Showing papers in "Journal of Medical Genetics in 1992"

Prader-Willi syndrome.

Abstract: Prader-Willi syndrome is a complex disorder affecting multiple systems with many manifestations relating to hypothalamic insufficiency. Major findings include infantile hypotonia, developmental delay and mental retardation, behaviour disorder, characteristic facial appearance, obesity, hypogonadism, and short stature. Obesity and the behavioural problems are the major causes of morbidity and mortality. Prader-Willi syndrome is caused by abnormalities of the imprinted region of proximal 15q and results from absence of the normally active paternal genes in this region. Such absence results from paternal interstitial deletion, maternal uniparental disomy, or a mutation or other abnormality in the imprinting process. Diagnostic identification of all causes has become available in recent years, permitting early detection and institution of appropriate management. This testing has permitted recent identification of some phenotypic differences among affected subjects of different race and between those with deletions and uniparental disomy as a cause.

A genetic study of type 2 neurofibromatosis in the United Kingdom. I. Prevalence, mutation rate, fitness, and confirmation of maternal transmission effect on severity.

Abstract: A clinical and genetic study of type 2 neurofibromatosis (NF2) has been carried out in the United Kingdom. Virtually complete ascertainment of cases in the north-west of England was achieved and suggests a population incidence of 1 in 33,000 to 40,000. In the UK as a whole, 150 cases have been identified and been used to study the clinical and genetic features of NF2. The autosomal dominant inheritance of NF2 was confirmed, 49% of cases were assessed as representing new mutations, and the mutation rate was estimated to be 6.5 x 10(-6). Evidence to support a maternal gene effect was found in that age at onset was 18.17 years in 36 maternally inherited cases and 24.5 in 20 paternally inherited cases (p = 0.027). The preponderance of maternally inherited cases was also significant (p = 0.03). Data are presented which suggest that there are two types of NF2, one with later onset and bilateral vestibular schwannomas as the only usual feature, and the other with earlier onset and multiple other tumours. A considerable number of cases did not fall easily into one or other group and other factors such as maternal effect on severity and anticipation need to be considered.

Estimates of the frequency of chromosome abnormalities detectable in unselected newborns using moderate levels of banding.

Abstract: Data on structural chromosome abnormalities identified during prenatal diagnosis were used to estimate the number of such abnormalities that would be detectable in an unselected series of newborns using moderate levels of banding (400 to 500 bands). These estimates were compared with the rates detected in nonbanded surveys of newborns. Between 1976 and 1990 prenatal diagnosis using banding techniques was carried out in our laboratory on 14,677 women aged 35 and over. Among these, we detected 112 structural rearrangements, 32 unbalanced and 80 balanced. These figures were adjusted by two methods to give an estimate of the frequency of structural abnormalities in the newborn. Our data suggest that the use of moderate levels of banding increases the frequency of unbalanced structural abnormalities from 0.052 to 0.061% and of balanced structural abnormalities from 0.212 to 0.522%. Thus, the total number of chromosome abnormalities detectable in the newborn is increased from 0.60% in unbanded preparations to 0.92% in banded preparations.

Polyglandular autoimmune syndrome type I among Iranian Jews.

Abstract: Polyglandular autoimmune syndrome (PAS) has been well characterised and the accepted criteria for diagnosis are the presence of at least two of the three major components: hypoparathyroidism (HPT), candidiasis, and adrenal insufficiency (AI). HPT may, however, be the only manifestation of the syndrome. Iranian Jews, having a high rate of consanguinity, appear to be a community in which PAS type I is frequent. We report on 19 families of patients with HPT from the Iranian Jewish community assuming that they are in fact affected with PAS type I. In the 19 families, 23 patients were affected, including 11 males and 12 females. All the patients but one had HPT (96%), and most were diagnosed by the age of 20 years (91%). AI was diagnosed in five of our patients; in all cases but one it appeared after HPT. Mild oral candidiasis was present in four patients and six of the patients (three males and three females) had hypogonadism. Other features of the syndrome found in some of our patients were pernicious anaemia, hypothyroidism, and alopecia. The disease is autosomal recessive and the calculated prevalence among the Iranian Jews is 1:6500 to 1:9000. The disease is also found with a very high incidence among Finns. A comparison of the symptoms between the two groups showed clinical differences including the relative rarity of candidiasis and absence of keratopathy among the Iranian Jews.

Association between schizophrenia and homozygosity at the dopamine D3 receptor gene.

Abstract: Disturbances in dopamine neurotransmission have been postulated to underlie schizophrenia. We report data from two independent studies of a BalI polymorphism in the dopamine D3 receptor gene in patients with schizophrenia. In both studies, more patients than controls were homozygous (p = 0.005, p = 0.008). When pooled data were analysed, this difference was highly significant (p = 0.0001) with a relative risk of schizophrenia in homozygotes of 2.61 (95% confidence intervals 1.60-4.26).

Recognition of thalidomide defects.

Abstract: Thalidomide: a brief history Thalidomide (alpha-phthalimido-glutarimide) was developed by the German firm Chemie Grunenthal as an anticonvulsant drug. Early trials showed it to be unsuitable for this purpose but indicated that it had sedative properties. Furthermore, it had one remarkable property: overdoses simply caused prolonged sleep, not death. The drug was first marketed in Germany in 1957 under the name Contergan, and in the UK in April 1958 as Distaval. Later, compound preparations which combined thalidomide with other drugs were marketed for a wide variety of indications: Asmaval for asthma, Tensival for hypertension, Valgraine for migraine, and so forth. The promotion of these products laid great stress on the safety of thalidomide, based on the remarkable property described above. German paediatricians and geneticists began to see children with gross limb malformations of a most unusual pattern. When two cases were shown at a paediatric meeting in Kassel by Kosenow and Pfeiffer in October 1960, few people present had ever seen similar limb defects. Wiedemann in 1961 described 13 affected infants who had been referred to him over a period of 10 months, and noted that this amounted to an epidemic. He drew attention to a number of associated malformations in these children, including congenital heart disease, microphthalmos and coloboma, intestinal atresia, renal malformations, abnormal pinnae, and facial naevus. In November 1961, Lenz suggested that these deformities resulted from the mothers having taken thalidomide. By a remarkable coincidence, the same suggestion was made at much the same time by McBride in Australia. Confirmation of this suggestion came rapidly from all parts of the British Isles, Kenya, Japan, Sweden, Belgium, Switzerland, Lebanon, Israel, Peru, Canada, Brazil, the Netherlands, and the USA. The drug had been released only for clinical trials in the USA because of concerns following reports from Europe of irreversible peripheral neuritis as a side effect of thalidomide. Consequently there were very few cases. By contrast, it had been on sale over the counter in Germany, and there were consequently more affected children there than anywhere else. In the UK the drug was available on prescription only, but it was used very widely for, among other problems, common symptoms of early pregnancy. Thirty years later, subjects are still coming forward (albeit, in small numbers) with claims that they have birth defects which have (or may have) been caused by thalidomide taken by their mothers during early pregnancy, and that they should therefore be accepted as beneficiaries of whatever forms of financial assistance may be available. In the UK, this is the Thalidomide Trust. Thalidomide caused a wide variety of birth defects, not one of which was unique to that drug. Nevertheless, the nature and pattern of the defects are, in most cases, characteristic enough to be recognisable to an experienced eye. Indeed, many of the present beneficiaries of the Trust have been accepted on the basis of clinical judgements, without direct evidence of thalidomide exposure. As the number of doctors with wide experience of this problem is small (possibly only three in the UK) and will become smaller with the passage of time, and as new claims continue to arise, it seems timely to record, in as much detail as possible, the observations which underlie these clinical judgements. As well as describing the defects and patterns associated with thalidomide, it will be appropriate to discuss 'differential diagnosis', that is, recognisable defects and syndromes which, to a greater or lesser degree, resemble thalidomide defects. Some of these are unlikely to confuse an experienced eye: others can present considerable difficulty. In considering a new claim, attention will obviously be paid to the claimant's date of birth. In the UK, thalidomide was first marketed in April 1958, initially in very small quantities, so it is not to be expected that it would damage anybody born before January 1959 (unless supplies had been obtained from West Germany). Sales in the UK stopped in November 1961. Had consumption stopped at the same time, no 'thalidomide babies' should have been born after August 1962. However, many people still had tablets containing thalidomide in their homes, and either did not hear promptly of its dangers, or did not realise that their tablets contained thalidomide. In fact, children with defects accepted as attributable to thalidomide (though not necessarily with documentary evidence of prescription) continued to be born up to about May 1963, and, very exceptionally, beyond this date. In trying to establish a yardstick or benchmark for bona fide thalidomide defects, it is necessary to start with cases in which there is 5 North Grange Mews, North Grange Road, Leeds LS6 2EW. R W Smithells

The correlation of age of onset with CTG trinucleotide repeat amplification in myotonic dystrophy.

Abstract: The gene for myotonic dystrophy (DM) has recently been isolated and amplification of an unstable CTG trinucleotide repeat, located within the DM gene, has been identified in virtually all patients studied to date. A high proportion of DM families who are studied show a progressively earlier age of onset with succeeding generations and, in the few pedigrees reported so far, an increasing degree of amplification of the CTG repeat has been noted to parallel this trend. It has been implicit in several of the original reports on the nature of the changes in the DM gene that knowledge of CTG amplification status at the DM locus of a person will provide useful information concerning prognosis. However, no studies of genotype-phenotype correlation have been reported and there are no specific data on which to base such counsel. In this paper we report the correlation between the degree of CTG amplification and age of onset in 109 DM gene carriers from 17 families. Included are parent-child and sib-sib comparisons which provide a framework in which to incorporate DNA diagnostic studies when counselling subjects and families at risk for DM.

Hereditary haemorrhagic telangiectasia: a clinical analysis.

Abstract: Data from 98 patients with hereditary haemorrhagic telangiectasia (HHT) are presented. All were symptomatic by 40 years of age and 62% by 16 years. Nose bleeding was the first symptom of disease in 90% of cases with mucocutaneous telangiectases appearing 5 to 20 years later. Complications of HHT are discussed and an age of onset curve given.

Reverse chromosome painting: a method for the rapid analysis of aberrant chromosomes in clinical cytogenetics.

Abstract: We describe a method, termed reverse chromosome painting, which allows the rapid analysis of the content and breakpoints of aberrant chromosomes. The method involves the sorting of small numbers of the aberrant chromosome from short term blood culture preparations or cell lines by using bivariate flow karyotype analysis. The sorted chromosomes are amplified and biotin labelled enzymatically using a degenerate oligonucleotide-primed polymerase chain reaction (DOP-PCR), the product annealed to metaphase spreads from normal subjects, and hybridisation detected using fluorescence in situ hybridisation (FISH). We show the usefulness of this method for routine clinical cytogenetics by the analysis of cases involving an insertion, a deletion, a translocation, and two cases of a chromosome with additional material of unknown origin. The method has particular application for the rapid resolution of the origin of de novo unbalanced chromosome duplications.

Causes of death in patients with Huntington's disease and in unaffected first degree relatives.

Abstract: Causes of death were examined from death certificates for 395 Danish subjects with Huntington's disease (HD) and for 282 unaffected sibs and compared with the causes of death in the general Danish population. For both the HD subjects and the sibs, pneumonia and cardiovascular diseases were the most frequent primary causes of death. Suicides accounted for 5.6% of all deaths among the HD subjects and, unexpectedly, for 5.3% among the sibs, some of whom may have been carriers of the HD gene. Both were significantly higher than the corresponding frequency of 2.7% in the general Danish population, but there was no evidence of differences in the age specific proportions for the HD subjects and for the sibs compared to the general population. Some accidents leading to death in the sibs may have been hidden suicides. The rate of cancer was low for the HD patients, being only 5.3% compared with 31.2% for the sibs. Neurological diseases were reported with an increased frequency in the HD patients compared to the general population, 6% v 1%.

A genetic study of type 2 neurofibromatosis in the United Kingdom. II. Guidelines for genetic counselling

Abstract: The major defining features, age at onset of symptoms, and survival in 150 patients with type 2 neurofibromatosis (NF2) have been studied. The mean age at onset was 21.57 years (n = 110) and no cases presented after 55 years of age. Patients presented with symptoms attributable to vestibular schwannomas (acoustic neuroma), cranial meningiomas, and spinal tumours. In 97 cases studied personally by the authors, skin and eye examination were found to be useful to detect early signs of the condition. Examination of the skin is likely to assist in early diagnosis in at least 10% of cases and examination of the eye for a lens opacity or cataract in at least as many again. There are marked interfamilial differences in disease severity and tumour susceptibility. Vestibular schwannomas are not fully penetrant, but the condition is usually expressed in another way. Alteration to the current diagnostic criteria is advocated to cover the lack of provision for new mutations. A screening protocol is proposed and the effect of disease heterogeneity on management is discussed.

Inheritance of the fragile X syndrome: size of the fragile X premutation is a major determinant of the transition to full mutation.

Abstract: The fragile X mental retardation syndrome is caused by unstable expansion of a CGG repeat Two main types of mutation have been categorised Clinical expression is associated with the presence of the full mutation, while subjects who carry only a premutation do not have mental retardation Premutations have a high risk of transition to full mutation when transmitted by a female We have used direct detection of the mutations to characterise large families who illustrate the wide variation in penetrance which has been observed in different sibships (a feature often called the Sherman paradox) A family originally found to show tight genetic linkage between the factor 9 gene and the fragile X locus was reanalysed, confirming the original genotype assignments and the observed linkage The size of premutations was measured by Southern blotting and by using a PCR based test in 102 carrier mothers and this was correlated with the type of mutation found in their offspring The risk of transition to full mutation was found to be very low for premutations with a size increase (delta) of about 100 bp, increasing up to 100% when the size of premutation was larger than about 200 bp, even after taking into account (at least partially) ascertainment bias These results confirm and extend those reported by Fu et al (1991) and Yu et al (1992) and explain the Sherman paradox(ABSTRACT TRUNCATED AT 250 WORDS)

Confirmation of genetic linkage between atopic IgE responses and chromosome 11q13.

Abstract: Genetic linkage between atopic IgE responses and chromosome 11q13 (D11S97) has been previously reported in a limited number of extended families. Difficulties of phenotyping in the older family members, poor family structure in some families, and genetic heterogeneity were proposed as possible explanations for the variability in lod scores. To test this finding a second linkage study of 64 young nuclear families was undertaken and gave a two point lod score of 3.8 at theta = 0.07 (assuming theta m = theta f). A test of genetic heterogeneity in the nuclear families shows that atopic IgE responses are linked to this locus in 60 to 100% of families (approximate 95% confidence limits).

Estimation of the size of the chromosome 17p11.2 duplication in Charcot-Marie-Tooth neuropathy type 1a (CMT1a). HMSN Collaborative Research Group.

Abstract: We have previously shown a duplication in 17p112 with probe pVAW409R3 (D17S122) in 12 families with hereditary motor and sensory neuropathy type I (HMSN I) or Charcot-Marie-Tooth disease type 1 (CMT1) In this study we aimed to estimate the size of the duplication using additional polymorphic DNA markers located in 17p112-p12 Two other 17p112 markers, pVAW412R3 (D17S125) and pEW401 (D17S61), were found to be duplicated in all HMSN I patients tested Furthermore, all HMSN I patients showed the same duplication junction fragment with probe pVAW409R3 On the genetic map the duplicated markers span a minimal distance of 10 cM while on the physical map they are present in the same NotI restriction fragment of 1150 kb The discrepancy between the genetic and physical map distances suggests that the 17p112 region is extremely prone to recombinational events The high recombination rate may be a contributing factor to the genetic instability of this chromosomal region

Family history and risk of breast cancer.

Abstract: The risk of breast cancer in first degree relatives of patients with breast cancer can be derived from family history and is dependent upon the age at diagnosis in the index patient. For the relatives of index patients older than 55, the relative risk is 1.57, if less than 55 the relative risk is 2.29, and 3.85 if less than 45 (95% confidence limits 0.83 to 2.68, 1.18 to 4.01, and 1.67 to 3.85, respectively). First degree relatives of patients with bilateral breast cancer have a 6.43-fold increase in risk (95% confidence limits 1.32 to 18.77). The genetic contribution to overall lifetime liability to breast cancer in the relatives declines rapidly with increasing age of onset of breast cancer in the index patient from 37% at 20 years to 8% by 45 years. This information can be used in clinical practice for counselling and the establishment of screening programmes.

The cyclops and the mermaid: an epidemiological study of two types of rare malformation.

Abstract: Infants with cyclopia or sirenomelia are born at an approximate rate of 1 in 100,000 births. Eight malformation monitoring systems around the world jointly studied the epidemiology of these rare malformations: 102 infants with cyclopia, 96 with sirenomelia, and one with both conditions were identified among nearly 10.1 million births. Maternal age is somewhat increased for cyclopia, indicating the likely inclusion of some chromosomally abnormal infants which were not identified. About half of the infants are stillborn. There is a female excess among infants with cyclopia. Excess twinning occurred for cyclopia and possibly also for sirenomelia. An analysis of associated malformations indicates the similarity between the two conditions, which is in agreement with recent embryological analysis.

Sensorineural deafness inherited as a tissue specific mitochondrial disorder.

Abstract: We present here a large Israeli-Arab kindred with hereditary deafness. In this family 55 deaf subjects (29M, 26F), who are otherwise healthy, have been identified and traced back five generations to one common female ancestor. The deafness is progressive in nature, usually presenting in infancy and childhood. Audiometry on six deaf and seven unaffected subjects was consistent with severe to profound sensorineural hearing loss. Based on formal family segregation analysis, the inheritance of deafness in this family closely fits the expectation of a two locus model owing to the simultaneous mutation of a mitochondrial gene and an autosomal recessive gene. Thus, this disorder appears to have the unusual features of being an inherited tissue specific mitochondrial disease and apparently requiring the homozygous presence of a nuclear gene for clinical expression. Most importantly, this disorder presents a unique opportunity to investigate the molecular basis of hereditary non-syndromic deafness and normal hearing.

Bilateral retinopathy, aplastic anaemia, and central nervous system abnormalities: a new syndrome?

Abstract: A male infant was found to have bilateral exudative retinopathy at 6 months of age. A month later severe aplastic anaemia was diagnosed, eventually leading to the infant's death. Additional features of this seemingly new syndrome were intrauterine growth retardation, fine sparse hair, fine reticulate skin pigmentation, ataxia because of cerebellar hypoplasia, cerebral calcifications, extensor hypertonia, and progressive psychomotor retardation.

Distal 8p deletion (8p23.1----8pter): a common deletion?

Abstract: The clinical manifestations and cytogenetic details of five patients with a de novo deletion of the short arm of chromosome 8, del(8)(p23), are described. Of the four surviving children all had mild mental retardation and subtle facial anomalies; three of the five had cardiac abnormalities. The clinical features seen in these patients are compared with those of three previous single case reports with del(8)(p23), and with patients described as having the '8p-' syndrome associated with del(8)(p21). The findings in these patients suggest that major congenital anomalies, especially congenital heart defects, are frequent even in small distal 8p deletions, but facial dysmorphism may be subtle and mental retardation less severe than in those with deletions associated with more proximal breakpoints. The five patients were detected within a four year period, suggesting that this deletion syndrome is relatively frequent. The possible mechanisms for the formation of terminal deletions are discussed.

Effects of genetic screening on perceptions of health: a pilot study.

Abstract: The aim of the current study was to determine how carriers of a recessive gene, which confers no risk to their own health, perceive their health, relative to non-carriers. Perceptions of health in three groups were compared: those screened and found to carry the gene for Tay-Sachs disease, those screened and not found to carry the gene for Tay-Sachs disease, and a community based sample who, it was presumed, had not undergone screening. The groups did not differ in their perceptions of their current health or their past health. Carriers, however, viewed their future health with less optimism than the other two groups. The causes and consequences of this altered perception need to be explored in future studies. With the advent of population based screening for cystic fibrosis carrier status, these results highlight the importance of assessing in detail people's experiences of screening before the introduction of any mass genetic screening programmes.

The OEIS complex (omphalocele-exstrophy-imperforate anus-spinal defects): recurrence in sibs.

Abstract: The OEIS complex comprises a combination of defects including omphalocele, exstrophy of the cloaca, imperforate anus, and spinal defects. It may represent the most severe manifestation of a spectrum of birth defects, the exstrophy-epispadias sequence. The OEIS complex affects 1 in 200,000 to 400,000 pregnancies and is of unknown cause. The purpose of the current report is to document the occurrence of OEIS in sibs from separate pregnancies and suggest that some cases may have a genetic basis.

Analysis of quantitative PCR for the diagnosis of deletion and duplication carriers in the dystrophin gene.

Abstract: A direct, non-radioactive method of quantitative PCR amplification has been investigated for the diagnosis of deletion and duplication carriers in the dystrophin gene. The simultaneous amplification of two loci, or several loci using multiplex PCR, allows for the direct comparison of relative amounts of products from normal homozygous loci and potentially heterozygous deleted/duplicated loci. Sufficient cycles of PCR are performed to enable visual analysis or densitometric quantification of products on ethidium bromide stained gels. The method has been verified in blind trials performed on known genotypes and by showing that under the conditions used the assay remains within the exponential phase of amplification.

Confirmation of an association between RFLPs at the transforming growth factor-alpha locus and non-syndromic cleft lip and palate.

Abstract: Three RFLPs at the TGFA locus were studied in 60 unrelated British Caucasian subjects with non-syndromic cleft lip/palate and 60 controls. A highly significant association between the TaqI RFLP and the occurrence of clefting was found (chi 2 = 15.04, p = less than 0.001). No significant association was found with the two other RFLPs studied (BamHI and RsaI). Haplotypes derived from the three RFLPs at the TGFA locus also showed an over-representation of the C2A2B2 haplotype in cases compared to controls. Analyses of genotypes according to type of cleft and the presence or absence of a family history of clefting were also carried out. These results provide further support for the role of TGFA as a gene of major effect in the development of orofacial clefts in humans.

The mapping of a gene for craniosynostosis: evidence for linkage of the Saethre-Chotzen syndrome to distal chromosome 7p.

Abstract: Craniosynostosis or premature closure of the cranial sutures is a common abnormality occurring in about 1 in 2500 children. There is evidence of mendelian inheritance in some 20% of cases. Published reports of patients with structural alterations of the short arm of chromosome 7 have suggested that two or more genes for craniosynostosis may be situated in this region. The Saethre-Chotzen syndrome (acrocephalosyndactyly type III) is one of the most common autosomal dominant craniosynostosis syndromes. Results of molecular genetic linkage studies provide evidence for localisation of the gene responsible to distal chromosome 7p.

Comparison of the myotonic dystrophy associated CTG repeat in European and Japanese populations.

Abstract: Gene amplification using polymerase chain reaction (PCR) was carried out on DNA samples from a total of 92 normal subjects and 52 subjects with myotonic dystrophy (DM) from European and Japanese populations, to determine the copy number of the CTG repeat associated with DM for each group. In the two populations, the number of repeats on normal chromosomes only were compared, as CTG copy number on DM chromosomes was difficult to determine by PCR alone. In this study, normal chromosomes were found which had as many as 35 copies of the repeat, which is larger than the normal range reported previously but still does not overlap with the repeat number associated with DM pathology, which is at least 50 copies. Using data from normal chromosomes from unrelated subjects, the frequencies of five, 11, and 13 copies of the CTG repeat were found to be significantly different between the two populations, with five and 11 copies more commonly seen in the European population and 13 copies in the Japanese population. This difference may be the result of natural divergence of the normal chromosomes between the population groups.

Cartilage-hair hypoplasia in Finland: epidemiological and genetic aspects of 107 patients.

Abstract: Cartilage-hair hypoplasia (CHH) is an autosomal recessive form of metaphyseal chondrodysplasia characterised by short limbed short stature, hypoplastic hair growth, and impaired cell mediated immunity and erythrocyte production. The syndrome is exceptionally prevalent among the Finns and among the Old Order Amish in the United States; sporadic cases have been reported from other countries. An epidemiological and genetic study of CHH in Finland showed 107 patients, 46 males and 61 females, in 85 families. Eighteen of them had died, seven before the age of 1 year. The living patients ranged in age from 1 to 51 years, median 21 years. The incidence was estimated to be 1:23,000 live births. Consanguinity was found in two families and interfamilial relationships in 20 families. Geographical distribution of the birth places of the patients and their great grandparents showed accumulation in a small area in western Finland and regional clusters were seen in other parts of the country as well. The result of the segregation analysis was in accordance with recessive inheritance with reduced penetrance.

Sex reversal in a child with a 46,X,Yp+ karyotype: support for the existence of a gene(s), located in distal Xp, involved in testis formation.

Abstract: We report on a sex reversed Japanese child with a 46,X,Yp+ karyotype, minor dysmorphic features, and no testicular development. The Yp+ chromosome was derived by translocation of an Xp fragment (Xp21-Xp22.3) to Yp11.3. This has resulted in deletion of distal part of the Y chromosome pseudoautosomal region (DXYS15-telomere) and duplication of the X specific region (DXS84-PABX) and proximal part of the pseudoautosomal region (MIC2-DXYS17). No deletion of the Y specific region was detected nor was any mutation found in SRY. Cytogenetic analysis suggests that the proximal part of the Xp fragment is the most distal part of the short arm of the Yp+ chromosome (Xp21----Xp 22.3::Yp11.3----Yqter). No chromosomal mosaicism was detected. These results are similar to previous reports of sex reversal in four subjects with a 46,Y,Xp+ karyotype. We conclude that the sex reversal is a direct, or indirect, consequence of having two active copies of the distal part of Xp and may indicate the presence of a gene(s) which acts in the testis determination or differentiation pathway.

A non-isotopic in situ hybridisation study of the chromosomal origin of 15 supernumerary marker chromosomes in man.

Abstract: Fifteen patients presenting with mosaic or non-mosaic karyotypes containing a distamycin-DAPI negative de novo or familial supernumerary marker chromosome were studied with non-isotopic in situ hybridisation using a library of alphoid centromere specific and satellite II/III probes. The in situ hybridisation studies showed that seven markers were derived from satellited autosomes (three chromosome 13/21, two chromosome 14, two chromosome 22), six from non-satellited autosomes (two chromosome 4, one chromosome 12, one chromosome 16, two chromosome 19), and one from the Y chromosome. One non-mosaic marker was negative for all the alphoid and satellite II/III probes used.