Disruption of the ProSAP2 gene in a t(12;22)(q24.1;q13.3) is associated with the 22q13.3 deletion syndrome.

The terminal 22q13.3 deletion syndrome is characterized by severe expressive-language delay, mild mental retardation, hypotonia, joint laxity, dolichocephaly, and minor facial dysmorphisms. We identified a child with all the features of 22q13.3 deletion syndrome. The patient's karyotype showed a de novo balanced translocation between chromosomes 12 and 22, with the breakpoint in the 22q13.3 critical region of the 22q distal deletion syndrome [46, XY, t(12;22)(q24.1;q13.3)]. FISH investigations revealed that the translocation was reciprocal, with the chromosome 22 breakpoint within the 22q subtelomeric cosmid 106G1220 and the chromosome 12q breakpoint near STS D12S317. Using Southern blot analysis and inverse PCR, we located the chromosome 12 breakpoint in an intron of the FLJ10659 gene and located the chromosome 22 breakpoint within exon 21 of the human homologue of the ProSAP2 gene. Short homologous sequences (5-bp, CTG[C/A]C) were found at the breakpoint on both derivative chromosomes. The translocation does not lead to the loss of any portion of DNA. Northern blot analysis of human tissues, using the rat ProSAP2 cDNA, showed that full-length transcripts were found only in the cerebral cortex and the cerebellum. The FLJ10659 gene is expressed in various tissues and does not show tissue-specific isoforms. The finding that ProSAP2 is included in the critical region of the 22q deletion syndrome and that our proband displays all signs and symptoms of the syndrome suggests that ProSAP2 haploinsufficiency is the cause of the 22q13.3 deletion syndrome. ProSAP2 is a good candidate for this syndrome, because it is preferentially expressed in the cerebral cortex and the cerebellum and encodes a scaffold protein involved in the postsynaptic density of excitatory synapses.

Reduced expression of the BRCA1 gene and increased chromosomal instability in MCF-7 cell line.

Using clonal cell cultures, a significant increase in chromosomal aberrations (aneuplolidy, dicentrics and chromatid breaks) were observed in MCF-7 cells compared with HeLa. BRCA1 expression was lower in MCF-7 cells than in HeLa cells. Since BRCA1 is known to play a role in the maintenance of chromosomal integrity, the increase in chromosomal aberrations in MCF-7 clones suggests that downregulation of BRCA1 expression could be one of the possible mechanisms for increased chromosomal instability in this cell line.

Meiotic segregation analysis by FISH investigation of spermatozoa of a 46,Y,der(X),t(X;Y)(qter-->p22::q11-->qter) carrier.

Chromosome analysis performed on a 30-year-old man revealed a 46,Y,der(X),t(X;Y)(qter-->p22::q11-->qter) karyotype, confirmed by fluorescence in situ hybridization (FISH). The man was of short stature, and no mental retardation was noticed; genitalia and testes were normal, as were the patient's FSH, LH, and testosterone blood levels. Sperm analysis showed azoospermia at the time of the first sampling and severe oligozoospermia, with 125,000 spermatozoa/milliliter, at the time of the second sampling. The sperm gonosomal complement of this patient and of a 46,XY donor were analyzed using multicolor FISH with X- and Y-chromosome probes. Our results clearly indicated that germinal cells carrying the translocation are able to complete the meiotic process by producing spermatozoa compatible with normal embryonic development, with more than 80% of the spermatozoa having either a Y chromosome or a der(X); however, a high level of spermatozoa with gonosomal disomies was observed. We also found a significant increase in the frequency of autosomal disomies in the carrier, which would suggest an interchromosomal effect. All previously reported cases in adult males were associated with azoospermia; testicular histological studies, performed in patients carrying the same X;Y translocation, showed spermatogenetic arrest after pachytene. To our knowledge, this is the first molecular analysis of the gonosomal complement in spermatozoa of men with a t(X;Y)(qter-->p22::q11-->qter).

[Ring chromosome 20: an epileptic channel disorder?]. / Cromosoma 20 en anillo: una canalopatía epiléptica?

INTRODUCTION: The ring-shaped chromosome 20 (r20) syndrome is an infrequent chromosopathy which is associated with epileptic seizures, behaviour disorders and mental retardation. It results from the fusion of the two arms of the chromosome with deletion of the telomeric portions. CLINICAL CASE: We present a case of r20, review published cases and describe the clinical and neurophysiological characteristics. CONCLUSIONS: The r20 syndrome is the third type of epilepsy known to be of genetic basis related to chromosome 20. It has clinical and neurophysiological characteristics which give it a distinctive character and are easily identified. The fact that on locus 20q13 (telomeric portion of the long arm of chromosome 20) two genes related to epileptic channelopathies (CHRNA4 and KCNQ2) have been described, suggest the hypothesis that the subjacent deletion in cases of r20 syndrome affect one of these genes and explains the epileptogenicity. We consider this hypothesis and the possibility that r20 syndrome may be an epileptic channelopathy.

Ductus venosus blood flow in chromosomally abnormal fetuses at 11 to 14 weeks of gestation.

This article reviews the role of ductus venosus (DV) Doppler evaluation in the screening for aneuploidies at 11 to 14 weeks of gestation. Ductus venosus flow velocity waveforms were obtained immediately before fetal karyotyping in 515 consecutive singleton pregnancies at 11 to 14 weeks. We found 446 normal and 69 abnormal karyotypes. Abnormal flow in the DV was the only significant difference between both groups. Sensitivity of the test was 80% and false positive rate < 1%. Normal karyotype but abnormal flow in the DV was recorded in 17 of 446 cases, 7 presenting a cardiac defect. Increased nuchal translucency seems to be related, in most cases, to early cardiac dysfunction. Chromosomal abnormalities and/or cardiac defects were often found in cases with increased nuchal translucency and abnormal flow in the DV. We suggest that the evaluation of ductal flow between 11 to 14 weeks of gestation should be adopted as a second level screening test to reduce invasive test rate derived from the exclusive measurement of nuchal translucency.

The syndrome of inv dup (15): clinical, electroencephalographic, and imaging findings.

The clinical and laboratory data of four pediatric patients and one adult patient with inverted duplication (inv dup) (15) are reported. The most evident findings were dysmorphic features with frontal bossing; genital abnormalities, such as macropenis or hypospadias; mental retardation; autistic behavior; and seizures. Two additional adults with inv dup (15) from other institutions were also diagnosed in our laboratory. Seizures and mental retardation were the reasons for their referral. The clinical picture of inv dup (15) seems to be quite variable since the phenotype can also be normal. However, karyotyping and fluorescent in-situ hybridization, focused in particular on chromosome 15, appear to be indicated in patients with dysmorphic phenotypes, such as the one present in our patients, and in subjects with early-onset seizures and psychomotor retardation with autistic features.

Parental origin and phenotype of triploidy in spontaneous abortions: predominance of diandry and association with the partial hydatidiform mole.

The origin of human triploidy is controversial. Early cytogenetic studies found the majority of cases to be paternal in origin; however, recent molecular analyses have challenged these findings, suggesting that digynic triploidy is the most common source of triploidy. To resolve this dispute, we examined 91 cases of human triploid spontaneous abortions to (1) determine the mechanism of origin of the additional haploid set, and (2) assess the effect of origin on the phenotype of the conceptus. Our results indicate that the majority of cases were diandric in origin because of dispermy, whereas the maternally-derived cases mainly originated through errors in meiosis II. Furthermore, our results indicate a complex relationship between phenotype and parental origin: paternally-derived cases predominate among "typical" spontaneous abortions, whereas maternally-derived cases are associated with either early embryonic demise or with relatively late demise involving a well-formed fetus. As the cytogenetic studies relied on analyses of the former type of material and the molecular studies on the latter sources, the discrepancies between the data sets are explained by differences in ascertainment. In studies correlating the origin of the extra haploid set with histological phenotype, we observed an association between paternal-but not maternal-triploidy and the development of partial hydatidiform moles. However, only a proportion of paternally derived cases developed a partial molar phenotype, indicating that the mere presence of two paternal genomes is not sufficient for molar development.

Molecular cytogenetic analysis of eight inversion duplications of human chromosome 13q that each contain a neocentromere.

Neocentromeres are fully functional centromeres that have arisen in previously noncentromeric chromosomal locations on rearranged chromosomes. The formation of neocentromeres results in the mitotic stability of chromosomal fragments that do not contain endogenous centromeres and that would normally be lost. Here we describe a unique collection of eight independent patient-derived cell lines, each of which contains a neocentromere on a supernumerary inversion duplication of a portion of human chromosome 13q. Findings in these patients reveal insight into the clinical manifestations associated with polysomy for portions of chromosome 13q. The results of FISH and immunofluorescent analysis of the neocentromeres in these chromosomes confirm the lack of alpha-satellite DNA and the presence of CENtromere proteins (CENP)-C, -E, and hMAD2. The positions of the inversion breakpoints in these chromosomes have been placed onto the physical map of chromosome 13, by means of FISH mapping with cosmid probes. These cell lines define, within chromosome 13q, at least three distinct locations where neocentromeres have formed, with five independent neocentromeres in band 13q32, two in band 13q21, and one in band 13q31. The results of examination of the set of 40 neocentromere-containing chromosomes that have thus far been described, including the 8 neocentromere-containing chromosomes from chromosome 13q that are described in the present study, suggest that chromosome 13q has an increased propensity for neocentromere formation, relative to some other human chromosomes. These neocentromeres will provide the means for testing hypotheses about sequence requirements for human centromere formation.

Health supervision and anticipatory guidance of individuals with Wolf-Hirschhorn syndrome.

Wolf-Hirschhorn syndrome (WHS) is a well-known malformation syndrome due to microdeletion of the short arm of chromosome 4 (4p-). Almost 120 cases have been reported so far, yet there is still limited information on its natural history. It is generally thought that these children have severe developmental disabilities and tend to be mere survivors devoid of personality. It is evident to us [Battaglia et al., 1999a, 1999b], however, that individuals with WHS are capable of greater psychomotor development than previously suggested [Guthrie et al., 1971]. Thus, it is even more important to establish guidelines for health supervision and anticipatory guidance of such patients. This would help professionals and families in developing the most appropriate individualized plan for each child, in order to allow the maximum achievement possible. In the present article we propose guidelines for health supervision and anticipatory guidance of individuals with WHS. These guidelines derive from our experience with the natural history of several children, adolescents, and adults with WHS, gained through the literature, personal observation, and contacts with the national support groups in North America and Italy.

Clinical correlation to genetic variations of hereditary multiple exostosis.

Hereditary multiple exostosis (HME) is an autosomal dominant disorder leading to polyostotic periphyseal osteochondroma formation. These tumorous lesions can cause growth disturbances, painful local symptoms, restriction of joint motion, and neurologic compromise. Malignant transformation has been noted. The reports of the incidence of these complications vary widely in the literature. Recently, genetic lineage mapping disclosed three locations for HME with loci on chromosomes 8, 11, and 19. It is possible that these three genotypes may result in different phenotypic expression of HME and thus explain the variable manifestations of the disease. This study attempts to record the clinical findings of HME patients who have undergone genetic mapping to determine whether varying clinical patterns may exist for each genotype of HME.

First trimester umbilical venous Doppler sonography in chromosomally normal and abnormal fetuses.

In 342 singleton pregnancies in which the patients were undergoing chorionic villus sampling at 11 to 14 weeks of gestation, color Doppler sonography was used to obtain waveforms from the umbilical cord. The prevalence of pulsatile flow in the umbilical vein was higher in the 18 fetuses with trisomy 18 or 13 (16 of 18; 88.9%) than in the 18 fetuses with trisomy 21 (6 of 18; 33.3%) or the 302 chromosomally normal fetuses (73 of 302; 24.2%).

Investigation of nonimmune hydrops fetalis: multidisciplinary studies are necessary for diagnosis--review of 94 cases.

This review of 94 cases of nonimmune hydrops fetalis (NIHF) over a 10-year period was undertaken to evaluate the frequency of this pathology among fetal and infant deaths and to determine the most common likely etiologies in a northeastern region of France. NIHF represented 6% of the fetal deaths examined in our laboratory. The combination of findings from morphologic examination of the placenta and fetus with the results of microbiological and cytogenetic investigations (conventional cytogenetic study, fluorescent in situ hybridization [FISH], or DNA ploidy image analysis) led to an etiologic diagnosis for NIHF in two-thirds of the cases and suggested a diagnosis in an additional 23% of cases. The most common causes of NIHF were chromosome abnormalities (33%), infections (16%), and cardiac pathology (13.8%). The detection of a cause for NIHF is important for genetic counseling and management of subsequent pregnancies. Our experience suggests that a diagnosis is possible in a large majority of NIHF when obstetricians and pathologists carefully coordinate the management of prenatal and postnatal investigations and when new techniques, such as molecular biology and DNA quantification, are used.

Subfertile men with constitutive chromosome abnormalities do not necessarily refrain from intracytoplasmic sperm injection treatment: a follow-up study on 75 Dutch patients.

A follow-up study was performed to investigate the impact of the detection of a chromosome abnormality in infertile men who are candidates for intracytoplasmic sperm injection (ICSI) treatment. In this collaborative study between clinical genetics centres and fertility clinics in the Netherlands, 75 ICSI couples of which the male partners had a chromosome abnormality were included. All couples were extensively counselled on the risk of having a chromosomally unbalanced child. Forty-two out of 75 couples chose to proceed with the ICSI treatment. So far, treatment has resulted in a pregnancy in 11 cases. Four of them opted to have invasive prenatal diagnosis. Despite the genetic risks related to a chromosome abnormality in infertile men, a small majority (56%) of the couples did not refrain from the ICSI treatment.

Quality of life in Turner syndrome is related to chromosomal constitution: implications for genetic counselling and management.

Issues of self-appraisal, friendships and academic attainments are uniquely salient for all adolescents. For girls with Turner syndrome, social problems and learning difficulties often become more serious at this time, yet may be unacknowledged by those responsible for paediatric care because their focus is on growth and sexual maturation. Data on the social and educational adjustment of 110 45,X (monosomic) females aged between 6 and 25 years is presented. Detailed information on the patients' precise karyotype was used to demonstrate systematic differences in adjustment between those whose single X chromosome was maternally derived and those in whom it was paternal. Implications for educational support and parental guidance are discussed.

Ring chromosome 14 complicated with complex partial seizures and hypoplastic corpus callosum.

A Japanese male with mosaicism of ring chromosome 14 and chromosome 14 monosomy is described. He demonstrated the characteristic morphologic features of ring chromosome 14, in addition to mental retardation and epileptic seizures. Clusters of complex partial seizures, one of which originated in the left frontocentral region on electroencephalographic monitoring, were evident. His seizures responded to phenobarbital, and his mental and motor development was only mildly retarded. Magnetic resonance imaging revealed a hypoplastic corpus callosum, previously unknown in association with this syndrome.

Genetic diseases with rheumatic manifestations in children.

Many nonrheumatic diseases of childhood present with musculoskeletal abnormalities. A significant proportion of these disorders have a genetic basis, many involving defects in structural proteins of the connective tissue. Chief among these are collagen mutations resulting in spondyloepiphyseal dysplasias and Ehlers-Danlos syndrome, as well as fibrillin defects associated with Marfan's syndrome. A variety of other chromosomal anomalies are associated with musculoskeletal abnormalities, and may result from as yet unidentified connective tissue defects. In addition, metabolic diseases may result in findings of hyper- or hypomobility, or carpal tunnel syndrome. Helpful clinical clues to identify nonrheumatologic musculoskeletal disease, as well as recent advances in our understanding of the genetic basis of several of these disorders, are reviewed here.