Abstract:
THE GENETIC ANALYSIS OF RETINAL DYSTROPHIES IN
SELECTED PAKISTANI FAMILIES
Retinal Dystrophies (RD) are the major cause of inherited blindness in Pakistan. The
worldwide prevalence of RD is 1 in 3,000-5,000 individuals. There are 42 known loci
and 154 genes that have been reported to be associated with RD. In Pakistan the
percentage of recessive diseases are higher than dominant or X-linked disorders,
which might be due to the high level of cousin marriages. Therefore the purpose of
the present study was to determine the frequency of the mode of inheritance of RD in
the Pakistani population and to evaluate the genetic basis of RD in a cohort of
consanguineous families collected from different areas of Pakistan.
To determine the inheritance pattern of RD in the Pakistani population, data about
medical and family history of 80 families suffering from RD were collected from
different areas of Pakistan. Homozygosity mapping was used to map the genetic
defect in 23 RD families. The families were analyzed for homozygosity at the known
arRP loci using highly informative microsatellite markers and were analyzed for
homozygous chromosomal regions by genome-wide SNP microarrays. Known RD
genes residing in homozygous regions were screened for mutations by sequence
analysis. Identified mutations were analyzed in a cohort of 28 or 44 Pakistani RP
probands and 100 ethnically matched control individuals by allele-specific PCR or
restriction fragment length analysis.
In the Pakistani families with RD that were studied, the occurrence of autosomal
recessive, autosomal dominant and X-linked inheritance forms was found to be 87%,
6%, and 2% respectively while 3% families were with uncertain genetic mode of
inheritance. We thus conclude that autosomal recessive forms of the disease are more
frequent among RD patients in the Pakistani population compared to other
populations of the world. Homozygosity mapping and candidate gene analysis
resulted in the identification of seven novel mutations, including four in known arRP
genes; one in CRB1, one in PDE6B, two in CNGB1 while one known mutation was
identified in RHO. In addition one novel mutation was identified in GRKI causing
Oguchi disease, two novel mutations, one in CNGA3 and CNGB3 were identified in
patients suffering from achromatopsia. In addition to these novel mutations, a new
arRP locus at chromosome 11 was identified in a large consanguineous family. The 7
iifamilies that excluded known arRP loci showed homozygosity at different
chromosomal locations that needs to be further confirmed through microsatellite
markers. The current genetic studies of RD was helpful in obtaining the correct
diagnoses of RD families who had previously been clinically misdiagnosed and
facilitated the provision of a clinical therapy for patients of achromatopsia. In addition
genetic counseling was carried out in those areas of Pakistan where there is little
awareness of inherited diseases.