Whole Exome Sequence of Pakistani Acute Lymphocytic Leukemia Patient from Pakhtuns Ancestry Reveal the Novel Genetic Variant Characterization in the GLDC Gene

Author(s): Shahid Ullah, Alex Tonks, Maryam A Halawi, Alruwaili A M, Alkuwaykibi M S, Azhar A Halawi, Amir Hayat, Hedib Alkoumi H Alrawili, Maryam Alanazi, Abdul Wadood, Asifullah Khan, Muhammad Arif Lodhi

Background: Acute Lymphoblastic Leukemia (ALL) is the most common malignant disease in children and often involves numerical chromosomal abnormalities, fusion genes, or minor localized deletions that are significant in the development of leukemia. Glycine Decarboxylase (GLDC) gene overexpression and mutation is associated with oncogenic activity in various cancers. However, the pathophysiological roles and structural consequences of GLDC in acute lymphocytic leukemia have not been investigated.

Objective: We aimed to identify novel variant in acute lymphocytic leukemia through whole exome sequencing. Methods: This study employs whole exome sequencing to examine seven pediatric patients with Acute Lymphoblastic Leukemia (ALL) in Pakistan. The patients under investigation are of Pakistani origin. The deleterious effect was predicted by SIFT, PolyPhen2, CADD, FATHMM, HOPE, and Mutation Assessors. Structure stability assessment was performed using the I-Mutant-3.0server. The atomic structure of the Single Nucleotide Polymorphism (SNP) was analyzed utilizing the Molecular Dynamics (MD) with WEBGRO server.

Results: The present study identified a novel pathogenic heterozygous variant NM_000170.2:p.Ser551Cys/c.1651A>T in GLDC gene of early stage diagnose ALL patient the variant was not present in the dbSNP & 1000Genome Project databases. Structural instability, disrupted function, and altered 3D structure were observed in the mutant GLDC protein model compared to the wild-type structure.

Conclusion: The novel SNP was found in a highly conserved region of the GLDC protein and is predicted to be a high-risk candidate for leukemia. This variant greatly affects the stability of the protein.

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