Background: Hereditary cancer susceptibility syndrome (HCSS) has been reported to impact cancer predisposition at an early age, therefore, identification of HCSS has found to be crucial for surveillance, managing therapeutic interventions and referring the patients and their families for genetic counselling. The aims of this study are to assess the prevalence of HCSS as hereditary leukemia and hematologic malignancy syndrome by using ACMG guidelines and to assess parental consanguinity as the criterion for referring patients for the genetic counselling. Methods: A total of 300 acute lymphoblastic leukemia subjects were recruited from the Children’s Hospital, Lahore, Pakistan during the period of December 2018 to September 2019. Structured self-reporting questionnaire based on family and medical history of the disease was utilized for the data collection.Results: In our cohort, 60.40% of ALL patients were identified to have HCSS and among them 40.65% patients solely fulfil the criteria due to the presence of parental consanguinity. Parental consanguinity was shown to have protective impact on the onset at early age of disease [OD=0.44 (0.25-0.77), p-value= 0.00] while family history of cancer increase the risk of cardiotoxicity [OD= 2.46 (1.15-5.24), p-value=0.02]. Parental consanguinity in the population shows no significant impact on the family history of cancer and the number of relatives with cancer. Conclusions: The higher prevalence of HCSS in Pakistani population is attributed to the presence of parental consanguinity in more than 50% of the patients when assessed through ACMG guidelines. Our study suggests revisiting ACMG guidelines for the criterion of parental consanguinity in the highly consanguineous population and formulating the score based criteria for the identification of inherited ALL for genetic counselling.

Chemotherapy related toxicities have been the major factor limiting the success of acute lymphoblastic leukemia (ALL) induction therapy. Several factors, including the pharmacogenetics of asparagenase and anthracyclines, could contribute to difference in treatment outcome in ALL. We investigated the significance of variations in genes that are involved in hepatic toxicity and cardiotoxicity in acute lymphoblastic leukemia (ALL). Genotyping of SOD2 (rs4880), PNPL3 (rs738409) and ABCC1 (rs4148350), CBR1 (rs9024) and ABCG2 (rs2231142) was performed by Tetra-ARMS PCR-based technique to evaluate the genotype-phenotype correlation. Our results showed only the minor allele G of SOD2 rs4880 increase the risk of hepatic toxicity [OR=2.63 (1.42-4.84), P=<.05] while minor alleles of other SNPs showed protective impact. However, the genetic contrast analysis showed a recessive form of SOD2 rs4880 [OR=7.82 (3.86-15.85), P=<0.05] and PNPLA3 I148M [OR=5.82 (3.43-9.87), P=<0.05] variants whereas dominant genotype of ABCC1 rs4148350 [OR=2.52 (1.55-4.10), P=<0.05] significantly predisposes hepatotoxicity. Furthermore, heterozygous form of ABCG2 rs2231142 [OR=5.25 (1.84-14.95), P=<0.05] and recessive genotype of 3′UTR variant CBR1 rs9024 [OR=2.31 (1.31-4.07), P=<0.05] were strongly associated with cardiotoxicity. The information obtained from these genetic variations could offer biomarkers for individualization of therapeutic intervention in ALL.