CYTOGENETIC ANDMOLECULAR GENETIC STUDIES OF CHILDREN WITH DOWN SYNDROME AND ASSOCIATED RISK FACTORS IN KANO STATE,
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Ahmadu Bello University Zaria
Abstract
Down syndrome (DS) is the most common type of chromosomal trisomy found in the newborn.
It is associated with hypotonia, delayed development, mental retardation and characteristic facial
features.This study of cytogenetic analysis was conducted toconfirm the clinical diagnosis of
Down syndrome (DS)and to evaluate the risk factors associated with trisomy 21 in a group of
subjects in Kano State of Nigeria.The study alsodemonstrate sensitivity of DNA diagnosis of
Down syndrome using polymerase chain reaction (PCR) and short tandem repeat (STR) markers,
and to determine the origin of the non-disjoined chromosome 21. The study further determined
the relationship between the socio-demographic data with the presence of CHD in DS subjects.
DS patients (=35) were recruited for the study, but 16 DS subjects comprising of 9 males and 7
females with sex ratio was 1.3:1 were randomly selected for karyotyping analysis. GTG-band
was done according to the standard protocols.Molecular analysis was carried out by PCR based
method, using polymorphic microsatellite markers D21S11 situated on the long arm of the
chromosome 21 at 21q21. The amplified products were subjected to 8% polyacrylamide gel
electroscopes and alleles were scored by staining with ethidium bromide. Pearson’s Chi square
test, independent sample, and receiver operating characteristic curve, box and whisker plots were
used to analyze the data. Probability ˗ value (p< 0.05) was set as level of significance used to analyze the data. The results show that among the 16 cases with DS selected for karyotyping, all of them (100%) had free trisomy 21 with no translocation and mosaic DS.Trisomy 21 was detected by the presence of three distinct alleles and transmission of alleles from in all DS families. The STR marker D21S11 was able to detect 100% cases of trisomy 21 and also emphasize the fact that trisomy 21 was due to meiotic errors in maternal chromosomes. Age diagnosis was 60% in DS children < 1 year, 32% in DS between 1-2 years and 8% in DS > 2 years. Birth order was an important risk factor associated with trisomy 21, 21% of affected xxiii children were of last or second last birth order.Of the 35 DS subjects, the prominent craniofacial features noted were upward slanting fissures(17.5 %), facial profile (17.5%), low set ears (17.5%), simian crease (17.5%), flat occiput in 35 of DS (17.5%), macroglossia (19%) in 33 and short
neck (33%), microcephaly in 34 (17%of) DS subjects, congenital heart disease was diagnosed in
8 cases (4%).Hypothyroidism in 2 subjects (1%), pes planus was seen in 1 DS subjects (0.5%). A total of 35 cases, 29 (14.5%) had documented hypotonia. The prevalence of CHD in 35 DS
children reviewed,20% had an associated CHD while 80% had no CHD. The most common isolated cardiac lesion was ventricular septal defect (VSD), found in 57% patients, and followed
by atrioventricular septal defect (AVSD) in 43%. The mean maternal age at birth of the affected children was 35.66 ± 8.593 years. It was significantly higher than mothers of non-trisomic children (31.28 ± 5.96 years; p = 0.0002). There was a significant difference in the maternal and
paternal ages of patient with DS and non trisomic subjects. Children with free trisomy of chromosome 21 are more frequently born to mothers older than 35 years of age.In both maternal and paternal mean ages of DS patients, the mean was higher compared to that of control.
Maternal age was a significant (AUC= 0.67, p=0.025) risk factor of giving birth to children with
DS.A cut-off value of 42 years and above indicates the risk of giving birth to child with DS
(Sensitivity = 0.31, Specificity= 1.00).However, the paternal age had no effect (AUC= 0.62, p=0.132) as a risk factor of giving birth to DS subject, but 47 years of age was found to have the best sensitivity and specificity in discriminating paternal age of DS birth (Sensitivity = 0.51, Specificity= 0.84).Among the eight DS with CHD, it was found that 3% of male DS cases had CHD, whereas only 5% of female cases had CHD.Confirmation of clinical diagnosis by the
identification of specific types of chromosomal abnormalities in DS children is very important as
it will be used to create awareness about the recurrence risk of having children trisomy 21.The xxiv PCR-based DNA diagnostic method using STR was found to be sensitive, reproducible, and efficient, not only for diagnosis of trisomy 21, but also for tracing allelic transmission from parents to the offspring. This method can also be employed in the diagnosis of trisomy 13 and 18.