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Interstitial deletions involving 14q13.1q21.1 are rare. In the literature at least 10 cases involving this region have been described and all patients showed a phenotype within the holoprosencephaly (HPE) spectrum. Previous studies suggested the HPE8 region as a candidate locus for HPE at 14q13. We report an adolescent with a 14q13.1q21.1 deletion encompassing the HPE8 region associated with intellectual disability (ID), bilateral microphthalmia, and coloboma, without cerebral anomalies typical of HPE. Except for ocular defects (i.e., microphthalmia, coloboma) consistent with HPE-type anomalies, the minor facial dysmorphia was not suggestive for HPE and the absence of cerebral anomalies should rule out this diagnosis. The deletion of the potential HPE candidate genes NPAS3, EAPP, SNX6, and TULIP1, raises doubts about their pathologic role in determining HPE. It is likely that deletions of HPE genes are not sufficient to cause HPE, and that multiple genetic, chromosomal, and environmental factors interact to determine the variable clinical expression of HPE. This is the first case of a 14q deletion encompassing the HPE8 locus with the only features consistent with HPE-type anomalies affecting the ocular system (i.e., microphthalmia, coloboma), and without cerebral anomalies specific for HPE. The inclusion of potential HPE candidate genes in the deletion raises the question whether this patient is affected by a less severe form of HPE (HPE microform), or whether he has a new ID/MCA deletion syndrome.

We report two individuals with developmental delay and dysmorphic features, in whom array-based comparative genomic hybridization (array CGH) led to the identification of a 2p15p16.1 de novo deletion. In the first patient (Patient 1) a familial deletion of 6q12, inherited from her father, was also detected. In the second patient (Patient 2) in addition to the 2p15p16.1 microdeletion a de novo deletion in Xq28 was detected. Both individuals shared dysmorphic features and developmental delay with the six reported patients with a 2p15p16.1 microdeletion described in medical literature. Conclusion: in the first patient a 642 kb 2p16.1 deletion (from 60.604 to 61.246 Mb), and a 930 kb 6q12 familial deletion, was detected and in the second a 2.5 Mb 2p15p16.1 deletion (from 60.258 to 62.763 Mb), with a Xq28 deletion, was discovered. The common dysmorphic features and neurodevelopmental delay found in these patients are in agreement with the clinical phenotype of a microdeletion syndrome involving 2p15p16.1. Our data confirm the hypothesis suggesting that 2p15p16.1 deletion is a contiguous gene syndrome.

Chromosome 22, particularly the q11.2 sub-band, has long been recognized as responsible for multiple congenital anomaly disorders. In particular, its susceptibility to subtle microdeletions or, more rarely, microduplications has been attributed to the presence of several low-copy repeats spanning the region as mediators of nonallelic homologous recombination that result in 22q11.2 rearrangements. While recent data suggest that the frequency of 22q11.2 microduplications could be approximately half of all deletions, now only 50 unrelated cases have been reported thus far. However, it is reasonable to suppose that microduplications of 22q11.2 may be largely undetected as a result of a less-distinct, unpredictable, and/or milder phenotype ranging from normal to mild learning difficulties with/without other multiple defects. We report on the first case of myoclonic epilepsy in a 10-year-old boy carrying a de novo 22q11.2 microduplication. Emphasizing that this rare association could be one of the many unrecognized aspects underlying this new emerging syndrome and once again its clinical heterogeneity, we suggest further investigation of the function of the RAB36 gene and propose that in the screening of individuals with developmental delay, minor behavioral problems mild dysmorphology and seizures, investigation of 22q11.2 microduplications should be considered.

Objective We surveyed the datasheets of 29 laboratories concerning prenatal diagnosis of de novo apparently balanced chromosome rearrangements to assess the involvement of specific chromosomes, the breakpoints distribution and the impact on the pregnancy outcome. Method By means of a questionnaire, data on 269.371 analyses performed from 1983 to 2006 on amniotic fluid, chorionic villus and fetal blood samples were collected. Results A total of 246 balanced anomalies were detected at frequencies of 72% for reciprocal translocations, 18% for Robertsonian translocations, 7% for inversions and 3% for complex chromosome rearrangements. The total frequencies of balanced rearrangements were 0.09%, 0.08% and 0.05% on amniotic fluid, chorionic villus and fetal blood samples. Conclusion A preferential involvement of chromosomes 22, 7, 21, 3, 9 and 11 and a less involvement of chromosomes X, 19, 12, 6 and 1 was observed. A nonrandom distribution of the breakpoints across chromosomes was noticed. Association in the location of recurrent breakpoints and fragile sites was observed for chromosomes 11, 7, 10 and 22, while it was not recorded for chromosome 3. The rate of pregnancy termination was about 20%, with frequencies decreasing from complex chromosomal rearrangements (33%), reciprocal translocations (24%) to inversions (11%) and Robertsonian translocations (3%). Copyright © 2009 John Wiley & Sons, Ltd.

We report a modified method for the rapid detection of aneuploidies directly on human uncultured amniocytes that simplifies and shortens the entire experimental procedure, yielding signals which allow correct diagnosis of trisomy 21 in 97% of cases. The improvement is based on two points : 1) use of cosmid pockets specific for the Down's syndrome minimal region as FISH probes, and 2) a modified protocol for the fixation and preparation of amniocytes.

As the knowledge of parental origin and meiotic stage of nondisjunction is the prerequisite to evaluation of the possible etiological factors in trisomy 21, we have examined 343 families with at least one Down syndrome child. Of these, 322 were primary trisomies, including 24 mosaics, and 21 were structural rearrangements. This study was carried out by analysing chromosome 21 cytogenetic heteromorphisms and molecular RFLPs. In our study first maternal meiotic nondisjunction (75.3%) is the most common mechanism leading to primary trisomies. In the 24 mosaic cases, the most frequent error occurred at the first meiotic division (83%). The origin of structural rearrangements was maternal in 15 of 21 cases. Trisomy 21q21q was due to an isochromosome, and not to a translocation.

To test the hypothesis that meiotic nondisjunction may be caused by reduced chiasma frequency, hence recombination, we investigated 60 families with a trisomic child affected with Down syndrome (DS). We analyzed cytogenetic heteromorphisms (CH) and a number of restriction fragment length polymorphisms spanning regions 11.1 through 22.3 of 21q in both parents, in the DS child and, when available (21 families), in a normal sib. The parental origin and meiotic stage of nondisjunction were determined by combining the results of both CH and RFLP analysis. Crossover events were detected as switches in the parental haplotype expected in both DS and normal sibs. Available recombination frequency data were used to calculate the expected number of crossover events in nondisjoined and in normally segregating chromosomes, given the allele combination present in each family. The observed number of crossover events in normal meioses and in second-division nondisjunctions were consistent with the calculated figures. However, a significant reduction in the observed number of crossover events was found in nondisjoined chromosomes derived from errors in the first meiotic division and, in particular, in the proximal portion of 21q.

The existence of latent centromeres has been proposed as a possible explanation for the ectopic emergence of neocentromeres in humans. This hypothesis predicts an association between the position of neocentromeres and the position of ancient centromeres inactivated during karyotypic evolution. Human chromosomal region 15q24-26 is one of several hotspots where multiple cases of neocentromere emergence have been reported, and it harbors a high density of chromosome-specific duplicons, rearrangements of which have been implicated as a susceptibility factor for panic and phobic disorders with joint laxity. We investigated the evolutionary history of this region in primates and found that it contains the site of an ancestral centromere which became inactivated about 25 million years ago, after great apes/Old World monkeys diverged. This inactivation has followed a noncentromeric chromosomal fission of an ancestral chromosome which gave rise to phylogenetic chromosomes XIV and XV in human and great apes. Detailed mapping of the ancient centromere and two neocentromeres in 15q24-26 has established that the neocentromere domains map approximately 8 Mb proximal and 1.5 Mb distal of the ancestral centromeric region, but that all three map within 500 kb of duplicons, copies of which flank the centromere in Old World Monkey species. This suggests that the association between neocentromere and ancestral centromere position on this chromosome may be due to the persistence of recombinogenic duplications accrued within the ancient pericentromere, rather than the retention of “centromere-competent” sequences per se. The high frequency of neocentromere emergence in the 15q24-26 region and the high density of clinically important duplicons are, therefore, understandable in the light of the evolutionary history of this region.

Here we describe a foetus with intrauterine growth retardation (IUGR), cerebral malformations and a 46,XY,der(1),t(1;6)(p36.3;q25.2) karyotype owing to a familial cryptic translocation segregating in three generations. A balanced translocation was present in the mother, the maternal uncle, the aunt and the grandmother. A female first cousin with dysmorphisms, hydrocephalus and mental retardation was a carrier of a partial trisomy 1p and a partial monosomy 6q. Multiple miscarriages were present in the family pedigree. Parents of the foetus had three other pregnancies: a male with a balanced translocation, and two foetuses with 1p36.3-pter monosomy and 6q25.2-qter trisomy.

We report on a 2-year-old girl with a de novo mutation [45,XX,der(5),t(5;14) (pter;q11.2)] with corpus callosum agenesis, multiple cysts (cerebral and cardiac), subtle eye abnormalities, and at least two different skin defects, strongly indicating neuroectodermal involvement, as a neuromuscular choristoma (hamartoma) and an eccrine hamartoma. Fluorescent in situ hybridization with different single-locus probes showed that chromosome 5 has a very small deletion, confined to a region composed of repetitive sequences. By contrast, the long (q) arm of chromosome 14 seems to be much more involved in the rearrangement, with partial monosomy spanning from the centromere to the D14S72 and D14S261 loci. The extent of the deleted region of chromosome 14 is approximately 16 cM. To our knowledge, this is the smallest reported deletion involving the chromosome 14q11.2 region to be associated with a developmental disorder resulting in variable eye, skin, and brain anomalies. We suggest that a new syndrome, mimicking in some ways the MLS phenotype, is caused by a deletion in the chromosome 14q11.2 region.

Only a few reports on supernumerary r(1) chromosomes associated with a clinical phenotype have been published. We describe two unrelated patients with congenital malformations and developmental delay who were found to have a de novo supernumerary r(1) in 50% (Case 1) and 80% (Case 2) of the examined cells. Conventional cytogenetic techniques (QFQ, CBG, and DA-DAPI), complemented by fluorescence in situ hybridization studies using alpha satellite probes, showed that both small marker chromosomes (SMCs) primarily consisted of the centromere and heterochromatin of chromosome 1, a conclusion that was also supported by chromosome 1 painting. In an attempt to establish phenotype-genotype correlations, a further investigation was performed using YACs mapped to the chromosome 1 pericentromeric region. A fluorescent signal was evident after hybridization with Y934G9 (1q21) in Case 1 and Y959C4 (1p11.1-12) in Case 2. Partial trisomy of unique sequences flanking pericentromeric sequences is shown to underlie the clinical phenotype in both patients. This evidence should be taken into account when SMCs are ascertained, particularly in prenatal diagnosis.

Subtelomeric terminal 6p deletion has been recognized as a clinically identifiable syndrome including facial dysmorphism, malformation of the anterior eye chamber, hearing loss, heart defect and developmental delay. Genotype –phenotype correlations of previously published patients have been strongly suggested anterior eye segment anomalies as one of major malformation of the syndrome if the critical 6p25 region containing the FOXC 1 gene. In addition it has been hypothesized the presence in this region of one or more genes involved in hearing loss. We report on a case of terminal 6p deletion in a 47, XYY karyotype. Further characterization of the deletion with array comparative genome hybridization revealed also a cryptic microduplication on chromosome 19. The patient showed dysmorfic features, neuromotor retardation and profound language impairment, in absence of hearing loss and structural eye anomalies. As far as we know this is the first reported terminal 6p25.1 deletion case without eye dysgenesis precisely characterized by array-CGH. Our result could confirm that no genes in this region could be considered as an obvious candidate for hearing loss and demonstrate the need for further elucidation about function of the genes involved in eye developmental processes.

Current literature provides more than 30 patients with interstitial deletions in chromosome 2q31q33. Only a few of them were studied using high-resolution methods. Among these, two patients had presented with a particular consistence of some clinical features associated to a deletion between bands q31.2 and q32.3 of chromosome 2. This clinical pattern, labeled as "2q31.2q32.3 syndrome," consists of multiple dysmorphisms, developmental delay, mental retardation and behavioural disturbances. We report an adult female patient with a 4.4 Mb deletion in the 2q31.2q32.3 region, showing facial dysmorphisms, mental retardation and absence of speech. The region overlaps with the deletion found in the two cases previously reported. The critical region points to a few genes, namely NEUROD1, ZNF804A, PDE1A, and ITGA4, which are good candidates to explain the cognitive and behavioural phenotype, as well as the severe speech impairment associated with the 2q31.2q32.3 deletion.

Background: The Italian external quality assessment scheme in classical cytogenetics was started in 2001 as an activity funded by the National Health System and coordinated by the Italian Public Institute of Health. Objectives: The aim of our work is to present data from the first 4 years of activity, 2001–2004. Methods: Italian cytogenetics public laboratories were enrolled on a voluntary basis, and this nationwide program covered prenatal, postnatal and oncological diagnosis. The scheme is annual and retrospective; a panel of experts reviewed the quality of images and reports in order to assess technical, analytical and interpretative performance. Results: Over the 4-year period, the number of participating laboratories increased: from 36 in 2001, 46 in 2002, 49 in 2003 to 51 in 2004. The overall technical performance was satisfactory. Inadequacy or lack of information in reporting was the most frequent analytical inaccuracy identified in all parts of the scheme. However, the percentage of complete reports increased significantly during the period: by 36% in postnatal diagnosis between 2001 and 2004 (p < 0.001) and by 42% in oncological diagnosis between 2002 and 2004 (p = 0.003). Conclusions: Our experience reveals that participation in external quality assessment programs has significant advantages, helping to standardize and to assure quality in cytogenetic testing.

Vertebrate telomeres consist of tandem repeats of the TTAGGG sequence that cap the ends of chromosomes, protecting them from degradation and fusion. Extensive evidence has shown that telomere shortening and erosion lead lo chromo¬some end-to-end fusions and genomic instability, causing mental retardation and/or malformation syndromes. So far, over 19,000 patients with mental retardation have been tested and reported of whom -2.5% appeared to have a subtelomeric rearrange¬ment [Ravnan et al., 2006; Ballif et al., 2007; Ledbetter and Martin, 2007]. Since the identification of sub¬microscopic subtelomeric rearrangements as a major cause of mental retardation [Flint et al., 1995], testing for subtelomeric abnormalities among patients with mental retardation has become an important diag¬nostic tool. Although widespread screening among patients with mental retardation might be desirable, the current cost of testing is considered too expensive to allow unselected testing. Therefore clinical preselection is important. So far, selection for subtelomere testing has often been based on the checklist proposed by De Vries et al. [20011. (F, Family history of mental retardation; 2, prenatal onset growth retardation; 3, postnatal growth abnormal¬ities; 4, >2 facial dysmorphic features; 5, one or more non-facial dysmorphic features and/or congenital abnormality).Here we report on a patient with a 10 q26-10gter deletion. Our patient is a male, the first-born child of healthy non-consanguineous parents, with no family history of mental retardation or birth defects. He was born by caesarean delivery at 38 weeks of gestation.

Chromosomal abnormalities may cause autism by disrupting a gene or by providing a permissive genetic environment for mutations elsewhere in the genome to become expressed as autism. We report here on a patient with an apparently balanced de novo translocation of chromosomes 1q and 5q. He presented with minor dysmorphic features and renal malformations, mental retardation, and autism. Further characterization of the chromosomal rearrangement by FISH revealed a deletion in chromosome 1 from q23.3 to q24.2 corresponding to a region of rising interest in the research of autism susceptibility genes. The array-CGH technique gave better resolution of the breakpoints and the size of the deletion was calculated to be 4.97 Mb.

We describe a 3-year-old boy with complete agenesis of corpus callosum, developmental delay/mental retardation, anterior diaphragmatic hernia, Morgagni type, severe hypermetropia, and facial dysmorphism suggesting the diagnosis of Donnai–Barrow syndrome. Subtelomeric FISH analysis revealed a paternally-derived t(9;16) (q34.3;q24.3) translocation with partial 9q monosomy and partial 16q trisomy. As some facial features resemble the 9q emerging phenotype, we suggest the hypothesis that some patients with Donnai–Barrow syndrome might be abscribed to 9q terminal deletion. © 2006 Wiley-Liss, Inc.

The aim of this report is to provide an update on the natural history of the Cri du Chat Syndrome by means of the Italian Register (I.R.). Two hundred twenty patients were diagnosed by standard cytogenetic methods and 112 of these were also characterised by molecular-cytogenetic investigation (FISH). FISH analysis showed interstitial deletions, short terminal deletions and other rare rearrangements not previously correctly diagnosed by standard cytogenetics. The diagnosis was made in the first month of life in 42% and within first year in 82% of cases. The remaining 18% were diagnosed at an age ranging from 13 months to 47 years. At the last follow-up, patient age ranged from 8 months to 61 years. Mortality, already low, has decreased over time as it is lower between 1984-2002 compared to 1965-1983. Mortality was higher in patients with unbalanced translocations resulting in 5p deletions. Our data confirm that the cat-like cry and peculiar timbre of voice are the most typical signs of the syndrome, not only at birth but also later and these are the only signs which might suggest the diagnosis in patients with small deletions and mild clinical picture. A cytogenetic and clinical variability must be underlined. Cardiac, cerebral, renal and gastrointestinal malformations were more frequent in the patients with unbalanced translocations resulting in 5p deletions. Sucking and feeding difficulties and respiratory infections are frequent in the first months or years of life. Intubation difficulties linked to larynx anomalies must be considered. Psychomotor development is delayed in all patients but there is a variability related to deletion size and type as well as other genetic and environmental factors. However, the results showed an improvement in the acquisition of the development skills and progress in social introduction which should encourage caregivers and parents to work together in carrying out the rehabilitative and educational interventions.

PURPOSE: We evaluated the experiences of 19 Italian laboratories concerning 241 small supernumerary marker chromosomes (sSMCs) with the aim of answering questions arising from their origin from any chromosome, their variable size and genetic content, and their impact on the carrier's phenotype. METHODS: Conventional protocols were used to set up the cultures and chromosome preparations. Both commercial and homemade probes were used for the fluorescent in situ hybridization analyses. RESULTS: A total of 113 of the 241 sSMCs were detected antenatally, and 128 were detected postnatally. There were 52 inherited and 172 de novo cases. Abnormal phenotype was present in 137 cases (57%), 38 of which were antenatally diagnosed. A mosaic condition was observed in 87 cases (36%). In terms of morphology, monocentric and dicentric bisatellited marker chromosomes were the most common, followed by monocentric rings and short-arm isochromosomes. The chromosomes generating the sSMCs were acrocentric in 132 cases (69%) and non-acrocentric chromosomes in 60 cases (31%); a neocentromere was hypothesized in three cases involving chromosomes 6, 8, and 15. CONCLUSION: The presented and published data still do not allow any definite conclusions to be drawn concerning karyotype-phenotype correlations. Only concerted efforts to characterize molecularly the sSMCs associated or not with a clinical phenotype can yield results suitable for addressing karyotype-phenotype correlations in support of genetic counseling.

Editor—Cryptic telomeric rearrangements are a significant cause of idiopathic mental retardation. Knight et al 1 found 7.4% of these rearrangements in children with moderate to severe mental retardation. Clinical selection criteria for testing patients with subtelomeric chromosome specific probes are still not clear cut and the importance of other surveys to define this point has been stressed.2With this aim, we examined 200 patients with idiopathic mental retardation, either isolated or associated with dysmorphism and/or congenital anomalies, using FISH analysis with subtelomeric chromosome specific probes. The sample was collected in four Italian Genetic Centres. Patients were selected on the basis of the following criteria: (1) the presence of mental retardation that was classified as mild, moderate, or severe according to DSM IV3; (2) patients under 1 year of age, too young for psychological assessment, were selected for the presence of developmental delay; (3) exclusion of pre- or perinatal distress through an accurate evaluation of the pre-, peri-, and postnatal patient history; and (4) exclusion of Mendelian syndromes and of genomic disorders4 5 for which a specific diagnostic test is available. The essential elements of evaluation also included family history, a complete physical and neurological examination of the patients with particular attention to the presence of mental retardation and multiple congenital anomalies, and assessment of the behavioural phenotype. Electroencephalograms, brain CT scan, and MRI were performed in specific situations. Abnormal methylation and expansion at FRAXA and FRAXE6 were excluded in 52 and 50 males and in 37 and 32 females, respectively. Routine cytogenetic analysis at the 400-550 band level was performed in all the patients. In those patients in whom a cryptic subtelomeric rearrangement was identified by FISH, prometaphase chromosomes were also analysed to determine if the rearrangement could be detected in retrospect by cytogenetic …

The majority of deletions of the short arm of chromosome 5 are associated with cri du chat syndrome (CdCS) and patients show phenotypic and cytogenetic variability. To perform a genotype-phenotype correlation, 80 patients from the Italian CdCS Register were analysed. Molecular cytogenetic analysis showed that 62 patients (77.50%) had a 5p terminal deletion characterised by breakpoint intervals ranging from p13 (D5S763) to p15.2 (D5S18). Seven patients (8.75%) had a 5p interstitial deletion, four (5%) a de novo translocation, and three (3.75%) a familial translocation. Of the remaining four patients, three (3.75%) had de novo 5p anomalies involving two rearranged cell lines and one (1.25%) had a 5p deletion originating from a paternal inversion. The origin of the deleted chromosome 5 was paternal in 55 out of 61 patients (90.2%). Genotype-phenotype correlation in 62 patients with terminal deletions highlighted a progressive severity of clinical manifestation and psychomotor retardation related to the size of the deletion. The analysis of seven patients with interstitial deletions and one with a small terminal deletion confirmed the existence of two critical regions, one for dysmorphism and mental retardation in p15.2 and the other for the cat cry in p15.3. Results from one patient permitted the cat cry region to be distally narrowed from D5S13 to D5S731. Furthermore, this study lends support to the hypothesis of a separate region in p15.3 for the speech delay. Keywords: cri du chat syndrome; 5p deletion; phenotype-genotype correlation; FISH

Editor—Cri du chat syndrome (CdCS) is one of the more common deletion syndromes, involving the short arm of chromosome 5, with an incidence of 1 in 50 000 live births. Classically, patients with this syndrome present with microcephaly, a round face, hypertelorism, micrognathia, prominent nasal bridge, epicanthic folds, hypotonia, and severe psychomotor retardation. Infants also exhibit a high pitched cry similar to the mewing of a cat, which is usually considered diagnostic for this syndrome.1 2 Recently, genotype-phenotype studies in CdCS led to the identification of two separate chromosomal regions, hemizygosity for which is associated with specific phenotypes.3 A deletion of 5p15.3 results in the manifestation of a cat-like cry4, while a deletion of 5p15.2 results in the presentation of the other major clinical features of the syndrome.5 Moreover, a region for speech delay in 5p15.3 has been identified.6 From a review of 331 published cases, Niebuhr2 estimated that most CdCS cases are the result of de novo deletions (about 80%), some derive from a familial rearrangement (12%), and only a few show other rare cytogenetic aberrations, such as mosaicism (3%), rings (2.4%), and de novo translocations (3%). Chromosomal mosaicism in CdCS has been described involving a cell line with a 5p deletion and a cell line with a normal karyotype.2 7 We describe the first three reported cases of mosaic de novo 5p anomalies involving two rearranged cell lines in CdCS out of 80 (3.75%) patients from the Italian Register of CdCS8analysed in a large study of correlation between 5p deletion and phenotypic effect (Cerruti Mainardi et al , manuscript in preparation). Patient 1 was the first female child of healthy, unrelated parents. At birth the mother was 29 and the father 31 years old. The pregnancy was …

A large Sardinian family including 13 Martin-Bell syndrome (MBS) patients, several instances of normal transmitting males or females, and the G6PD-Mediterranean mutant segregating in some of its branches, has been thoroughly investigated with the hope of gaining further insight on the nature of the FRAX-mutation. All the MBS patients and the 15 obligate heterozygous women present in the pedigree could be traced back through their X-chromosome lineage to the same ancestress, who must have been heterozygous for a silent premutation at the FRAX-locus. This premutation appears to have turned into a true FRAX-mutation at least 9 times during the gametogenesis of the ancestress' X-related descendants of whom four are males. This finding alone suggests that the transition from the FRAX premutation to the true mutation can be the result of intra- as well as interchromosomal events. This conclusion is supported by the additional observation that the genetic phase between the FRAX and the G6PD loci remained unaltered when the transition occurred in a repulsion double heterozygote for the premutation and the G6PD-Mediterranean mutant. The data described are compatible with the hypothesis that MBS patients and normal transmitting males are, respectively, hemizygous for deletion or duplication products generated by aberrant recombination events at a highly recombinogenic site of the region Xq27-Xqter. The overall message stemming from this report is that no firm conclusion can be drawn on the genetic linkage between the FRAX-locus and other markers of this region until the nature of the FRAX-mutations and the mechanism of their occurrence are fully understood.

In a series of 156 females and 149 males with a Down syndrome (DS) child, a case-control study was performed to evaluate the effect of abdominal-pelvic exposure to diagnostic x-rays prior to conception on nondisjunction (ND). Cytogenetic analysis using QFQ banding allowed unequivocal identification of ND parents as cases. Partners of ND parents were treated as control group. Odds ratio for the association of x-rays exposure and ND occurrence (stratified for sex and age) was 1.85 (borderline to significance: with a 95% confidence interval 1-3.44). Such an association appeared highly significant in older fathers and borderline to significant in younger mothers, when age groups were analyzed separately. By comparing mean parental ages at birth of the propositus, the prevalence of exposure to x-rays appeared moderately associated with aging in control parents of both sexes. Furthermore, the mean age of unexposed ND parents of paternally derived SD cases was the same as the referent population's, suggesting that age is not a risk factor for ND in the male, except for being associated with increasing exposure risk. Conversely, risk attributable to x-rays exposure in the female appears to be progressively diluted with increasing age, by strongly age-dependent high risk, presumably due tomore » biologic factors that are not affected by environmental exposure.« less

Several studies have attempted to define the role of parental age in determining the prevalence of 47, +21 according to the origin of nondisjunction. This report analyzes the original data of 197 informative families from Italy and reviews the available literature (96 families from Denmark and 201 from other countries). Mothers whose gametes showed nondisjunction are treated as cases, and those with normal meiosis as controls within each study. To utilize the data fully, maternal age at birth of a 47, +21 individual is treated as a continuous variable in a nonparametric comparison. The combined evidence indicates that nondisjunction in the female is associated with a significant age difference between cases and controls which is mostly due to errors in the second meiotic division. It may be inferred that in the general population, aging enhances nondisjunction at both first and second division in the female, while aging in the male is presumably associated mostly (or only) with first division errors. Implications and alternative models are discussed.

The precise origin of the supernumerary chromosome can be defined in the majority of trisomy 21 cases. This is achieved by evaluating the chromosome 21 short arm polymorphism and analysing restriction fragment length polymorphisms (RFLPs) of multiple chromosome 21 loci. We report a study on 37 Italian families with Down's syndrome. In 35 cases (94.6%) both the parental and the meiotic stage of non-disjunction could be established. Knowledge of the origin of the extra chromosome 21 is a pre-requisite for investigations of genetic or environmental factors that may affect the meiotic process.

After primary trisomy, "de novo" 21q21q trisomy is the most frequent chromosomal aberration responsible for Down syndrome. This rearrangement is more commonly referred to as a Robertsonian translocation or centric fusion product than as an isochromosome, e.g., t(21q;21q) instead of i(21q); however, in practice, it has not so far proved possible to distinguish between these alternatives. The aim of this work was to establish which of the two alternatives is acceptable.

The 18q- syndrome [MIM #601808] is a terminal deletion of the long arm of chromosome 18. The most common deletion extends from region q21 to qter. We report here a nine-year-old boy possessing a simple 18q- deletion who had abnormalities of the brain, skull, face, tooth, hair, bone, and skin, plus joint laxity, tongue palsy, subtle sensoneural deafness, mental and speech delay, attention deficit hyperactivity disorder (ADHD), tic, and restless legs syndromes. His karyotype was 46, XY, del (18)(q21.31-qter). The size of the deletion was approximately 45 cM. Most of these abnormalities were not explained by the 18q- deletion. The family pedigree suggested the presence of a subtle involvement of ectodermal and/or mesodermal structures. Karyotypes of the other family members were normal.