Judith A. Brown

Clinical heterogeneity in 80 home-reared childrenwith cri du chat syndrome

A population of 80 home-reared children with cri du chat syndrome was investigated to document the clinical heterogeneity of the syndrome and to analyze the factors influencing the severity of the phenotypic characteristics. When individuals with isolated deletions were compared with those possessing unbalanced translocations involving other chromosomes in addition to number 5, the latter group had a greater incidence of physical anomalies, more frequent hospitalizations, and a higher mortality. Chronic complaints in both groups included upper respiratory tract infection, otitis media, and a previously unrecognized association with gastrointestinal tract anomalies. In children with terminal deletions, there was a significant negative correlation between the size of the deletion and the individuals intelligence quotient. In addition, patients with larger deletions had more severe growth retardation, particularly with respect to the degree of microcephaly. The gradual progression with age of the characteristic facial features remained consistent regardless of differing racial backgrounds and the size of the deletion. Our findings delineate the variation in the clinical and karyotypic features of this syndrome.

The Insulin Gene Is Located on the Short Arm of Chromosome 11 in Humans

The human insulin gene has been previously localized to chromosome 11. We have analyzed the human ONA sequences present in a human-mouse somatic cell hybrid line possessing a translocation involving human chromosomes 11 and X. These data indicate that the human insulin gene is located on the short arm of chromosome 11 in the region p13→pter.

Psychomotor development in 65 home-reared children with cri-du-chat syndrome

The psychomotor development of 65 noninstitutionalized individuals with cri-du-chat syndrome was examined through parental questionnaire responses and supporting medical records. Social quotients determined by a Vineland Maturity Scale ranged from 6 to 85, the ages at which developmental milestones were attained varied from the upper limits of normal to six years delayed. Achievement levels were influenced favorably by the early introduction of special education, and were affected adversely by the presence of an unbalanced translocation. This study suggests that many children with cri-du-chat syndrome can attain developmental and social skills normally seen in 5- to 6-year-old children, although their linguistic abilities are seldom as advanced. Contrary to the commonly portrayed clinical picture of severe mental retardation and bedridden debilitation, the older home-reared cri-du-chat child was usually ambulatory, had a moderate degree of independence in self-care skills, and was able to communicate either verbally or through gestural sign language. Physicians and parents should be aware of the full range of psychomotor potential of the child with cri-du-chat syndrome in order to make informed decisions concerning institutional placement.

A molecular genetic approach to the identification of isochromosomes of chromosome 21

SummaryThe largest class of de novo chromosomal rearrangements in Down syndrome are rea(21q21q). Classically, these rearrangements have been termed Robertsonian translocations, implying an attachment of two different chromosome 21 homologues. Additionally, a Robertsonian translocation between two chromosomes 21 cannot be distinguished from an isochromosome composed of genetically identical arms by cytogenetic analyses. Therefore, we have used molecular techniques to differentiate between true Robertsonian translocations and isochromosomes. Samples were obtained from 12 probands, ascertained for de novo rearrangements between homologous chromosomes 21 [11 rea(21q21q) and 1 rea (21;21)(q22;q22)], their parents (n = 24) and available siblings (n = 7). The parental origins of the de novo rearrangements were assigned using molecular and cytogenetic analyses. Although not statistically significant, there was a two-fold increase in the number of paternally derived de novo rearrangements (n = 8) as compared with maternally derived rearrangements (n = 4). To distinguish between rob(21q21q) and i(21q), we used restriction fragment length polymorphisms (RFLPs) spanning the length of chromosome 21. Using all informative and partially informative RFLPs, we used the method of maximum likelihood to assign the most likely rearrangement definition (i or rob) and parental origin in each family. The maximum likelihood estimates indicated that all rearrangements tested (n = 8) were isochromosomes. C-banding revealed two centromeres in three cases indicating that a U-type exchange occurred between sister chromatids in these rearrangements. Our results suggest that the majority of de novo rea(21q21q) are isochromosomes derived from a single parental chromosome 21.

Stain intensity of human nucleolus organizer region reflects incorporation of uridine into mature ribosomal RNA

The stain intensity of the nucleolus organizer regions (NORs) of acrocentric chromosomes was correlated positively with incorporation of [3H]uridine into 18S rRNA and 28S rRNA from cultured diploid human skin fibroblasts. An analysis of these data from twins by a path model indicated that no other common genetic or environmental parameters were required to explain the relationship between NOR scores and uptake of [3H]uridine into mature rRNA species.

Translocations that highlight chromosomal regions of differentiated activity

The frequent translocation of the c-myc oncogene into the immunoglobulin loci in tumors of B lymphocytes prompted us to ask whether or not disease-associated chromosomal translocations specific for other disorders in different cell types would also involve regions of the genome encoding important differentiation-specific products made by these cells. We have studied the karyotypes of two patients with erythroleukemia and an established erythroleukemia cell line, K562 (late passages), and find translocations within the chromosomal regions to which the genes that encode alpha and beta globin have been assigned. Additionally, we have analyzed the karyotype of cloned B-lymphocytes, including both kappa and lambda producing cells, from a patient with ataxia telangiectasia (AT) and find a translocation between the regions encoding immunoglobulin (Ig) light and heavy chain genes whereas a different translocation not involving these regions is seen in T-lymphocytes from the same patient. These examples provide insight into the mechanism of chromosomal translocation in both cancerous and noncancerous conditions and lead to the speculation that genomic activity is a necessary factor in the generation of some chromosomal translocations.

GM1-gangliosidosis: Chromosome 3 assignment of theβ-galactosidase-A gene (βGAL A )

The structural gene (βGALA) coding for lysosomal β-galactosidase- A (EC 3.2.1.23) has been assigned to human chromosome 3 using man-mouse somatic cell hybrids. Human β-galactosidase-A was identified in cell hybrids with a species-specific antiserum to human liver β-galactosidase-A. The antiserum precipitates β-galactosidase-A from human tissues, cultured cells, and cell hybrids, and recognizes cross-reacting material from a patient with GM1 gangliosidosis. We have analyzed 90 primary man-mouse hybrids derived from 12 separate fusion experiments utilizing cells from 9 individuals. Enzyme segregation analysis excluded all chromosomes for βGALA assignment except chromosome 3. Concordant segregation of chromosomes and enzymes in 16 cell hybrids demonstrated assignment of βGALA to chromosome 3; all other chromosomes were excluded. The evidence suggests that GM1 gangliosidosis is a consequence of mutation at this βGALA locus on chromosome 3.

Antenatally Detected Klinefelter's Syndrome in Twins

An increased incidence of twinning has been reported among patients with Klinefelters syndrome (XXY) and their relatives, but no data have been reported about the incidence of XXY among twins. Results from our institutions antenatal testing clinic provide data about twins and XXY. In 1842 pregnancies tested, 21 were noted to be twin gestations. Five fetuses with XXY were detected in all pregnancies, of which there was a pair of MZ twins concordant for XXY and a pair of DZ twins discordant for XXY. The incidence of XXY in twins was thus 7,1%. The fetal phenotype of XXY was examined in aborted MZ twins and found to be mild. Notably, the testicular histology was normal. These cases confirm the previously reported association of twinning and XXY. The association of twinning and XXY implies a commonality of causation; however, a maternal age effect cannot be excluded. Our data suggest that there is an increased risk of XXY among twins.

Quinacrine mustard and nucleolar organizer region heteromorphisms in twins

Patterns of NOR activity in 640 metaphase spreads from twelve monozygotic (MZ) and eight dizygotic (DZ) twin pairs were studied to evaluate the heritability of this chromosomal heteromorphism. NORs were stained by a modification of the Ag-AS technique and counterstained with quinacrine mustard dihydrochloride to facilitate chromosome identification and assess their value in zygosity determination. In this study, all karyotypes were read blind with respect to zygosity and pair membership. A discriminant function analysis of pair score differences in MZ and DZ twins revealed that, in our sample, the probability of accurately determining zygosity with NOR scores was 0.93 and with QFQ scores was 0.99. We conclude that NOR and QFQ scores are highly heritable and of great value in zygosity determination. Data were collected from 687 metaphase spreads on the frequency with which an acrocentric chromosome was found in a satellite association. A significant correlation was found between this frequency and the degree of Ag-AS stain of the NOR. This study, therefore, confirms previous results showing that a high degree of NOR activity is found in those chromosomes most often involved in satellite associations.

Gene assignment of α-fucosidase and glucose dehydrogenase to the p21→pter region of chromosome 1 in man

Assignment of human genes coding for α-fucosidase (αFUC) and glucose dehydrogenase (GDH) to chromosome 1 has been confirmed and a location in the p21→pter region demonstrated using man-mouse somatic cell hybrids. The regional location af αFUC andGDH was established in cell hybrids using human cells possessing 1/2 translocation chromosomes [46,XX,t(1;2)(p21;q37)]. Hybrids which retained the 2q+ chromosome carrying the 1p21→1pter region concordantly expressed αFUC, GDH, and the short-arm markers ENO1, AK2, and PGM1. Hybrids which retained the 1p21→1qter region only expressed human PEPC and FH. Data obtained from hybrids in which spontaneous breaks in chromosome 1 had occurred indicate that the gene order in 1p21ar1pter is (ENO1,GDH)-αFUC-AK2-PGM1.