Identification of a Novel Homozygous GLS Gene Variant Associated with Developmental and Epileptic Encephalopathy (DEE) Type 71.

Developmental and epileptic encephalopathy (DEEs) (OMIM#618,328) is characterized by seizures, hypotonia, and brain abnormalities, often arising from mutations in genes crucial for brain function. Among these genes, GLS stands out due to its vital role in the central nervous system (CNS), with homozygous variants potentially causing DEE type 71. Using Whole Exome Sequencing (WES) on a patient exhibiting symptoms of epileptic encephalopathy, we identified a novel homozygous variant, NM_014905.5:c.1849G > T; p.(Asp617Tyr), in the GLS gene. The 5-year-old patient, born to consanguineous parents, presented with developmental delay, encephalopathy, frequent seizures, and hypotonia. Sanger sequencing further validated the GLS gene variant in both the patient and his family. Furthermore, our bioinformatics analysis indicated that this missense variant could lead to alteration of splicing, resulting in the activation of a cryptic donor site and potentially causing loss of protein function. Our finding highlights the pathogenic significance of the GLS gene, particularly in the context of brain disorders, specifically DEE71.

Novel splicing variant and gonadal mosaicism in DYRK1A gene identified by whole-genome sequencing in multiplex autism spectrum disorder families.

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with considerable genetic heterogeneity. The disorder is clinically diagnosed based on DSM-5 criteria, featuring deficits in social communication and interaction, along with restricted and repetitive behaviours. Here, we performed whole-genome sequencing (WGS) on four individuals with ASD from two multiplex families (MPX), where more than one individual is affected, to identify potential single nucleotide variants (SNVs) and structural variants (SVs) in coding and non-coding regions. A rigorous bioinformatics pipeline was employed for variant detection, followed by segregation analysis. Our investigation revealed an unreported splicing variant in the DYRK1A gene (c.-77 + 2T > C; IVS1 + 2T > C; NM_001396.5), in heterozygote form in two affected children in one of the families (family B), which was absent in the healthy parents and siblings. This finding suggests the presence of gonadal mosaicism in one of the parents, representing the first documented instance of such inheritance for a variant in the DYRK1A gene associated with ASD. Furthermore, we identified a 50 bp deletion in intron 9 of the DLG2 gene in two affected patients from the same family, confirmed by PCR and Sanger sequencing. In Family A, we identified potential candidate variants associated with ASD shared by the two patients. These findings enhance our understanding of the genetic landscape of ASD, particularly in MPX families, and highlight the utility of WGS in uncovering novel genetic contributions to neurodevelopmental disorders.

Association of Interleukin-28B Polymorphisms (rs12979860 C/T, rs12980275 A/G, rs8099917 T/G) and Risk of Hepatocellular Carcinoma in an Iranian Population.

BACKGROUND: Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world. The association of interleukin 28B (IL-28B) polymorphisms and HCC has been investigated in several populations. However, the findings are controversial. This study aimed to address the association between IL-28B polymorphisms (rs 8099917 T/G, rs12979860 C/T, rs12980275 A/G) and the risk of HCC in an Iranian population. METHODS: We have evaluated the association between IL-28B polymorphisms (rs 8099917 T/G, rs12979860 C/T, rs12980275 A/G) and HCC in 180 Iranian individuals (60 patients with HCC and 120 healthy matched controls) using polymerase chain reaction-restriction fragment length polymorphisms (PCR-RFLP) method. Single nucleotide polymorphism (SNP) association analysis and also haplotypes were estimated using the SNPstats online software. RESULTS: There was no significant association between these three polymorphisms of IL-28B and HCC (P>0.05). Moreover, haplotype analysis showed no significant association between the haplotypes and HCC. CONCLUSION: There was no association between IL-28B polymorphisms and HCC in an Iranian population.

A Novel Frameshift Mutation in Abnormal Spindle-Like Microcephaly (ASPM) Gene in an Iranian Patient with Primary Microcephaly: A Case Report.

Autosomal recessive primary microcephaly (MCPH) is a rare genetic disorder, leading to the defect of neurogenic brain development. Individuals with MCPH reveal reduced head circumference and intellectual disability. Several MCPH loci have been identified from several populations. Genetic heterogeneity of this disorder represents molecular testing challenge. An 8 yr old female, born from consanguineous parents, was attended to Fardis Central Lab, Alborz, Iran. Based on the reduced circumference and intellectual disability, MCPH was diagnosed. Whole exome sequencing of the patient identified a novel homozygous frameshift mutation (c.2738dupT, p.Cys914fs) in exon 9 Abnormal Spindle-like Microcephaly (ASPM) gene. By Sanger sequencing, segregation analysis showed that both parents were heterozygous carriers for this variant. The novel frameshift mutation likely truncates the protein, resulting in loss of normal function ASPM in homozygous mutation carriers. The study might add a new pathogenic variant in mutations of the ASPM gene as a causative variant in patients with MCPH and might be helpful in genetic counseling of consanguineous families.

The X-ray Repair Cross-Complementing Group 1 Arg399Gln Genetic Polymorphism and Risk of Hepatocellular Carcinoma in an Iranian Population.

BACKGROUND The association between X-ray repair cross-complementing group 1 (XRCC1) Arg399Gln gene polymorphism and hepatocellular carcinoma (HCC) has been investigated in several populations. However, the findings are controversial. The aim of this study was to address the association between XRCC1 Arg399Gln polymorphism and HCC in an Iranian population. METHODS We have evaluated the association between XRCC1 Arg399Gln gene polymorphism and HCC in 151 Iranian individuals (50 patients with HCC and 101 healthy matched controls) using polymerase chain reaction-restriction fragment length polymorphisms (PCR-RFLP) method. RESULTS Significant association was found for the XRCC1 A allele and HCC [OR = 1.93, 95% CI (1.16 - 3.25), P = 0.0099]. Also, genotype analysis by SNPStats online software showed a significant association between XRCC1 gene polymorphisms and HCC under co-dominant, dominant, and recessive genetic models. CONCLUSION Our study provides evidence that the XRCC1 Arg399Gln polymorphism may be associated with the risk of HCC development in Iranian population.