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Cytogenetic profile of Down syndrome cases seen by a general genetics outpatient service in Brazil

Down syndrome or trisomy 21 can be caused by three types of chromosomal abnormalities: free trisomy 21, translocation or mosaicism. The cytogenetic diagnosis, made through karyotypic examination, is important mainly to determine recurrence risks to assist genetic counselling. The object of this work was to carry out a cytogenetic profile of confirmed cases of Down syndrome seen in the General Genetics Outpatient Service in a teaching hospital - Hospital de Base in São José do Rio Preto - from the implementation of the service in 1973 to November 2005, with the purpose of establishing the nature of the cytogenetic abnormalities of these patients. A retrospective study was performed, in which the karyotypes of patients with Down syndrome consulted at the General Genetics Outpatient Service of HB-FAMERP from 1973 to November 2005 were investigated. The results of cytogenetic analysis were obtained from the consultation register and patients' hospital records. The results show 387 Down syndrome cases confirmed by karyotypic examinations. Of these, 357 (92.2%) patients had free trisomy of chromosome 21, 24 (6.2%) had translocation involving chromosome 21 and 6 (1.5%) had mosaicism. Nondisjunction was the main cause of Down syndrome, as the majority of the patients have free trisomy of chromosome 21. The cytogenetic pattern of Down syndrome is variable among different studies.

Down Syndrome Research and Practice


Down syndrome is the commonest autosomal genetic disorder in humans with a prevalence of 1:660 newborns[1]. It can be caused by three types of chromosomal abnormalities: free trisomy 21, translocation or mosaicism[2].

Free trisomy 21 is characterised by the presence of three complete copies of chromosome 21, generally resulting from nondisjunction during maternal meiosis[3] and is seen in about 95% of cases. Translocations are attributed to 3-4% of the cases, with Robertsonian translocation involving chromosomes 14 and 21 being the most common type. Mosaicism, characterised by some cells containing 46 chromosomes and others with 47 chromosomes, is reported in 1% of Down syndrome cases. These rates of cytogenetic abnormalities are described in the basic literature but specific surveys report variations in the cytogenetic pattern of the syndrome[4-9].

Although there is considerable variation in the physical features of individuals with Down syndrome, most present with a range of characteristics that enable clinical diagnosis of the syndrome[8,9,10]. However, cytogenetic diagnosis is important for confirmation of the clinical diagnosis and, importantly, to determine the risk of recurrence, thereby helping genetic counselling. This risk differs greatly between the cases as free trisomy and mosaicism generally do not recur in siblings of people with Down syndrome (approximate risk of 1% for women under 30 years old), whilst translocation may be recurrent. For translocations, if both parents present with normal karyotypes, the risk of recurrence is 2% to 3%. However, if one of the parents is the carrier of a balanced translocation, the risk of recurrence depends on this parent's gender and on the type of translocation[2]. In the case of Robertsonian translocations, the recurrence risk is around 10 to 15% when the mother is the carrier and from 2 to 15% when the carrier of this balanced translocation is the father[11]. On the other hand, if one of the parents is the carrier of a balanced translocation involving two chromosomes 21, the recurrence risk for Down syndrome is 100%. Thus, once diagnosed as a case of Down syndrome due to a translocation, a karyotypic analysis of both parents is recommended[2].

The object of this work was to examine the cytogenetic abnormalities in patients with Down syndrome in the Genetics Outpatient Service of a teaching hospital in Brazil.

Material and methods

A retrospective study was performed, in which the karyotypic results of patients with Down syndrome seen in a public healthcare service that routinely performs karyotypic examinations only by conventional cytogenetic techniques (chromosome GTG-banding) were analysed[12]. The results of cytogenetic analysis were obtained from the consultation register and patients' hospital records. All patients with available karyotypic results were included in the study.

Statistical analysis of the data was performed utilising the Likelihood Ratio Test with a level of significance at 5%.


Over the 32 years of the existence of the general genetics outpatient service of HB-FAMERP in São José do Rio Preto, 387 cases of Down syndrome confirmed by cytogenetic analysis were registered. Of these, 357 (92.2%) patients had free trisomy, 24 (6.2%) presented with translocation involving chromosome 21, and 6 (1.5%) patients had mosaicism (Figure 1).

Figure 1 | Frequencies of cytogenetic abnormalities in Brazilian patients with Down syndrome


According to the literature, Down syndrome is a consequence of free trisomy of chromosome 21 in about 95% of cases, translocation in 3-4% and mosaicism in 1%[2].

Publications on cytogenetic studies of patients with Down syndrome have shown differences in the frequencies of these chromosomal abnormalities. Ahmed et al. observed in a sample of 295 patients, frequencies of 95.6%, 3.7% and 0.7% respectively for free trisomy, translocation and mosaicism[9]. These frequencies do not significantly differ from those observed by Mutton et al. with 95% for free trisomy, 4% for translocations and 1% for mosaicism in a total of 5737 patients (p-value = 0.98)[5]. The study of Verma et al., which included the karyotyping results of 645 patients, identified 93% of free trisomy, 4.1% of translocations and 2.6% of mosaicism[4]. Kava et al. observed frequencies of 95%, 3.2% and 1.8% for free trisomy, translocation and mosaicism, respectively in a series of 221 patients[8]. The study of Jyothy et al. of 101 patients differs by the high frequency of mosaicism (7.7%), even higher than the frequency of translocations (4.4%)[6]. Mohktar et al. observed a lower frequency of translocations (2.7%) with values of 96.6% for free trisomy and 0.7% for mosaicism for the 673 in their cohort[7]. Our study differs from the studies mentioned above because of the high distribution of translocations with a frequency of 92.2% for free trisomy, 6.2% for translocations and 1.5% for mosaicism. An analysis of all these results, including our own data, revealed that the observed frequencies are significantly different among the different studies (p-value < 0.05).

It is difficult to suggest reasons for the discrepancy in the frequencies of cytogenetic abnormalities among the different investigations. Ahmed et al. attributed this divergence to differences in the study periods, maternal ages and the populations studied[9]. The majority of the cited studies, including ours, considered the karyotyping results of only live-born infants born to mothers of all ages[4,6,7,8]. Exceptions were Mutton et al., who also considered data coming from miscarriages and pre-natal diagnoses[5], and Ahmed et al., who included only patients over 18 years old in their study[9]. Even so, the investigations illustrate that chromosomal nondisjunction is the main cause of Down syndrome, as the majority of the patients have free trisomy of chromosome 21[3].

It is well known that advanced maternal age increases the risk of having a child with Down syndrome[2,13,14]. The risk of a woman of up to 25 years old having a child with Down syndrome is 1:1300 and 1:365 at 35 years old. At 45 years old, this risk increases to 1:30[2]. However, a published metanalysis showed that this risk does not continue to rise with age for women older than 45 years[15]. According to the authors, possible explanations for this fact are early miscarriages in older women, fertility treatment including egg donation and pre-implantation diagnosis [15]. Apart from advanced maternal age, several hypotheses have been suggested to explain the aetiology of chromosomal nondisjunction in humans[16-23]. More recently, hypomethylation of the centromeric DNA as a result of abnormal folate metabolism has been implicated in abnormal chromosomal segregation and studies point to the role of polymorphisms in some genes involved in homocysteine metabolism as risk factors for Down syndrome[20,21,22].

Cytogenetic investigations of individuals who present with clinical characteristics of the syndrome are fundamental to establish a precise diagnosis, which may have implications in the genetic counselling process. Additionally, the karyotype of affected individuals identify cases that may have been inherited making an investigation of the parents' karyotypes necessary as they may be carriers of a balanced translocation involving chromosome 21. In this case, the cytogenetic investigation of the genitors is essential to establish the risk of recurrence of the syndrome in future generations. Thus, all individuals with a diagnosis suggestive of Down syndrome should be referred to a genetic counselling service.

The growth of the General Genetics Outpatient Service of HB-FAMERP over the last few years, together with the increasing publicity related to genetics and its applications in medicine, has led to an increase in the number of cytogenetic diagnoses of individuals with Down syndrome. Currently, about two new cases of Down syndrome are identified every month, many more than at the start of the service. Our investigation did not include cases with clinical diagnosis of Down syndrome but without karyotypal confirmation at the time of the study, thus a greater number of cases with a diagnosis of possible Down syndrome have been seen by the service.

It is important to stress that, in a broad review of publications, reports on this theme in the Brazilian population were not found. Although our outpatients' service is located in the city of São José do Rio Preto, these data do not reflect the prevalence of Down syndrome in this city, as the hospital to which the outpatients' service is attached covers a region of 99 municipalities[24].

In conclusion, the cytogenetic pattern of Down syndrome is variable among different studies. Free trisomy of chromosome 21, resulting from a chromosomal nondisjunction is the most frequent cause. All cases with a clinical diagnosis of Down syndrome should be referred to a genetic counselling service.


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The authors wish to thank Prof. Dr. José Antônio Cordeiro for his assistance in the statistical analysis and FAMERP / FUNFARME, the State of São Paulo Research Foundation (FAPESP), the National Council for Scientific and Technological Development (CNPq) and Coordination for the Improvement of Higher Education Personnel (CAPES) for their support in this work.


Received: 11 December 2006; Accepted: 14 February 2007; Published online: 24 October 2008