Background: Autosomal recessive congenital ichthyoses (ARCI) are a group of rare nonsyndromic genodermatoses characterized by generalized scaly appearance of the epidermis with markedly impaired cutaneous barriers owing to defects in keratinization related genes. In this study, we ascertained a consanguineous Pakistani family affected with ARCI. Aims: To investigate genetic defect underlying disease phenotype in the affected family. Methods: All available members of the family (affected and unaffected) were sampled. Whole exome sequencing (WES) was performed on DNA of the proband and the data were analyzed for probable pathogenic variants. Segregation of the identified variant was validated by Sanger sequencing. Results: Analysis of the WES data identified a novel nonsense mutation, c.762C>G, in the PNPLA1 (patatin-like phospholipase domain containing 1) gene. The protein product of of this gene is involved in lipid organization during cornified cell envelope formation. The variant is predicted to result in the generation of a premature truncation site at amino acid position 254 (p.Tyr254*). This would result in the loss of a large C-terminal portion of the protein suggesting it to be rendered nonfunctional. In silico protein structure modeling confirmed a detrimental effect of the variation on protein structure. Conclusions: The study supports the evidence for the prevalence of PNPLA1 mutations in distant ethnic groups. Despite the significant number of reported ARCI cases with PNPLA1 variants, a straightforward genotypephenotype correlation cannot be established.

BackgroundPompe disease (PD) is an autosomal recessive metabolic myopathy with an average incidence of one in 40,000 live births. It has a variable age of onset and can be diagnosed within the first 3 months. Heart involvement and muscle weakness are its primary manifestations.Case presentationWe describe two families affected by PD with two rare, novel variants. To date, pathogenic variants in acid α-glucosidase (GAA) alone have accounted for all cases of the disease. Both families were screened for pathogenic sequence variations. This study presents the implications of regulatory or modifier sequences in the disease pathogenesis for the first time. A homozygous missense p.Arg854Gln variant in family A and a single heterozygous variant (p.Asn925His) in family B were found to be segregating according to the disease phenotype. The variants were not detected in our in-house database comprising 50 whole-exome sequences of healthy individuals from a local unrelated Pakistani population. In silico analyses predicted that the variants would have deleterious effects on the protein structure.ConclusionsThe variants likely underlie the infantile-onset PD (IOPD) in these Pakistani families. The study expands the mutation spectrum of GAA associated with IOPD and highlights the insufficiency of screening the GAA coding sequence to determine the cause of IOPD. The work should be helpful in carrier identification, improving genetic counselling, and prenatal diagnosis.

Autosomal recessive osteopetrosis is a severe fatal disorder with an average incidence of around 1:250,000. It is diagnosed soon after birth or within the 1st year of life with severe symptoms of abnormal bone remodelling. This study was aimed to identify the underlying genetic cause of the disease in a Pakistani family segregating infantile malignant osteopetrosis in autosomal recessive pattern. Whole exome sequencing of the proband was performed using the 51 Mb SureSelect V4 library kit and sequenced using the Illumina HiSeq2500 sequencing system. The reads were analysed using standard bioinformatic data analysis pipeline. The genotype of candidate variants was confirmed in the proband and his normal parents by Sanger sequencing. Two novel homozygous missense variants were found in the same codon 204 of CLCN7 NM_001287.5:c.[610A>T;612C>G] predicting p.(Ser204Trp) variant in the protein. Sanger sequencing and RFLP assay verified that both these variants were heterozygous in the unaffected parents. Moreover, these variants were not detected in the unrelated healthy Pakistani subjects (200 chromosomes), ExAC, dbSNP, or the 1000 Genomes Project data. Multiple bioinformatics tools unanimously predicted the p.(Ser204Trp) variant as deleterious. CLCN7 mutation p.(Ser204Trp) is the likely cause of the osteopetrosis disease in the Pakistani family. This study expands the restricted spectrum of CLCN7 mutations associated with infantile malignant osteopetrosis and indicates clinical significance of whole exome sequencing in the diagnosis of clinically and genetically heterogenous osteopetrosis phenotype. These data should be helpful in the improved genetic counselling, carrier identification and prenatal diagnosis of the affected family.

Background Familial hypokalemic periodi9c paralysis (hypoKPP) is a rare autosomal dominant disorder characterized by episodic paralytic attacks caused by fall in blood potassium. CACNA1S, SCN4A or KCNJ2 variants can cause hypoKPP. Case presentation We investigated a Pakistani family affected with autosomal dominant familial hypoKPP through whole exome sequencing (WES). A heterozygous KCNJ2 missense variant c.919A > G was found segregating with the disease phenotype in the family. Conclusions The KCNJ2 missense variant is the likely cause of the disorder in the affected family. The finding should help improve antenatal screening and genetic counselling of this family.

Lumpy dermatitis (LSD) is a widespread illness that affects farm animals, including water-based cattle.The illness is caused by LSD, the disease which is part of the Poxiviridae family Capripox genera. Skin wounds are considered the most common site of infection because the virus can survive for a long time in a wound or scab. LSD's initial medical applications were described in 1929 in Zimbabwe. This skin disease has also had an impact on Pakistan; several animal farms in Karachi have infected large numbers of animals, and 190,000 instances were recently documented across the country, with over 7,500 deaths attributed to disease. LSD has a huge impact on Pakistan's economic condition, resulting in livestock loss and reduced milk production. The Ministry of Research and the Security of Food in Pakistan has organised a task force to create a plan for controlling the spread of disease to cows & buffaloes. Awareness initiatives should include both private and government veterinary technicians, the two areas and abattoirs, vet students, cultivators, livestock merchants, livestock transporters, and artificial insemination.