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Abstract Aim and Objective Intellectual disability (ID) is a heterogeneous condition affecting brain development, function, and/or structure. The X-linked mode of inheritance of ID (X-linked intellectual disability; XLID) has a prevalence of 1 out of 600 to 1000 males. In the last decades, exome sequencing technology has revolutionized the process of disease-causing gene discovery in XLIDs. Nevertheless, so many of them still remain with unknown etiology. This study investigated four families with severe XLID to identify deleterious variants for possible diagnostics and prevention aims. Methods Nine male patients belonging to four pedigrees were included in this study. The patients were studied genetically for Fragile X syndrome, followed by whole exome sequencing and analysis of intellectual disability-related genes variants. Sanger sequencing, co-segregation analysis, structural modeling, and in silico analysis were done to verify the causative variants. In addition, we collected data from previous studies to compare and situate our work with existing knowledge. Results In three of four families, novel deleterious variants have been identified in three different genes, including ZDHHC9 (p. Leu189Pro), ATP2B3 (p. Asp847Glu), and GLRA2 (p. Arg350Cys) and also with new clinical features and in another one family, a reported pathogenic variant in the L1CAM (p. Glu309Lys) gene has been identified related to new clinical findings. Conclusion The current study's findings expand the existing knowledge of variants of the genes implicated in XLID and broaden the spectrum of phenotypes associated with the related conditions. The data have implications for genetic diagnosis and counseling.

Abstract Objective Gamma‐aminobutyric acid (GABA), the major inhibitory neurotransmitter in the adult central nervous system, plays an important role during embryonic neural network formation. GAD67 is the rate‐limiting enzyme in GABA synthesis, and its deficiency leads to developmental and epileptic encephalopathy 89 (DEE 89). Patients who suffered from this syndrome generally manifested severe to profound neurodevelopmental delay, seizures, and often congenital anomalies such as the cleft palate or/and omphalocele. Up to now, only three papers on this syndrome have been published, and our knowledge about the disease's clinical course and pathophysiology is in its infancy. Methods We used whole‐exome sequencing (WES) and multiple in‐silico tools to detect a potential causative variant in a patient with severe neurodevelopmental delay and refractory epilepsy. Moreover, by molecular docking and molecular dynamics simulation, we investigate the effect of the candidate variant on the GAD67 function and structure. Results WES data analysis revealed a novel deleterious variant (NM_000817.3: c.850C>T; p.Leu284Phe) in the GAD1 gene, which encodes the GAD67 enzyme. Molecular docking and molecular dynamics simulation showed that this variant has deleterious effects on the structure and function of the GAD67. This study's patient, in addition to typical symptoms of the DEE89, showed microcephaly and clonus in the toe, which were novel clinical findings. Significance Our findings expand the mutational and clinical spectrum of DEE 89. Also, by gathering clinical symptoms and genetic findings of previously reported cases, moreover providing a comprehensive clinical picture of the disease, we found that there was no common drug therapy among patients whose epilepsy was controlled. Furthermore, the comparison of clinical symptoms between patients with missense and truncating mutations did not show any significant clinical difference, except that patients with missense mutations did not show cleft palates or omphaloceles.

Background: Only 5 to 10% of cancers are hereditary, but they are particularly important since they can be passed down from generation to generation, and family members are at elevated risk. Although screening methods are one of the essential strategies for dealing with hereditary cancers, they do not have high specificity and sensitivity. The emergence of whole-exome sequencing (WES) causes a significant increase in the diagnostic rate of cancer-causing variants in at-risk families. Materials and Methods: We performed WES on the proband's DNA sample from an Iranian family with multiple cancer-affected members to identify potential causative variants. Multiple in silico tools were used to evaluate the candidate variants' pathogenicity and their effects on the protein's structure, function, and stability. Moreover, the candidate variants were co-segregated in the family with Sanger sequencing. Results: The WES data analysis identified two pathogenic variants (CHEK2: NM_007194.4: c.538C>T, p.Arg180Cys and MLH1: NM_000249.4, c.844G>A, p.Ala282Thr). Sanger sequencing data showed each of the variants was incompletely segregated with phenotype, but both of them explained the patient's phenotype together. Also, the structural analysis demonstrated that due to the variant (c.538C>T), a salt bridge between arginine 180 and glutamic acid 149 was lost. Indeed, several protein stability tools described both variants as destabilizing. Conclusion: Herein, we interestingly identify two distinct deleterious causative variants (CHEK2: NM_007194.4: c.538C>T, p.Arg180Cys and MLH1: NM_000249.4, c.844G>A, p.Ala282Thr) in a family with several cancer-affected members. Furthermore, this study's findings established the utility of WES in the genetic diagnostics of cancer.

Suspicion is an ambiguous concept that prevents execution of criminal sentences and some religious effects of behaviors.In terms of criminal law, is any effective prosecution in the opinion of the judge, which affects the elements of the crime or proofs of evidence in hudud and tazir crimes and causes stopping the execution of the penalty or commutation of sentence. in islamic penal code ratified in 2013,this mechanism is set out in article 120 and 121 but there is no defintion for suspicion and only adresses its examples. after conceptual analysis of the suspicion mode, the basic issue of the writer`s perspective is: which of the effects of suspicion should be applied and what strategies should take in this mode that in addition to accordance with the Shari'a doctrines, ultimately, the damage caused by the functional imbalance in the judical system is reduced. after analyzing the functions in different situations, the result of this research is the recognition of direct interaction between suspicion and functional requirements, such as the princople of individual punishment and targeted attitude toward punishments.