Delineating the Spectrum of Genetic Variants Associated with Bardet-Biedl Syndrome in Consanguineous Pakistani Pedigrees.

This study aimed to find the molecular basis of Bardet-Biedl syndrome (BBS) in Pakistani consanguineous families. A total of 12 affected families were enrolled. Clinical investigations were performed to access the BBS-associated phenotypes. Whole exome sequencing was conducted on one affected individual from each family. The computational functional analysis predicted the variants' pathogenic effects and modeled the mutated proteins. Whole-exome sequencing revealed 9 pathogenic variants in six genes associated with BBS in 12 families. The BBS6/MKS was the most common BBS causative gene identified in five families (5/12, 41.6%), with one novel (c.1226G>A, p.Gly409Glu) and two reported variants. c.774G>A, Thr259LeuTer21 was the most frequent BBS6/MMKS allele in three families 3/5 (60%). Two variants, c.223C>T, p.Arg75Ter and a novel, c. 252delA, p.Lys85STer39 were detected in the BBS9 gene. A novel 8bp deletion c.387_394delAAATAAAA, p. Asn130GlyfsTer3 was found in BBS3 gene. Three known variants were detected in the BBS1, BBS2, and BBS7 genes. Identification of novel likely pathogenic variants in three genes reaffirms the allelic and genetic heterogeneity of BBS in Pakistani patients. The clinical differences among patients carrying the same pathogenic variant may be due to other factors influencing the phenotype, including variants in other modifier genes.

Visual impairment and progressive phthisis bulbi caused by recessive pathogenic variant in MARK3.

Developmental eye defects often severely reduce vision. Despite extensive efforts, for a substantial fraction of these cases the molecular causes are unknown. Recessive eye disorders are frequent in consanguineous populations and such large families with multiple affected individuals provide an opportunity to identify recessive causative genes. We studied a Pakistani consanguineous family with three affected individuals with congenital vision loss and progressive eye degeneration. The family was analyzed by exome sequencing of one affected individual and genotyping of all family members. We have identified a non-synonymous homozygous variant (NM_001128918.2: c.1708C > G: p.Arg570Gly) in the MARK3 gene as the likely cause of the phenotype. Given that MARK3 is highly conserved in flies (I: 55%; S: 67%) we knocked down the MARK3 homologue, par-1, in the eye during development. This leads to a significant reduction in eye size, a severe loss of photoreceptors and loss of vision based on electroretinogram (ERG) recordings. Expression of the par-1 p.Arg792Gly mutation (equivalent to the MARK3 variant found in patients) in developing fly eyes also induces loss of eye tissue and reduces the ERG signals. The data in flies and human indicate that the MARK3 variant corresponds to a loss of function. We conclude that the identified mutation in MARK3 establishes a new gene-disease link, since it likely causes structural abnormalities during eye development and visual impairment in humans, and that the function of MARK3/par-1 is evolutionarily conserved in eye development.

Seroprevalence of transfusion transmitted infections among different blood group donors at Blood Bank LUMHS, Hyderabad.

OBJECTIVES: To study the prevalence of HBsAg, Anti-HCV, HIV, Syphilis and Malaria in blood donors. METHODS: This is a cross sectional descriptive study, conducted at Blood bank and Transfusion center at Liaquat University of Medical & Health Sciences (LUMHS) Hyderabad, during the period from January, 2014 to June, 2015. A total of 4683 blood donors were screened for HBsAg, Anti-HCV and HIV on Architect 20001 (manufactured by Abbott), employing chemiluminescent microparticle immunoassay (CMIA). For Syphilis, VDRL ICT kits were used and Malaria parasite was screen through MP slides. Blood grouping was performed by both forward and reverse methods. RESULTS: This study showed a high frequency of HBsAg, VDRL and malaria positivity among the O-ve blood group donors, i.e. 3.70%, 9.25% and 0.61% respectively. Blood group B-ve individuals were commonly infected with HCV (12.5%) as compared with all other blood group donors. HIV is more commonly reported in A+ve blood group individuals. Blood group O+ve is more prevalent (37.41 %). CONCLUSION: High frequency of HCV infection in blood donors advocates implementation of strict screening policy for donors and public awareness campaigns about preventive measures to reduce the spread of this infection as well as other transfusion transmissible infections.