to be neither a normal 21 nor 22. It must have arisen from a rearrangement in a parental gamete since it was not present in either parent's karyotype.No constellation of clinical findings, in association with an extra G chromosome, is sufficient evidence for the diagnosis of trisomy 22. The positive identification of the extra chromosome must be made using fluorescence and banding.

Characterization of alternative amino acid substitutions at arginine 830 of the androgen receptor that cause complete androgen insensitivity in three families.

We have studied two different missense mutations at arginine-830 in exon 7 of the human androgen receptor (hAR) gene that cause complete androgen insensitivity (CAIS) in three families. These substitutions result from point mutations at nucleotide 2489: a G-->T transversion causes Arg830Leu and a G-->A transition causes Arg830Gln. Genital skin fibroblasts of the patients have negligible androgen-binding capacity. The mutations were recreated in an hAR cDNA expression vector that was transiently transfected into COS-1 cells. Both mutant androgen receptors have increased dissociation rate constants and apparent equilibrium rate constants when measured with 5 alpha-dihydrotestosterone or the synthetic, nonmetabolizable androgens, mibolerone or methyltrienolone. The mutant androgen-binding activities share a distinctive thermal misbehavior. At 37 degrees C R830Q and R830L are about 40% and 10% of normal, respectively. At 22 degrees C both mutants gain androgen binding while the normal decreases by 20%; for R830Q the augmented value approaches 60% of the normal. During prolonged 18 h incubation at 37 degrees C, androgen binding of the normal AR is stable while that of both mutants decreases by at least 85%. Both mutants have a very reduced ability to transactivate a cotransfected androgen-responsive reporter gene, but R830Q is better than R830L. We conclude that arginine-830 is important for A-R complex stability, and that its replacement by glutamine or leucine yields distinctive functional aberrations.(ABSTRACT TRUNCATED AT 250 WORDS)