الفهرس 
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Abstract
The study comprised 49 children of Egyptian origin. They included 28 males and 21 females whose
ages ranged between 2 months and 18 years (with a mean of 4.25 + 4.19 years).
Fourteen Patients had Down ’s Syndrome without congenital heart disease, 21 had
Down’s syndrome and congenital heart disease and fourteen patients had . . congenital heart
disease without Down’s Syndrome.
Seventeen control samples were obtained from normal healthy unrelated individuals of matching sex
and ages as the patients of Egyptian origin . ..All subjects were subjected to full clinical
history, ·examination and cardiological assessment.
Molecular analysis of Exon 8 of the C-terminal of COL6A1 gene was perfonned on all the samples.
Amplification of Exon 8 by PCR was done using three primer pairs [F16/R16, F 17/R17& F18/R19].
The amplified PCR product from all children were screened for possible mutations and or
polymorphisms using single stranded conformation polymorphism (SSCP) technique
Multiple changes were detected utilising the SSCP
analysis, some of which were characterised at the DNA sequence level.
The changes found, using primer pairs F 16/R16 and F 18/R19, were in the form of 2 alleles
variants, allele
(A) and allele (B). SSCP analysis of the region
spanned by primer pair F 17/R17 showed 3 alleles variants (A), (B) and (C).
The changes in Exon 8 detected using primer pair (F16/R16) and (F18/R1?) were in apparent linkage
disequilibirium with changes identified from the most variable region spanned by primer F 17/R17.
All the polymorphisms detected in this study were present in euploid individuals. This.._is not
unexpected since parents of children with Down Syndrome are euploid.
However, the group of DS without CHD had significantly more individuals who were homozygous for
allele ”A” compared to the group ofDS with CHD, RR 0.13, 95% CI=0.02- 0.66. Therefore being
homozygous for allele A is protective against CHD.
Allele A is considered to be similar to the normal as the changes in amino acid composition would
not be expected to change the structure and function of the protein.
Sequence analysis has shown some of the C-terminal Exon 8 changes to be associated with amino acid
changes. Some of these mutations resulted in the change of a hydrophilic amino acid residue to a
hydrophobic one. This might increase the size of hydrophobic patches on the surface of COL6A 1
molecule.
The presence of a haplotype with a mutant allele could not explain the occurrence of CHD in Down
Syndrome patients, as some of these mutant alleles are present in the euploid individuals and the
parents who do not have CHD. -
Also the trisomic state of the COL6 A 1 is not sufficient to cause the heart defects, since they
are. present in only 40% of trisomy 21 individuals.
The role ofCOL6 Al mutations in CHD of trisomy 21 individuals can thus be due to combinations of
mutations embedded in particular COL6 A haplotypes which disturb the supramolecular structure of
collagen VI and modulate the predisposition of an individual to a single or several types of CHD.