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With its high rate of consanguineous marriages and diverse ethnic population, little is currently understood about the genetic architecture of autism spectrum disorder (ASD) in Pakistan. Pakistan has a highly ethnically diverse population, yet with a high proportion of endogamous marriages, and is therefore anticipated to be enriched for biallelic disease-relate variants. Here, we attempt to determine the underlying genetic abnormalities causing ASD in thirty-six small simplex or multiplex families from Pakistan. Microarray genotyping followed by homozygosity mapping, copy number variation analysis, and whole exome sequencing were used to identify candidate. Given the high levels of consanguineous marriages among these families, autosomal recessively inherited variants were prioritized, however de novo/dominant and X-linked variants were also identified. The selected variants were validated using Sanger sequencing. Here we report the identification of sixteen rare or novel coding variants in fifteen genes ( ARAP1 , CDKL5 , CSMD2 , EFCAB12 , EIF3H , GML , NEDD4 , PDZD4 , POLR3G , SLC35A2, TMEM214 , TMEM232 , TRANK1 , TTC19 , and ZNF292 ) in affected members in eight of the families, including ten homozygous variants in four families (nine missense, one loss of function). Three heterozygous de novo mutations were also identified (in ARAP1 , CSMD2 , and  NEDD4 ), and variants in known X-linked neurodevelopmental disorder genes CDKL5 and SLC35A2 . The current study offers information on the genetic variability associated with ASD in Pakistan, and demonstrates a marked enrichment for biallelic variants over that reported in outbreeding populations. This information will be useful for improving approaches for studying ASD in populations where endogamy is commonly practiced.

This study investigates the genetic basis of retinal diseases in four consanguineous families from Pakistan, focusing on mutations in the CNGA3, CACNA1F , and RPGRIP1 genes that are implicated in retinal dysfunctions such as achromatopsia, congenital stationary night blindness, and retinal dystrophies. We identified pathogenic variants in these genes, including the novel missense mutation c.955T > C; p.Cys319Arg in CNGA3 (Family 1), the frameshift mutation c.1443dupT; p.Ile482Hisfs*6 in CNGA3 (Family 2), the missense mutation c.2254G > A; p.Val752Met in CACNA1F (Family 3), and the frameshift mutation c.2789dupT; p.Pro931Thrfs*3 in RPGRIP1 (Family 4). Clinical features associated with these mutations include nystagmus, photophobia, reduced visual acuity, and color vision deficiency, with some patients progressing to complete blindness. The findings were validated through Sanger sequencing, segregation analysis, and in silico prediction tools. Additionally, molecular dynamics simulations were conducted to assess the impact of the CNGA3 p.Cys319Arg mutation on protein structure, revealing significant alterations in protein conformation and dynamics. These results highlight the significance of CNGA3, CACNA1F , and RPGRIP1 in retinal health and provide valuable insights into the genetic underpinnings of retinal disorders. Our findings contribute to improved genetic counseling, potential targeted therapies, and a deeper understanding of inherited retinal diseases.

Whole Exome Sequencing (WES) was performed on 265 Pakistani individuals with suspected neurodevelopmental disorders, revealing that seven of them carried homozygous mutations in the PLA2G6 gene, which is linked to neurodegenerative diseases such as Infantile Neuroaxonal Dystrophy (INAD) and Parkinson’s disease 14 (PD14). These patients presented with a typical cluster of symptoms, including ataxia, gait instability, cognitive decline, motor regression, and psychiatric manifestations like autistic features, impulsive behaviour, and emotional lability. However, the clinical presentation varied across patients, underscoring the phenotypic diversity associated with PLA2G6 mutations. We identified six distinct variants in the PLA2G6 gene (NM_003560.4) across seven affected individuals. These comprised two pathogenic variants ( c.2370T > G and c.1427 + 1G > T), three likely pathogenic variants c.929T > A (observed in two patients), c.1591 + 5G > C, and c.2276G > T, and one variant of uncertain significance c.905T > G. All these mutations were predicted to be disease-related by in silico tools, confirming their likely role in disease causation. This study elucidates the variety of clinical features due to PLA2G6 mutations, with manifestations ranging from motor-cognitive to psychiatric features. Our results emphasize the importance of new homozygous variants for the genetic heterogeneity of these diseases. We want to underscore the value of genetic testing in patients with progressive neurodevelopmental signs, like in the case of our patient, which may result in early diagnosis and help in deciding treatment later. Furthermore, this study provides additional insight into genotype-phenotype correlations of PLA2G6 -associated diseases and offers directions for future studies to develop tailored therapeutics.

One of the aggressive and lethal cancers, pancreatic ductal adenocarcinoma (PDAC) is characterized by poor prognosis and resistance to conventional treatments. Moreover, the tumor immune microenvironment (TIME) plays a crucial role in the progression and therapeutic resistance of PDAC. It is associated with T-cell exhaustion, leading to the progressive loss of T-cell functions with an impaired ability to kill tumor cells. Therefore, this study employed single-cell RNA sequencing (scRNA-seq) analysis of a publicly available human PDAC dataset, with cells isolated from the primary tumor and adjacent normal tissues, identifying upregulated genes of T-cells and cancer cells in two groups (“cancer cells_vs_all-PDAC” and “cancer-PDAC_vs_all-normal”). Common and unique markers of cancer cells from both groups were identified. The Reactome pathways of cancer and T-cells were selected, while the genes implicated in those pathways were used to perform PPI analysis, revealing the hub genes of cancer and T-cells. The gene expression validation of cancer and T-cells hub-genes was performed using GEPIA2 and TISCH2, while the overall survival analysis of cancer cells hub-genes was performed using GEPIA2. Conclusively, this study unraveled 16 novel markers of cancer and T-cells, providing the groundwork for future research into the immune landscape of PDAC, particularly T-cell exhaustion. However, further clinical studies are needed to validate these novel markers as potential therapeutic targets in PDAC patients.

Livestock is an important commodity playing a major role in the global economy. Red meat plays an important role in human life, as it is a good source of animal protein and energy. The fatty acid content of beef has been shown to impact the eating experience and nutritional value of beef. Therefore, this study aimed to identify genomic regions which can account for genetic variation in meat fatty acid content. Genotypes imputed to the Illumina BovineHD 770K BeadChip were used in this study. Thirty-six 1-Mb genomic regions with a posterior probability of inclusion (PPI) greater than 0.90 were identified to be associated with variation in the content of at least one fatty acid. The genomic regions (1Mb) which were associated with more than one fatty acid trait with high genetic variance and harbored good candidate genes were on Chromosome (Chr) 6 (fatty acid binding protein 2), Chr 19 (thyroid hormone receptor alpha, fatty acid synthase), Chr 26 (stearoyl-CoA desaturase), and Chr 29 (thyroid hormone responsive, fatty acid desaturase 2, and fatty acid desaturase 3). Further studies are required to identify the causal variants within the identified genomic regions. Findings from the present study will help to increase understanding of the variation in fatty acid content of beef and help to enhance selection for beef with improved fatty acid composition.

Background Oculocutaneous albinism (OCA) is a genetically heterogeneous condition that is associated with reduced or absent melanin pigment in the skin, hair, and eyes, resulting in reduced vision, high sensitivity to light, and rapid and uncontrolled eye movements. To date, seventeen genes have been associated with OCA including syndromic and non-syndromic forms of the condition. Methods Whole exome sequencing (WES) was performed to identify pathogenic variants in nine Pakistani families with OCA, with validation and segregation of candidate variants performed using Sanger sequencing. Furthermore, the pathogenicity of the identified variants was assessed using various in-silico tools and 3D protein structural analysis software. Results WES identified biallelic variants in three genes explaining the OCA in these families, including four variants in TYR, three in OCA2, and two in HPS1 , including two novel variants c.667C > T: p.(Gln223*) in TYR, and c.2009 T > C: p.(Leu670Pro) in HPS1 . Conclusions Overall, this study adds further knowledge of the genetic basis of OCA in Pakistani communities and facilitates improved management and counselling services for families suffering from severe genetic diseases in Pakistan.

The heart of learning genetics is in realizing that how the likelihood of inheriting a particular trait can be predicted. This fundamental approach is the basis for plant and animal breeding to get desired varieties as well as performing genetic analysis including prediction of patterns of inheritance in family lines and to calculate the recurrence risk for relatives etc. Punnett square is used to describe the possible combinations of paternal and maternal alleles for a particular cross. Described here is a line-dot method using ternary genotype codes to determine genotype probabilities in a very quick and simple way. Also ternary genotype codes along with gender symbols and affection status are used to modify the Punnett squares. On applying these modified Punnett squares along polygonal shapes covers all possible parental combinations and their genotypic and phenotypic outcomes in offspring.In this way, simple illustrations incorporate a considerable amount of information that provides the opportunity to determine genotype and phenotype probabilities for monogenic Mendelian traits without the need to draw Punnett square for every parental genotype combination. These illustrations provide information for both forward (phenotype to genotype) as well as reverse genetics (genotype to phenotype) approaches.

Specific language impairment (SLI) is a developmental disorder with substantial genetic contributions. A genome-wide linkage analysis and homozygosity mapping were performed in five consanguineous families from Pakistan. The highest LOD scores of 2.49 at 12p11.22-q11.21 in family PKSLI-31 and 1.92 at 6p in family PKSLI-20 were observed. Homozygosity mapping showed a loss of heterozygosity on 1q25.3-q32.2 and 2q36.3-q37.3 in PKSLI-20. A loss of heterozygosity mapped, in PKSLI-31 and PKSLI-34 flanks, NFXL1 and CNTNAP2, which are genes previously identified in SLI. Our findings report novel SLI loci and corroborate previously reported SLI loci, indicating the utility of a family-based approach.

Congenital idiopathic nystagmus (CIN) is an oculomotor disorder characterized by repetitive and rapid involuntary movement of the eye that usually develops in the first six months after birth. Unlike other forms of nystagmus, CIN is widely associated with mutations in the FRMD7 gene. This study involves the molecular genetic analysis of a consanguineous Pakistani family with individuals suffering from CIN to undermine any potential pathogenic mutations. Blood samples were taken from affected and normal individuals of the family. Genomic DNA was extracted using an in-organic method. Whole Exome Sequencing (WES) and analysis were performed to find any mutations in the causative gene. To validate the existence and co-segregation of the FRMD7 gene variant found using WES, sanger sequencing was also carried out using primers that targeted all of the FRMD7 coding exons. Additionally, the pathogenicity of the identified variant was assessed using different bioinformatic tools. The WES results identified a novel nonsense mutation in the FRMD7 (c.443T>A; p. Leu148 *) gene in affected individuals from the Pakistani family, with CIN resulting in a premature termination codon, further resulting in the formation of a destabilized protein structure that was incomplete. Co-segregation analysis revealed that affected males are hemizygous for the mutated allele c.443T>A; p. Leu148 * and the affected mother is heterozygous. Overall, such molecular genetic studies expand our current knowledge of the mutations associated with the FRMD7 gene in Pakistani families with CIN and significantly enhance our understanding of the molecular mechanisms involved in genetic disorders.

Congenital idiopathic nystagmus (CIN) is an oculomotor disorder characterized by repetitive and rapid involuntary movement of the eye that usually develops in the first six months after birth. Unlike other forms of nystagmus, CIN is widely associated with mutations in the FRMD7 gene. This study involves the molecular genetic analysis of a consanguineous Pakistani family with individuals suffering from CIN to undermine any potential pathogenic mutations. Blood samples were taken from affected and normal individuals of the family. Genomic DNA was extracted using an in-organic method. Whole Exome Sequencing (WES) and analysis were performed to find any mutations in the causative gene. To validate the existence and co-segregation of the FRMD7 gene variant found using WES, sanger sequencing was also carried out using primers that targeted all of the FRMD7 coding exons. Additionally, the pathogenicity of the identified variant was assessed using different bioinformatic tools. The WES results identified a novel nonsense mutation in the FRMD7 (c.443T>A; p. Leu148 *) gene in affected individuals from the Pakistani family, with CIN resulting in a premature termination codon, further resulting in the formation of a destabilized protein structure that was incomplete. Co-segregation analysis revealed that affected males are hemizygous for the mutated allele c.443T>A; p. Leu148 * and the affected mother is heterozygous. Overall, such molecular genetic studies expand our current knowledge of the mutations associated with the FRMD7 gene in Pakistani families with CIN and significantly enhance our understanding of the molecular mechanisms involved in genetic disorders.