Trisomic Conditions Research Articles

Transcriptome Profiling Uncovers Potential Common Mechanisms in Fetal Trisomies 18 and 21.

Human trisomies have recently been investigated using transcriptomics approaches to identify the gene expression (GE) signatures characteristic of each of these specific aneuploidy conditions. We hypothesized that the viability of cells with gross genomic imbalances might be associated with the activation of resilience mechanisms that are common to different trisomies and that are reflected by specific shared GE patterns. We report in this article our microarray GE analyses of amniocytes from fetuses with viable trisomy conditions, trisomy 21 or trisomy 18, to detect such common expression signatures. Comparative analysis of significantly differentially expressed genes in trisomies 18 and 21 revealed six dysregulated genes common to both: OTUD5, ADAMTSL1, TADA2A, PPID, PIAS2, and MAPRE2. These genes are involved in ubiquitination, protein folding, cell proliferation, and apoptosis. Pathway-based enrichment analyses demonstrated that both trisomies showed dysregulation of the PI3K/AKT pathway, cell cycle G2/M DNA damage checkpoint regulation, and cell death and survival, as well as inhibition of the upstream regulator TP53. Our data collectively suggest that trisomies 18 and 21 share common functional GE signatures, implying that common mechanisms of resilience might be activated in aneuploid cells to resist large genomic imbalances. To the best of our knowledge, this is the first study to use global GE profiling data to identify potential common mechanisms in fetal trisomies. Studies of other trisomies using transcriptomics and multiomics approaches might further clarify mechanisms activated in trisomy syndromes.

A tumor profile in Patau syndrome (trisomy 13).

Individuals with trisomic conditions like Down syndrome and Edwards syndrome are prone to certain types of malignancy. However, for Patau syndrome (constitutional trisomy 13), which occurs in 1/10,000-1/20,000 live births, the tumor profile has not been well characterized. An awareness of susceptibility to malignancies can improve care of affected individuals, as well as further our understanding of the contribution of trisomy to carcinogenesis. Therefore, we conducted an extensive review of the literature; we found 17 malignancies reported in individuals with Patau syndrome. These comprised eight embryonic tumors, three leukemias, two malignant germ cell tumors, two carcinomas, a malignant brain tumor, and a sarcoma. Benign tumors were mainly extragonadal teratomas. The small number of reported malignant tumors suggests that there is not an increased risk of cancer in the context of trisomy 13. The tumor profile in Patau syndrome differs from that observed in Edwards syndrome (trisomy 18) and Down syndrome (trisomy 21), suggesting that the supernumerary chromosome 13 could promote particular tumor formations as it does particular malformations. No general and direct relationships of tumor occurrence with organ weight, congenital malformations, histological changes, or presence of tumor suppressor genes on chromosome 13 were observed. However, some tumors were found in tissues whose growth and development are controlled by genes mapping to chromosome 13. Recent reports of successful outcomes following surgical treatment and adapted chemotherapy indicate that treatment of cancer is possible in Patau syndrome.

Application of Short Tandem Repeat markers in diagnosis of chromosomal aneuploidies and forensic DNA investigation in Pakistan

Short Tandem Repeat (STR) genetic markers hold great potential in forensic investigations, molecular diagnostics and molecular genetics research. AmpFlSTR® Identifiler™ PCR amplification kit is a multiplex system for co-amplification of 15 STR markers used worldwide in forensic investigations. This study attempts to assess forensic validity of these STRs in Pakistani population and to investigate its applicability in quick and simultaneous diagnosis and tracing parental source of common chromosomal aneuploidies. Samples from 554 healthy Pakistani individuals from 5 different ethnicities were analyzed for forensic parameters using Identifiler STRs and 74 patients' samples with different aneuploidies were evaluated for diagnostic strengths of these markers. All STRs hold sufficient forensic applicability in Pakistani population with paternity index between 1.5 and 3.5, polymorphic information content from 0.63 to 0.87 and discrimination power ≥0.9 (except TPOX locus). Variation from Hardy-Weinberg equilibrium was observed at some loci reflecting selective breeding and intermarriages trend in Pakistan. Among aneuploidic samples, all trisomies were precisely detectable while aneuploidies involving sex chromosomes or missing chromosomes were not clearly detectable using Identifiler STRs. Parental origin of aneuploidy was traceable in 92.54% patients. The studied STR markers are valuable tools for forensic application in Pakistan and utilizable for quick and simultaneous identification of some common trisomic conditions. Adding more sex chromosome specific STR markers can immensely increase the diagnostic and forensic potential of this system.

Maternal and Paternal Age at Pregnancy for Low Incidence Trisomy Groups: Preliminary Findings and Implications

Maternal and Paternal Age at Pregnancy for Low Incidence Trisomy Groups: Preliminary Findings and Implications number of studies have found a correlation between later maternal age and increased chances for conception of children with trisomy conditions while other studies have not. This inconsistency, along with collecting data on paternal age, deserves examination. The purpose of the present study is to examine maternal and paternal age at pregnancy related to children diagnosed with trisomy18, trisomy 13, and trisomy 9 mosaics. Results from 287 mothers and 285 fathers found that the majority of mothers were under the age of 35 (58.9% total). Paternal age closely mirrored mother’s age with 54.7% of fathers under the age of 35. Implications for additional research and for healthcare professionals including genetic counselors working in clinical settings are provided.

Selected birth defects data from population‐based birth defects surveillance programs in the United States, 2006 to 2010: Featuring trisomy conditions

The annual National Birth Defects Prevention Network (NBDPN) Congenital Malformations Surveillance Report includes state-level data on major birth defects (i.e., conditions present at birth that cause adverse structural changes in one or more parts of the body) and a directory of population-based birth defects surveillance systems in the United States. Beginning in 2012, these annually updated data and directory information are available in an electronic format accompanied by a data brief. This year’s report includes data from 41 population-based birth defects surveillance programs and a data brief highlighting the more common trisomy conditions (i.e., disorders characterized by an additional chromosome): trisomy 21 (commonly referred to as Down syndrome), trisomy 18, and trisomy 13. State-Specific Data Collection and Presentation for Selected Birth Defects Data collection The NBDPN Data Committee, in collaboration with the Centers for Disease Control and Prevention (CDC), invited population-based birth defects surveillance programs in the United States to submit data on major birth defects affecting central nervous, eye, ear, cardiovascular, orofacial, gastrointestinal, genitourinary, and musculoskeletal systems, as well as trisomies, amniotic bands, and fetal alcohol syndrome. Table 1 lists these 47 conditions and their diagnostic codes (International Classification of Diseases, 9th Revision, Clinical Modification [ICD-9-CM]; and Centers for Disease Control and Prevention/British Pediatric Association Classification of Diseases [CDC/BPA]). Table 1 ICD-9-CM and CDC/BPA Codes for 47 Birth Defects Reported in the NBDPN Annual Report Participating state birth defects programs provided counts of all cases of the birth defects listed in Table 1 as well as counts of live births and male live births in their catchment areas for births occurring from January 1, 2006 through December 31, 2010. The cases for all defects were reported by maternal census race/ethnic categories: White non-Hispanic, Black/African-American non-Hispanic, Hispanic, Asian/Pacific Islander non-Hispanic, American Indian/Alaska Native non-Hispanic. Additionally, trisomy cases were provided by six categories of maternal age at delivery: less than 20 years, 20 to 24 years, 25 to 29 years, 30 to 34 years, 35 to 39 years, and 40+ years.

Maternal serum protein profile and immune response protein subunits as markers for non‐invasive prenatal diagnosis of trisomy 21, 18, and 13

To use proteomics to identify and characterize proteins in maternal serum from patients at high-risk for fetal trisomy 21, trisomy 18, and trisomy 13 on the basis of ultrasound and maternal serum triple tests. We performed a comprehensive proteomic analysis on 23 trisomy cases and 85 normal cases during the early second trimester of pregnancy. Protein profiling along with conventional sodium dodecyl sulfate polyacrylamide gel electrophoresis/Tandem mass spectrometry analysis was carried out to characterize proteins associated with each trisomy condition and later validated using Western blot. Protein profiling approach using surface enhanced laser desorption/ionization time-of-flight mass (SELDI-TOF/MS) spectrometry resulted in the identification of 37 unique hydrophobic proteomic features for three trisomy conditions. Using sodium dodecyl sulfate polyacrylamide gel electrophoresis followed by Matrix Assisted Laser Desorption Ionization - Time of Flight/Time of Flight (MALDI-TOF/TOF) and western blot, glyco proteins such as alpha-1-antitrypsin, apolipoprotein E, apolipoprotein H, and serum carrier protein transthyretin were identified as potential maternal serum markers for fetal trisomy condition. The identified proteins showed differential expression at the subunit level. Maternal serum protein profiling using proteomics may allow non-invasive diagnostic testing for the most common trisomies and may complement ultrasound-based methods to more accurately determine pregnancies with fetal aneuploidies.

Erring on the Side of Life: Children with Rare Trisomy Conditions, Medical Interventions and Quality of Life

Erring on the Side of Life: Children with Rare Trisomy Conditions, Medical Interventions and Quality of Life The prevailing viewpoint on children with rare trisomy conditions such as trisomy 18 (t18) and trisomy 13 (t13) is almost uniformly negative. Yet, case studies offer information about long-term survivors. What is missing in the discussion is an unbiased examination of surviving children within the context of necessary, rather than “aggressive”, medical interventions and overall quality of life. A move beyond palliative or comfort care must be an option for this population.

‘We've been through it all together’: supports for parents with children with rare trisomy conditions

Parenting a child with a developmental disability can be a positive experience. A salient part of this outcome is support at the time of diagnosis and in an ongoing manner from immediate and extended family members. Studies are sparse on this topic for parents with a child with a rare trisomy condition. The present study examined the support needs of parents with a child or adult with a rare trisomy condition (n = 20). Participants were recruited from the Tracking Rare Incidence Syndromes (TRIS) project. The TRIS Family, Friends and Finances Protocol was the data collection instrument. The protocol included primarily open-ended items. Qualitative analyses were conducted to identify themes from the protocol and follow-up phone contacts. Support from immediate and extended family members varied from very positive to participants-describing very negative interactions with specific individuals. Many in the sample reported affirming experiences with spouses and difficulties with grandparents and other extended family members. Results both confirmed the literature and reflected the unique circumstances of the participants. It is critical to raise awareness of the similar and disparate support needs of this unique population, as the affected children are living longer and their families require continuing support to meet their and their children's needs.

Simultaneous Detection of Trisomies 13, 18, and 21 with Multiplex Ligation-Dependent Probe Amplification–Based Real-Time PCR

Trisomies 13, 18, and 21 account for the majority of chromosomal aneuploidies detected in prenatal diagnosis. Diagnosis of these trisomies relies mainly on karyotype analysis. Several molecular methods have been developed for trisomy detection, but performance or throughput limitations of these methods currently constrain their use in routine testing. We developed multiplex ligation-dependent probe amplification-based real-time PCR (MLPA/rtPCR) to simultaneously detect these 3 trisomy conditions with a single reaction. We applied the method to DNA isolated from 144 blinded clinical samples that included 32 cases of trisomy 21, 11 cases of trisomy 18, 1 case of trisomy 13, and 100 unaffected control samples; results were compared with karyotype analysis. As judged by the results of the karyotype analysis, MLPA/rtPCR correctly detected all 44 cases of trisomy in the analysis of the blinded clinical samples. The method was able to detect a change in chromosome dosage as low as 1.2-fold. This novel PCR-based technology simultaneously identified 3 types of trisomy in a single reaction and accurately detected trisomy with mosaicism, while reducing assay times and costs compared with conventional methods. The MLPA/rtPCR approach may have applicability in noninvasive prenatal diagnosis with maternal blood samples.

Pregnancy and birth history of newborns with trisomy 18 or 13: A pilot study

The prognosis for infant survival in newborns diagnosed with the trisomy conditions Edward syndrome (trisomy 18) and Patau syndrome (trisomy 13) is poor [Goldstein and Nielsen, 1988; Root and Carey, 1994; Brewer et al., 2002]. Major contributing factors to early mortality include gestational age of less than 32 weeks, limited use of life support measures, apnea and other respiratory difficulties and presence of cardiac anomalies [Root and Carey, 1994; Rasmussen et al., 2003]. Other authors have [Van Dyke and Allen, 1989; Baty et al., 1994; Rasmussen et al., 2003; Carey, 2005] discussed the medical management and overall health needs of survivors. Newborns, surviving past 2 months of age, typically present ongoing medical needs in addition to day-to-day newborn caregiving requirements [Baty et al., 1994; Niedrist et al., 2006; Pont et al., 2006]. Studies published in the 1980s and early 1990s offer an examination of the strengths and needs of newborns with these trisomy syndromes [e.g., Goldstein and Nielsen, 1988; Van Dyke and Allen, 1989; Boss and Broers, 1992; Root and Carey, 1994; Nembhard et al., 2001]. Some recent researchers have reviewed birth registers from the 1980s to the mid 1990s and have found improved outcomes compared to the others [Canfield et al., 2001; Parker et al., 2003]. Further, cardiac surgery has assisted in extending the life expectancy for some infants with rare trisomy conditions [Graham et al., 2004]. Less invasive procedures and interventions are also providing avenues for improved daily management and long term care [Kosho et al., 2006; Lin et al., 2006; Niedrist et al., 2006]. It is imperative to examine the varied courses and outcomes for newborns with these conditions in more detail. Newborns with trisomy 18 (t18) or 13 face an uncertain course in the NICU and after discharge [Baty et al., 1994;Walters, 1998; Rasmussen et al., 2003; McIntosh et al., 2004; Tripp and McGregor, 2006]. In recent years, European investigators have collaborated with clinicians and cytogeneticists throughout the world in the development of international registries of individuals with rare chromosome syndrome [http://decipher.sanger.ac.uk/; www.ecaruca.net]. Additional collaborative endeavors are needed and could include parents and caregivers. The Tracking Rare Incidence Syndromes (TRIS) project can contribute to such efforts through collection of phenotypic data [Bruns, 2006]. The previously described issues highlight the need to investigate maternal pregnancy experiences, childbirth history and presenting needs. This information can also provide useful, parent-completed data for registries, open new avenues for parentprofessional advocacy and collaboration, and demonstrate the utility of such databases. This pilot study sought to examine:

A trisomic transmission disequilibrium test.

Certain congenital disorders that are rare in the general population are quite common in individuals with trisomic conditions. For example, complete atrioventricular septal defect occurs in about 20% of individuals with Down syndrome, an approximately 500-fold increase in risk as compared to individuals without Down syndrome. Genetic variation on the chromosome involved in the trisomy may affect susceptibility to these trisomy-specific disorders. That is, increased dosage of a variant may be directly involved in increasing the risk of a disorder, or it may be indirectly involved by causing up- or downregulation of other genes. As in standard disomic gene-mapping, one can search for genes using linkage or association methods. Within association methods, one can consider case-control methods or family-based control methods such as the transmission disequilibrium test (TDT). Most gene-mapping methods need to be substantially redesigned for use with trisomic data. In this paper, we present a "trisomic TDT", a statistical method of testing for nonrandom transmission of alleles from parents to trisomic children. We demonstrate the method on a dataset of parent-child trios in which the child has Down syndrome.

Selective expression of major histocompatibility complex (MHC) antigens and modulation of T-cell differentiation in chickens with increased MHC-chromosome dosages

Increased dosage of genes belonging to the immunoglobulin superfamily may be responsible for some of the less noticeable but targeted phenotypic disturbances seen in trisomy conditions of humans and animals. We used an avian aneuploidy model to study the specific effects of extra major histocompatibility complex (MHC)-microchromosome dosage on the progression of thymocyte differentiation through a broad period of embryonic and neonatal development. The particular goal in the present investigation was to determine whether a reduction in the number of thymocytes, previously observed in the developing thymus of MHC aneuploids, is accompanied by particular alterations in thymocyte differentiation. We hypothesized that the subpopulation structure and/or developmental pattern for thymocyte differentiation are characteristically perturbed (delayed or modified) by increased MHC-chromosome dosage in cells. The regulation of MHC surface antigen expression in aneuploid thymocytes was also studied to detect dosage-dependent expression for one and possibly more sub-regions (class I, II, IV) of the avian MHC. Surface densities of MHC class I antigens on thymocytes were increased significantly at all ages studied, for example by 15% and 45% in trisomics and tetrasomics, respectively at 22 days post-hatching. The surface density of CT1 antigen, a thymocyte-specific marker, was also increased in a dosage-dependent manner, but only in juveniles. Increases in the proportion of αβ 1, TCR + and CD3 + thymocytes were observed in juveniles, with no alterations in other TCR-expressing thymocytes. No major alterations in CD4 and CD8 thymocyte populations were observed. These results demonstrate a targeted effect of extra MHC-chromosome dosage towards enhanced class I and CT1, and not class II or IV, expression. The increased MHC-microchromosome dosage appears to influence primarily immature thymocytes expressing αβ 1 TCR and CD3.

Maternal age effect: The enigma of Down syndrome and other trisomic conditions

Aneuploidy is the most frequently observed chromosome abnormality in human liveborn, abortuses and oocytes. The only etiological factor that has been established is advanced maternal age for the occurrence of trisomies, particularly trisomy 21 which causes Down syndrome. The maternal age effect remains an enigma. Recent molecular data bearing on this question are reviewed as are the hypotheses that have been proposed linking nondisjunction and maternal age. Rationale is presented for a compromised microcirculation hypothesis that explains the cause of nondisjunction and why its occurrence changes with maternal age from menarche to menopause. It takes into account two facts: (1) 95% of Down syndrome children receive their extra chromosome from their mother, and in 80% or more of these the nondisjunction occurred in the first meiotic division, which is completed in the ovary. (2) The ovarian follicle containing the primary oocyte has no internal circulation. The hypothesis proposes that aneuploid oocytes arise from a concatenation of events. It begins with hormonal imbalance that causes a less-than-optimal microvasculature to develop around the maturing and mature follicles. The resulting decrease in the size of the perifollicular capillary bed reduces the volume of blood flow through the area, leading to an oxygen deficit and a concomitant increase inside the follicle of carbon dioxide and anaerobic products, such as lactic acid. This in turn causes a decrease in the intracellular pH of the oocyte that diminishes the size of the spindle, with consequent displacement and nondisjunction of a chromosome. The compromised microcirculation hypothesis explains the occurrence of aneuploidy in primary and secondary oocytes, sperm precursor cells, tumor and embryonic cells. It also explains why women of all reproductive ages may have a Down syndrome child.

Abnormal neural fold development in trisomy 12 and trisomy 14 mouse embryos

ABSTRACT The early development of the exencephalic malformation in trisomy 12 (Tsl2) and trisomy 14 (Tsl4) mouse embryos was examined by means of scanning electron microscopy and compared with cranial neural tube formation in euploid litter-mates. Embryos from normal laboratory mice were used as additional controls. The euploid control embryos of the trisomy-inducing breeding system showed a slight delay and some variation in the timing of cranial neurulation. The pre-exencephalic trisomic embryos showed hypoplasia, and lower somite number when compared with euploid littermates; there was also a retardation of development of the whole neural tube, when related to the somite stage. External differences from the control embryos were observed at the late pre-somite stage, when the anterior part of the neural plate showed a crumpled appearance. At 6 somites the lateral edges of the forebrain were everted instead of elevated in Tsl2 and Tsl4 embryos. At later stages, however, the forebrain showed a tendency towards the normal morphogenetic pattern, so that the optic vesicles were eventually formed and the most anterior part fused. The caudal forebrain and the midbrain were more permanently affected by the disturbance of trisomic conditions and grew laterally, failing to appose or fuse in the midline in both Tsl2 and Tsl4 embryos. Hindbrain morphogenesis was different in Tsl2 and Tsl4 excencephaly : in Tsl2 embryos it did not close rostral to the otic pits, whereas in Tsl4 embryos it showed a normal closure up to the hindbrain/midbrain junction. These observations support the hypothesis that in mammalian embryos the mechanism of neural tube formation of the future brain region is more complex than that of the spinal neural tube and therefore may be more likely to react to a general delay of neurulation with a gross malformation. Tsl2 and Tsl4 exencephaly are due to a primary non-closure of the neural tube.

Parental age and recombination frequency in the house mouse.

SUMMARYThe relationship between parental age and recombination frequency in the offspring of mice has been studied using backcrosses to heterozygous males or females. The mice were allowed to breed until they became infertile. Data for several chromosomes were analysed, mostly from a stock carrying five markers covering approximately three-quarters of the length of chromosome 2.Analyses of two-point recombination ratios or of multi-point interference ratios revealed no consistent age-related heterogeneity in offspring of male or female heterozygotes. A significant age-related heterogeneity was detected in the offspring of female heterozygotes but not of males, when the number of offspring with no detectable recombination was compared to those with one or more. This difference between the sexes could be related to earlier cytological observations on chiasma frequency in oocytes and spermatocytes. The significance of these findings for the analysis of follicular growth in mammals and in the origin of human trisomic conditions is discussed.

Systematic approach to the study of trisomy in the mouse. II.

In pursuit of attempts at a systematic study of autosomal trisomy in the mouse, an experimental model is presented which permits the induction of specific trisomic conditions. It is based on (1) the occurrence of considerable rates of meiotic anaphase I malsegregation of double metacentric heterozygotes with monobrachial homology, (2) the expectation that trisomics may be found among the unbalanced conditions in the progeny of crosses of the double heterozygotes with "all acrocentric" mice, and (3) the observation that trisomy, in contrast to monosomy or combined monosomy plus trisomy, is the only unbalanced condition surviving beyond day 10. In this design, the specific nature of the trisomy is predetermined by the choice of the double metacentric heterozygote combination and recognized by such criteria as chromosome arm number and the presence of both metacentrics. All trisomic conditions of the mouse so far studied inevitably lead to early or late fetal death. Although the possibility of a systematic survey of all 19 possible autosomal trisomies in the mouse can be anticipated, this report is limited to a study of trisomies (Ts) 1, 8, 11, 12, and 17. Ts 8, 11, and 17 cause severe developmental inhibition at an early stage of development. Death occurs about day 11 or 12. Ts 1 displays a syndrome of moderate to marked developmental retardation and slight to more distinctly disproportionate hypoplasia. These embryos may survive until day 15. In contrast, a lesser extent of hypoplasia and retardation is observed in Ts 12, which, however, almost regularly shows exencephaly and microphtalmia. Obviously, variation of the severity of phenotypic manifestation of the trisomic conditions is due to genic heterogeneity of the animals used in the present study. Current attempts are directed to introduce a sufficient number of metacentrics in a defined background, thus providing the means for future systematic studies of the phenotypic expression of gross genomic imbalance.

Trisomy in the fetal backcross progeny of male and female metacentric heterozygotes of the mouse. i.

In the backcross progeny of single (Robertsonian) metacentric heterozygotes of the mouse, segregational impairment of fertility and reduced litter size are initiated by misdivision of trivalents in meiotic anaphase I. Males heterozygous for the metacentrics Rbl, Rb4, Rb5, and Rb7Bnr of the tobacco mouse series and for the Rb8–10Bnr metacentrics derived from other feral domestic mice produce variable rates of meiotic malsegregation, ranging from 4 % to 26 % unbalanced M II figures. Chromosomally unbalanced gametes become involved in fertilization and produce aneusomic zygotes. Fetal aneuploidy causes developmental breakdown and prenatal death. Mono-somic zygotes are eliminated at an early stage of development. Most aneuploid embryos observed beyond day 8 or 10 of gestation were trisomics. Aneuploidy (trisomy) of the zygotes was considerably more frequent in the progeny of heterozygous females than in that of heterozygous males. There was evidence that this disparity might be the result of a higher nondisjunction rate in the female gametogenesis. Mechanisms of selection against unbalanced male germ cells might operate on a small scale. The highest incidences of aneuploid implants were found (with decreasing frequencies) in the backcross progeny of the Rb(1.3)l, Rb(16.17)7, and Rb(11.13)4Bnr female heterozygotes. With the experimental design used in this study, several trisomic conditions could be observed and their phenotype and developmental profiles described, namely, trisomies (Ts) 1, 3, 4, 10, 11, 12, 13, 16, and 17. Among these, Ts 3, 11, and 17 were characterized by severe developmental impairment and relatively early death, whereas the others could survive until day 13 to 15 or, as in the case of Ts 12, even until day 17. Ts 1 displayed a syndrome of general hypoplasia (fetal runting), whereas exencephaly was found in Ts 12. It was the only trisomy observed in this study that was associated with gross malformation.

Nondisjunction in Males: Commoner Than Suspected?

To the Editor.— The idea that the mother is responsible for all trisomic conditions is commonly encountered from both patients and members of the medical profession. At the risk of striking a blow against the forces of male chauvinism, we think that nondisjunction in spermatogenesis may be playing a greater role in the etiology of Down's syndrome and other trisomies than is commonly thought. Shuttleworth, in his work Mentally Deficient Children (London, HK Lewis & Co, 1895), was the first to observe that children with mongolism tend to be born to older parents. Jenkins 1 showed that the incidence of mongolism increases with increasing age, both of the father and of the mother, and that the age of the mother was a better predictor of occurrence of the syndrome. By the use of the partial correlation technique followed by regression analysis in a population of 150 families, a study by

The association of acrocentric chromosomes in 1000 normal human male metaphase cells

Associations among the acrocentric chromosomes of man were first described by FergusonSmith & Handmaker (1961) and Harnden (1961). Various investigators have suggested that such associations, in conjunction with other prominent heteropycnotic secondary constrictions, play a role in the organization of nucleoli (Schultz & St Lawrence, 1949; Ohno et al. 1961; Hungerford, 1964 ; Ferguson-Smith, 1964). Participation of the acrocentric chromosomes in such associations has been postulated to increase the risk of non-disjunction with subsequent trisomic conditions of groups D and G (Harnden, 1961; Ferguson-Smith & Handmaker, 1961). In fact, several families possessing chromosomally abnormal individuals have been purported to exhibit possible ‘increased satellite association’ (Tips et al. 1964; Kiossoglou et al. 1964; Lyons, Thompson & Bigley, 1966; Zellweger, Abbo & Cuany, 1966; Abbo, Zellweger & Cuany, 1966). However, studies of this type have not been too well defined and in some cases both cytogenetically normal and abnormal individuals have been compared directly (Van Brink, Los & Nienhaus 1962; Froland & Mikkelsen, 1964; Bishun, 1966; Zellweger et al. 1966; Abbo et al. 1966). Such comparisons pose difficulties since the number of acrocentric chromosomes may not be the same in each case, e.g. trisomic and normal individuals. In addition, population data from a large series of normals on the frequency and distribution of satellite associations are meagre. In this paper, we present data on various aspects of satellite associations, in the hope that such results might form a basis for comparison between normal individuals and persons with abnormal cytogenetic constitutions.

Parental age in Down's syndrome (mongolism)

Because of the new insight afforded by recent cytogenetic discoveries, the need for further clarification of the parental age effect in Down's syndrome was apparent. As part of an epidemiologic study of Down's syndrome in Baltimore, Maryland, the relative significance of maternal and paternal ages as etiological factors was evaluated. By comparing a control group matched by birth certificates, parental age was studied directly, first by controlling maternal, and then paternal ages. There was no statistically significant association between paternal age and Down's syndrome, but the reltionship between Down's syndrome and increased maternal age remains unequivocal. Other observations are made about parental age in Down's syndrome and other trisomic conditions.