To identify the molecular basis of inherited retinal degeneration (IRD) in a familial case of Pakistani origin using whole-exome sequencing.
A thorough ophthalmic examination was completed, and ...genomic DNA was extracted using standard protocols. Whole exome(s) were captured with Agilent V5 + UTRs probes and sequenced on Illumina HiSeq genome analyzer. The exomeSuite software was used to filter variants, and the candidate causal variants were prioritized, examining their allele frequency and PolyPhen2, SIFT, and MutationTaster predictions. Sanger dideoxy sequencing was performed to confirm the segregation with disease phenotype and absence in ethnicity-matched control chromosomes.
Ophthalmic examination confirmed retinal degeneration in all affected individuals that segregated as an autosomal recessive trait in the family. Whole-exome sequencing identified two homozygous missense variants: c.1304G > A; p.Arg435Gln in ZNF408 (NM_024741) and c.902G > A; p.Gly301Asp in C1QTNF4 (NM_031909). Both variants segregated with the retinal phenotype in the PKRD320 and were absent in ethnically matched control chromosomes.
Whole-exome sequencing coupled with bioinformatics analysis identified potential novel variants that might be responsible for IRD.
To identify pathogenic mutations responsible for autosomal recessive retinitis pigmentosa (arRP) in consanguineous familial cases.
Seven large familial cases with multiple individuals diagnosed with ...retinitis pigmentosa were included in the study. Affected individuals in these families underwent ophthalmic examinations to document the symptoms and confirm the initial diagnosis. Blood samples were collected from all participating members, and genomic DNA was extracted. An exclusion analysis with microsatellite markers spanning the TULP1 locus on chromosome 6p was performed, and two-point logarithm of odds (LOD) scores were calculated. All coding exons along with the exon-intron boundaries of TULP1 were sequenced bidirectionally. We constructed a single nucleotide polymorphism (SNP) haplotype for the four familial cases harboring the K489R allele and estimated the likelihood of a founder effect.
The ophthalmic examinations of the affected individuals in these familial cases were suggestive of RP. Exclusion analyses confirmed linkage to chromosome 6p harboring TULP1 with positive two-point LOD scores. Subsequent Sanger sequencing identified the single base pair substitution in exon14, c.1466A>G (p.K489R), in four families. Additionally, we identified a two-base deletion in exon 4, c.286_287delGA (p.E96Gfs77*); a homozygous splice site variant in intron 14, c.1495+4A>C; and a novel missense variation in exon 15, c.1561C>T (p.P521S). All mutations segregated with the disease phenotype in the respective families and were absent in ethnically matched control chromosomes. Haplotype analysis suggested (p<10(-6)) that affected individuals inherited the causal mutation from a common ancestor.
Pathogenic mutations in TULP1 are responsible for the RP phenotype in seven familial cases with a common ancestral mutation responsible for the disease phenotype in four of the seven families.
This study was undertaken to identify causal mutations responsible for autosomal recessive retinitis pigmentosa (arRP) in consanguineous families.
Large consanguineous families were ascertained from ...the Punjab province of Pakistan. An ophthalmic examination consisting of a fundus evaluation and electroretinography (ERG) was completed, and small aliquots of blood were collected from all participating individuals. Genomic DNA was extracted from white blood cells, and a genome-wide linkage or a locus-specific exclusion analysis was completed with polymorphic short tandem repeats (STRs). Two-point logarithm of odds (LOD) scores were calculated, and all coding exons and exon-intron boundaries of RP1 were sequenced to identify the causal mutation.
The ophthalmic examination showed that affected individuals in all families manifest cardinal symptoms of RP. Genome-wide scans localized the disease phenotype to chromosome 8q, a region harboring RP1, a gene previously implicated in the pathogenesis of RP. Sanger sequencing identified a homozygous single base deletion in exon 4: c.3697delT (p.S1233Pfs22*), a single base substitution in intron 3: c.787+1G>A (p.I263Nfs8*), a 2 bp duplication in exon 2: c.551_552dupTA (p.Q185Yfs4*) and an 11,117 bp deletion that removes all three coding exons of RP1. These variations segregated with the disease phenotype within the respective families and were not present in ethnically matched control samples.
These results strongly suggest that these mutations in RP1 are responsible for the retinal phenotype in affected individuals of all four consanguineous families.
This study was conducted to identify the genetic basis of retinal dystrophies in consanguineous Pakistani families. We recruited two families with retinitis pigmentosa (RP) displaying visual ...difficulties, including nyctalopia and constricted visual fields. Linkage analysis and Sanger sequencing resulted in the identification of a previously reported nonsense mutation, c.847C > T, in exon 5 of CERKL in one family and a novel four-base pair deletion in exon 4 of RP1, c.delAGAA4218_4221, leading to premature protein termination in the second family. Here, we report two RP-causing mutations extending the genetic heterogeneity of the disease.
Abstract We report a case of paradoxical respiratory sinus arrhythmia (PRSA) caused by a retro-cardiac empyema in an ambulatory patient. The case describes the dynamics and deleterious impact of PRSA ...on cardio-respiratory cycle, its electrocardiographic, radiologic and echocardiographic findings. Furthermore, it discusses a probable mechanism of paradoxical respiratory sinus arrhythmia in the setting of a retrocardiac mass and suggests a need for physicians to check for the changes in ventilation perfusion mismatch and rise in physiological dead space in such patients. In conclusion, to the best of our knowledge, this is the first documented report of paradoxical respiratory sinus arrhythmia in an ambulatory, non-anesthetized spontaneously breathing patient.
Abstract
Objective: We conducted this study to review deaths due to dengue fever (DF) during a large outbreak of DF in Lahore, Pakistan. Methods: We reviewed deaths due to DF at Jinnah Hospital ...Lahore between August and November 2011. Clinical and laboratory data were abstracted. The 2011 World Health Organization Regional Office for South-East Asia (WHO SEARO) guidelines were used to classify the disease. Results: Out of 128,634 probable DF patients who visited the outpatient department, 2313 patients were hospitalized; 1699 (73.3%) were male. RT-PCR was positive in 92 of 114 hospitalized patients (DENV-2 in 91 patients and DENV-3 in 1 patient). Sixty dengue-related deaths were reported; 41 (68.3%) were male. The mean age (± standard deviation) was 44 (± 20.5) y. The diagnosis at the time of presentation was DF in 5 (8.3%), dengue haemorrhagic fever without shock in 16 (26.6%), dengue shock syndrome in 20 (33%), and expanded dengue syndrome in 19 (31.7%) patients. Expanded dengue syndrome included encephalopathy in 12 (20%) patients, intracerebral bleed in 3 (5%), multiorgan failure in 3 (5%), and Guillain-Barré syndrome in 1 (1.6%). Twenty-nine (48.3%) patients had at least 1 comorbidity. Conclusion: Dengue shock syndrome and expanded dengue syndrome were the most common causes of death.
