Xq-Yq interchange resulting in supernormal X-linked gene expression in severely retarded males with 46,XYq- karyotype.

The critical importance of dosage compensation is underscored by a novel human syndrome ("XYXq syndrome") in which we have detected partial X disomy, demonstrated supernormal gene expression resulting from the absence of X inactivation, and correlated this overexpression with its phenotypic consequences. Studies of three unrelated boys with 46,XYq- karyotypes and anomalous phenotypes (severe mental retardation, generalized hypotonia and microcephaly) show the presence of a small portion of distal Xq on the long arm of the Y derivative. Cells from these boys exhibit twice-normal activity of glucose-6-phosphate dehydrogenase, a representative Xq28 gene product. In all three cases, the presence of Xq DNA on a truncated Y chromosome resulted from an aberrant Xq-Yq interchange occurring in the father's germline.

Human thymidine kinase gene locus: assignment to chromosome 17 in a hybrid of man and mouse cells.

The human chromosome retained in a hybrid clone derived from human cells and a moluse line deficiemt in thymidine kinase has the quinacrinefluorescence pattern characteristic of chromosome 17.

Mapping the locus of the H-Y gene on the human Y chromosome.

The H-Y locus is on the short arm of the human Y chromosome in most individuals but on the long arm in at least one of 17 individuals with structural abnormalities of the Y.

Homogeneously staining region in a retinoblastoma cell line: relevance to tumor initiation and progression.

A human retinoblastoma cell line was found to contain a homogeneously staining region (HSR) on chromosome 1 (at 1p34). An HSR had previously been identified at the same site in a human neuroblastoma cell line. Of the original retinoblastoma line, a subpopulation was found which did not contain the 1pHSR but did contain a 3p+ chromosome in which the additional segment resembled a small HSR. The 3p+ was most likely the result of the translocation between the 1pHSR and the short arm of a chromosome 3. Preliminary results also indicate that the retinoblastoma cells with the 1pHSR produced tumors in athymic nu/nu mice in an average of 28 days, while identical numbers of the retinoblastoma cells with the 3p+ (probable HSR) produced tumors in an average of 75 days.

Trisomy 8 mosaicism syndrome.

Chromosome 8 is the largest autosome thus far found to be trisomic among liveborn infants. Trisomy 8 "mosaicism" syndrome (T8mS) consists primarily of individuals whose chromosome complement is mosaic for chromosome 8 (T8m), i.e., patients with a chromosomally normal cell line in addition to the trisomic 8 cell line, and a few known individuals with full trisomy 8 (T8), i.e., each cell observed contains an extra chromosome 8. Reported cases of both types share a number of common features and thus have helped to delineate a new syndrome. Common features of T8mS include mild-to-moderate mental retardation, strabismus, osseous and soft tissue abnormalities, lowset and/or malformed ears, broad bulbous nose, palate deformity, various types of congenital cardiovascular disorders, hydronephrosis, cryptorchidism, and characteristic dermatoglyphics. Since chromosomal mosaicism is often present in this syndrome it is not surprising that considerable phenotypic variation exists. The present report of one of the youngest individuals yet described with T8m adds two more physical findings (dense corneal clouding and a heretofore undescribed clavicular deformity) to the constellation of abnormalities associated with T8mS. On the basis of the phenotypic and cytogenetic findings in this and 17 similar patients previously reported it is proposed that T8mS is a distinct clinical entity.

Diagnosis of Angelman syndrome in infants.

The diagnosis of Angelman syndrome (AS) has seldom been made in infants because the previously described characteristic manifestations usually are not apparent until after age 2 years. We describe 4 AS patients, one of whom has oculocutaneous albinism, who were less than 2 years old when first evaluated. All 4 have deletions of the region q11.2-q13 of chromosome 15. In the 3 cases in which parents were available for study the deleted chromosome 15 was maternally derived, as determined by cytological markers. All of the patients presented with severe to profound global developmental delay and postnatal-onset microcephaly; they had seizures, hypotonia, hyperreflexia, and hyperkinesis. All were hypopigmented as compared to their relatives. Each had eye abnormalities; all had choroidal pigment hypoplasia. None were initially described as having an abnormal appearance. We believe that AS is far more common than previously thought and present these 4 children to emphasize the manifestations that may be helpful in making the diagnosis in the young patient. We also emphasize the hypopigmentation that patients with AS frequently have, including what we think is the first reported case of albinism and AS.

Multiple congenital anomalies/mental retardation (MCA/MR) syndrome due to partial 1q duplication and possible 18p deletion: a study of four individuals in two families.

We have evaluated four individuals from two unrelated families with a similar multiple congenital anomalies/mental retardation (MCA/MR) syndrome due to partial duplication of chromosome 1q and possible deletion 18p. In both families the mothers and several relatives were carriers of the balanced translocation rcp t(1;18) (q42;p11). The features which the four have in common are relative macrocephaly, prominent forehead, micrognathia, and highly arched palate; three of the four individuals have short stature, scoliosis, kyphosis, hirsutism, camptodactyly, sacral dimple, repaired inguinal hernias, and eye abnormalities. Reproductive histories of five balanced translocation carriers in these families indicate that they have a high risk of spontaneous abortions and infants with multiple malformations.

Presence of H-Y antigen in patients with Ullrich-Turner syndrome and X-chromosome rearrangements.

Cells from eight of ten patients with gonadal dysgenesis and an isochromosome for the long arm of X, (i(Xq)), have been found to be H-Y antigen-positive, using an assay that employs rat antiserum and Raji cells. In addition, two patients with del(Xq) were also found to be H-Y antigen-positive, whereas four patients in whom only a 45,X line was detected were H-Y antigen-negative. These findings suggest that the X chromosome plays a role in the expression of H-Y antigen in the absence of a Y chromosome. Since our patients with i(Xq) show no evidence of testicular differentiation, it is clear that there is not enough H-Y antigen on these patients' cells to direct the development of a testis. These findings are consistent with the view that the normal functioning of genes on the X and the Y chromosomes is necessary for testicular organogenesis to occur.

DNA-based genetic testing in fifty fragile X families.

During the past 4 years (1985-1989), we have analyzed 171 cases in 50 fragile X [fra(X)] families by DNA linkage methods. Most (140 cases; 81%) were for carrier detection, both female (98 cases; 57%) and male (41 cases; 24%). Women who were obligate carriers of the fra(X) mutation accounted for an additional 6 "prior-to-pregnancy" cases. Four pregnancies have subsequently occurred with 3 having been successfully monitored (one male, 2 females). One pregnancy miscarried early prior to testing. Prenatal diagnoses (26 cases; 15%) accounted for the remainder of cases (15 males, 11 females). These will be discussed in the companion paper by Shapiro et al. (Am J Med Genet, 1991). A diagnosis in the cytogenetically uninformative carrier cases was reached in greater than 75% of analyses with a panel of 5 probes: 3 proximal (F9, DXS105, DXS98) and 2 distal (F8, DSX52). Five additional probes, 3 proximal (DXS10, DSX51, DSX102) and 2 distal (DSX15, DXS33), were used in cases that were resistant to analysis with the standard panel. In 60% of cases, flanking markers were identified (proximal and distal). Given this panel, only 5% of cases did not have any informative markers identified. Thus, molecular methods can provide a useful adjunct to cytogenetic analysis in most situations. An unusual association between the rare allele (A1) of DXS10 with the X chromosome carrying the fra(X) mutation was observed. This occurred in both male and female carriers in the uppermost generation tested. The basis for this association is uncertain at the present time.

"Pseudomosaicism" for 4p- in amniotic fluid cell culture proven to be true mosaicism after birth.

Pseudomosaicism is noted in approximately 1% of amniotic fluid cell studies. Some represent numerical abnormalities, but pseudomosaicism for structural chromosomal abnormalities is also seen. Pseudomosaicism is not usually considered clinically significant. Recently, we evaluated a 13-month-old girl with developmental delay and minor anomalies suggestive of 4p- syndrome. In 5 of 100 peripheral lymphocytes, she had a deletion 46,XX,del(4)(p15). Review of a prenatal amniocentesis study performed on the mother of our patient disclosed that one colony of 18 examined from 2 in situ cultures had the same abnormality, whereas none of the 27 cells from a flask culture showed the abnormality. Results of this study had originally been reported as showing pseudomosaicism. To our knowledge, amniotic fluid pseudomosaicism of a structural abnormality has not previously been shown to reflect true mosaicism in fetal tissue or liveborn children. The actual incidence of this phenomenon is unknown, but it may be present in unexamined children with minimal clinical findings. Apparently only one previous case of mosaic 4p- in a liveborn individual has been reported.

Experience with multiple approaches to the prenatal diagnosis of the fragile X syndrome: amniotic fluid, chorionic villi, fetal blood and molecular methods.

We have had experience with 160 prenatal diagnosis cases for the fragile X syndrome [fra(X)] or Martin-Bell Syndrome. In 140, amniotic fluid was utilized; 98 had a documented family history of fra(X). The 94 completed cases included 4 no growth; 56 males of which 7 were fra(X)-positive and 2 false-negative; 38 females of which 5 were fra(X) positive. There was no fra(X) positive result when a family history of mental retardation was not documented as fra(X). Molecular methods (RFLPs) were utilized in 10 amniotic fluid and 5 chorionic villus specimens (CVS). Percutaneous umbilical blood sampling was used in 2 negative cases and 1 fra(X) positive case because of timing, tissue culture failure or confirmation of another method. CVS were received in 13 cases, and RFLPs were utilized in 5 of the CVS cases. There was no positive fra(X) CVS chromosome result in males, 1 positive result in a female, but 2 false negatives were detected by RFLPs. On the basis of the results, it can be concluded that cytogenetic and molecular methods are complementary and best used together and that multiple approaches can enhance the efficiency and reliability of fra(X) prenatal diagnosis.

Duplication of euchromatin without phenotypic effects: a variant of chromosome 16.

A family with an unusual variant of chromosome 16 is presented. The mother and son both with additional material present in the short arm of chromosome 16 adjacent to the centromere are phenotypically normal. The extra C-band negative region has been shown not to be composed of alpha satellite DNA. The literature regarding other familial cases of what appears to be the same variant of chromosome 16 is reviewed.

FISH diagnosis of partial trisomy 13 and tetrasomy 13 in a patient with severe trigonocephaly (C) phenotype.

An infant girl with manifestations resembling Optiz trigonocephaly (C) syndrome who died at age 6 days was found to have a complex chromosome abnormality with t(13;18)(q22;q23) and a recombinant chromosome 13 involving duplicated segments of 13q. Precise characterization was possible with the application of fluorescence in situ hybridization (FISH) using chromosome specific probes. The patient's phenotype is compared to that of other syndromes involving trigonocephaly.

Chromosome deletion 1q42-43.

We report on a newborn male and a female of 3 years 9 months with de novo 1q42 or 43-qter deletions. These cases are compared with ten other reported cases.

Trisomy 22 mosaicism syndrome and Ullrich-Turner stigmata.

Mosaic trisomy 22, ascertained in three unrelated patients, was found to be associated with body asymmetry and signs of the Ullrich-Turner syndrome including short stature, ptosis, webbed neck, nevi, cubitus valgus, dysplastic nails, malformed great vessels, and abnormal ovaries. These anomalies in trisomy 22 mosaicism have not been emphasized heretofore. In each of our patients, trisomy 22 mosaicism was found only in fibroblasts. In one patient, the trisomy resulted from a paternal first meiotic nondisjunction, and in the 46,XX cells, both chromosomes 22 were of paternal origin.

Report of two cases of distal deletion of the long arm of chromosome 6.

We report on two patients with distal deletions of 6q. In one case a de novo translocation between chromosomes 6 and 7 resulted in del(6q25----6qter). The other case had a de novo deletion, also from 6q25 to 6qter. There have been eight previous reports of distal deletions of 6q. These patients have developmental retardation, microcephaly, craniofacial anomalies, various types of congenital heart defects, and anomalies of hands and feet. The facial similarities of our two patients and those in six published photographs are subtle and may represent an emerging phenotype.

Familial occurrence of esophageal atresia with and without tracheoesophagel fistula: report of two unusual kindreds.

We describe 2 unique kindreds with familial occurrence of esophageal atresia (EA) with or without tracheoesophageal fistula (TEF) and reviewed the literature on familial EA +/- TEF. EA +/- TEF appears to be causally heterogeneous with evidence pointing to the existence of non-genetic developmental and multifactorial forms. The literature suggests that the parents of a single affected child should be given an empiric recurrent risk between 1/2 and 2%, rising to 20% if more than one sib is affected. The empiric risk of an affected child born to an affected parent is 3-4%. Empiric risk figures are useful in counseling families at the present time; however, the 2 kindreds presented here raise the possibility of autosomal dominant transmission in certain families. A third generation of affected offspring, or additional family reports should help to clarify this issue in the future.

H-Y antigen expression in patients with X-autosomal translocations and gonadal dysgenesis.

Cells from three patients with early gonadal failure and a balanced reciprocal translocation involving the long arm of the X chromosome and an autosome were studied. Fibroblasts from a patient with a similar balanced reciprocal translocation but normal reproductive capabilities were also studied. Two of the four patients were found to have serologically detectable H-Y antigen on their cells. Since H-Y antigen has been found on the cells of other patients with X chromosome abnormalities but without a Y chromosome, it is thought that the X chromosome plays a role in the regulation of H-Y antigen expression. This study suggests that the long arm of the X chromosome may be involved but the location of a regulatory gene cannot be identified in these studies. These cases do not permit us to implicate H-Y antigen as a cause of gonadal dysgenesis and early gonadal failure in females who have structurally abnormal X chromosomes.

Unusual mosaicism of de novo structural abnormalities and ocular anomalies in a male with 13 trisomy syndrome.

A body with the 13 trisomy syndrome was found to have a unique form of mosaicism in which each of the two cell lines had different structural rearrangements. The predominant cell line was partially trisomic for the distal portion of the long arm of chromosome 13, while the minor cell line was trisomic for all of the long arm of 13. The patient is also unusual because he had congenital glaucoma and was still alive at 10 years.

Cytogenetic diagnosis using midtrimester fetal blood samples: application to suspected mosaicism and other diagnostic problems.

Cytogenetic studies on fetal blood cells obtained at 18-25 weeks gestation have provided information for decision making in 25 cases identified as being at high risk of having an abnormal fetus. In particular, in the 21 cases studied to consider the possibility of true mosaicism, confirmation in fetal blood was obtained in three, one of which presented as a pseudomosaic on the original amniotic fluid cell study. Fetal blood was also informative in two cases (one positive and the other negative) in which a diagnosis of the fragile X syndrome was being considered. Furthermore, when high risk pregnancies presented late in gestation (21-24 weeks), these methods allowed for a rapid cytogenetic diagnosis. The procedure has proved useful in most of these cases since the couples involved had indicated that they would probably have terminated the pregnancy without the reassurance of normal fetal lymphocyte studies. Since the technique carries a much higher risk of pregnancy loss than does amniocentesis, its use should only be considered when there are compelling indications.