Pharmacogenetics of induction therapy-related toxicities in childhood acute lymphoblastic leukemia patients treated with UKALL 2003 protocol

Chemotherapy related toxicities have been the major factor limiting the success of acute lymphoblastic leukemia (ALL) induction therapy. Several factors, including the pharmacogenetics of asparaginase and anthracyclines, could contribute to difference in treatment outcome in ALL. We investigated the significance of variations in genes involved in hepatic and cardiac toxicity 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 minor allele G of SOD2 rs4880 increase the risk of hepatic toxicity [OR 2.63 (1.42–4.84), P = < 0.05] 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.

Case Report: Difficulties in the Treatment of a 12-Year-Old Patient With Homozygous Familial Hypercholesterolemia, Compound Heterozygous Form − 5 Years Follow-Up

The literature review we conducted reveals the limited use of proprotein convertase subtilisin/kexin type 9-inhibitors (PCSK9i) in children with familial hypercholesterolemia (FH). In 2015, a 10-year-old boy presented with round, xanthochromic lesions on his right knee and elbow. The values of total and LDL-cholesterol (LDL-C)−18 and 15 mmol/l, respectively—along with normal triglycerides and HDL-cholesterol (HDL-C) confirmed the lesions were xanthomas. The data suggested a homozygous form of FH. The level of lipoprotein (a) was high: 270 mg/dl. Initial treatment, based on European recommendations, included Atorvastatin 20 mg and Ezetimibe 10 mg and led to a decrease in LDL-C by 46% for 5 months; however, the patient developed severe statin intolerance. Atorvastatin was replaced with Rosuvastatin 10 mg, but the symptoms persisted. Success was achieved by switching to an intermittent regimen: Rosuvastatin 10 mg three times a week with a daily intake of Ezetimibe 10 mg. However, the results were far from the desired LDL target. LDL-apheresis was advisable, but unfortunately, it is not performed in Bulgaria. In May 2017, a genetic analysis [two pathological mutations within the LDLR gene: c.1519A&gt;G; p.(Lys507Glu) and c.2403_2406del; p.(Leu802Alafs*126)] confirmed the initial diagnosis: the patient had homozygous FH with compound heterozygosity indeed. Having turned 12 in September 2017, the patient was eligible for treatment with a PCSK9i: Evolocumab 140 mg. The mean reduction of LDL-C with the triple combination reached a reduction of 52.17% for the whole 2-year period. The LDL target was reached in January 2020. The triple therapy significantly reduced Apolipoprotein B by 29.16%. No statistically significant difference was found in Lp (a) levels (p &gt; 0.05) Our clinical case demonstrates that the triple lipid-lowering combination in a patient with compound heterozygous FH is a good therapeutic option for reaching the LDL-target.

Impact of SOD2, PNPLA3, ABCC1, CBR1 And ABCG2 Variants Upon Toxicities of Induction Therapy In Childhood Acute Lymphoblastic Leukemia

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.

SARS-CoV-2 Infection and Emery-Dreifuss Syndrome in a Young Patient with a Family History of Dilated Cardiomyopathy

Emery–Dreifuss muscular dystrophy (EDMD) is a rare genetic disease that affects the musculoskeletal system, including the heart, causing rhythm disorders and cardiomyopathy, sometimes requiring an implantable cardioverter-defibrillator (ICD) or heart transplantation due to severe heart damage. The case described herein concerns a 16-year-old girl, with grade II obesity, without other known pathological antecedents or cardiac pathology diagnosis given an annual history of cardiological investigations. She was admitted to the Infectious Diseases Department with SARS-CoV-2 virus infection. The anamnesis showed that the cardiological investigations performed in the past were completed due to the medical history antecedents of her sister, who had been diagnosed with dilated cardiomyopathy, having undergone the placement of an ICD and a heart transplant. Numerous investigations were performed during hospitalization, which revealed high levels of high-sensitive cardiac troponin I (hs-cTnI), creatine kinase (CK) and N-terminal pro b-type natriuretic peptide (NT-proBNP). Dynamic electrocardiographic evaluations showed ventricular extrasystoles, without clinical manifestations. The patient presented stage 2 arterial hypertension (AHT) during hospitalization. A cardiac ultrasound was also performed, which revealed suspected mild subacute viral myocarditis with cardiomyopathy, and antihypertensive medication was initiated. A heart MRI was performed, and the patient was diagnosed with dilated cardiomyopathy, refuting the suspicion of viral subacute myocarditis. After discharge, as the patient developed gait disorders with an impossible heel strike upon walking and limitation of the extension of the arms and ankles, was hospitalized in the Neurology Department. Electrocardiograms (ECGs) were dynamically performed, and because the rhythm disorders persisted, the patient was transferred to the Cardiology Department. On Holter monitoring, non-sustained ventricular tachycardia (NSVT) was detected, so antiarrhythmic treatment was initiated, and placement of an ICD was subsequently decided and was diagnosed with EDMD. Genetic tests were also performed, and a mutation of the lamin A/C gene was detected (LMNA gene exon 2, variant c448A > C (p.Thr150pro), heterozygous form, AD).

A Novel Association of Hbq India Trait with Sickle Cell Anemia: A New Insight in Hemoglobinopathies

HbQ India is a rare α-chain structural hemoglobinopathy usually asymptomatic and presents in the heterozygous form or co-inherited with β-thalassemia trait. Herein, we are reporting the third case of novel association of HbQ India with HbS trait hemoglobinopathy in a 30-years-old young male presented with chief complaints of yellowish discoloration of sclera since 5-years with raised serum bilirubin levels along with pedigree analysis of the family.

Whole exome sequencing identified a pathogenic mutation of COL2A1 causing Stickler syndrome in a Vietnamese family

Stickler syndrome is a group of rare inherited diseases associated with abnormalities in connective tissues, specifically collagen of the eyes, ears, craniofacies, skeleton and joints. The inheritance pattern of this disease is either an autosomal dominant or an autosomal recessive based on the causative gene. Stickler syndrome is characterized by severe nearsightedness, vitreous abnormalities, distinctive facial features, hearing problems and joint anomalies. Herein, we report a case of a 37-year-old man from Vietnam suspected of Stickler syndrome, presenting a phenotype of retinal detachment and complete loss of vision, and his 3-year-old son with congenital high myopia and vitreous abnormalities. Genetic analysis using whole exome sequencing (WES) revealed a nucleotide substitution (c.C2818T/p.R940X) in exon 42 of the COL2A1 gene that was previously reported as a pathogenic variant causing Stickler syndrome. Validation of COL2A1 c.C2818T in all members of this family by using Sanger sequencing detected the presence of this pathogenic variant in the heterozygous form in the affected father and son but not in the mother and another son without any signs of a vision problem. Thus, our study contributes to not only the knowledge base of clinical and genetic aspects of Stickler syndrome in Vietnam but also the awareness of the importance of genetic counseling in patients with COL2A1 c.C2818T mutation, as well as early diagnosis and appropriate treatment to prevent serious complications, especially blindness.

Molecular characterization of cytidine monophospho-N-acetylneuraminic acid hydroxylase (CMAH) gene and frequency of blood types in stray cats of İzmir, Turkey

Background Cytidine monophospho-n-acetylneuraminic acid hydroxylase (CMAH) gene associated with blood groups in cats encodes CMAH enzyme that converts Neu5Ac to Neu5Gc. Although variations in CMAH gene of pedigree cats have been revealed, the presence/lack of them in non-pedigree stray cats is unknown. Therefore, the present study aimed to investigate the variations in CMAH gene and the quantity of Neu5Ac and Neu5Gc on erythrocytes of non-pedigree stray cats (n:12) living in İzmir, Turkey. Also, the frequency of blood types was determined in 76 stray cats including 12 cats that were used for CMAH and Neu5A/Neu5Gc analysis. Results In total, 14 SNPs were detected in 5’UTR as well as in exon 2, 4, 9, 10, 11 and 12 of CMAH gene. Among these SNPs, -495 C > T in 5’UTR was detected for the first time as heterozygous in type A and AB cats, and homozygous and heterozygous in type B cats. The remaining 13 that have been detected in previous studies were also found as homozygous or heterozygous. Both Neu5Gc and Neu5Ac were detected in type A and AB cats. In type B cats, only Neu5Ac was detected. Among two type AB cats, the level of Neu5Ac was found higher in cat carrying heterozygous form (T/C) of 1392T > C. The prevalence of type B cats (67.1 %) was higher than others. Conclusions The presence of a new SNP as well as previous SNPs indicates that more variations can be found in stray cats with a more comprehensive study in the future. Also, the high prevalence of type B cats demonstrates the possible risk of neonatal isoerythrolysis among stray cats living in İzmir, Turkey.

Genetic variants of the EGFR ligand-binding domain and their association with structural alterations in Arab cancer patients

Objective This study aimed to identify novel genetic variants in the CR2 extracellular domain of the epidermal growth factor receptor (EGFR) in healthy individuals and patients with six different types of adenocarcinoma, in Arabian peninsula populations. It also aimed to investigate the effects of these variants on the EGFR structure and their eventual relevance to tumorigenesis. Results We detected seven new EGFR genetic variants in 168 cancer patients and 114 controls. A SNP rs374670788 was more frequent in bladder cancer but not significantly associated to. However, a missense mutation (V550M) was significantly associated to colon, ovary, lung, bladder and thyroid cancer samples (p < 0.05). Three mutations (H590R, E602K and T605T) were found in the heterozygous form only in colon cancer patients. Genomic analysis of the synonymous mutation (G632G) showed that the T/A genotype could be associated to thyroid cancer in Arab patients (p < 0.05). An additional novel SNP rs571064657 was observed in control individuals. Computational analysis of the genetic variants revealed a reduction in the stabilization of the EGFR tethered form for both V550M and the common R521K variant with low energetic state (− ∆∆G). Molecular interactions analysis suggested that these mutations might affect the receptor’s function and promote tumorigenesis.

Molecular Characterization of Cytidine Monophospho-N-Acetylneuraminic Acid Hydroxylase (CMAH) Gene and Frequency of Blood Types in Stray Cats of İzmir, Turkey

Cytidine monophospho-n-acetylneuraminic acid hydroxylase (CMAH) gene associated with blood groups in cats encodes CMAH enzyme that converts Neu5Ac to Neu5Gc. Although variations in CMAH gene of pedigree cats have been revealed, the presence/lack of them in non-pedigree stray cats is unknown. Therefore, the present study aimed to investigate the variations in CMAH gene and the quantity of Neu5Ac and Neu5Gc on erythrocytes of non-pedigree stray cats (n:12) living in İzmir, Turkey. Meanwhile, these 12 cats were typed using the mitochondrial DNA control region. Also, the frequency of blood types was determined in 76 stray cats including 12 cats that were used for CMAH and Neu5A/Neu5Gc analysis. In total, 14 SNPs were detected in 5’UTR as well as in exon 2, 4, 9, 10, 11 and 12 of CMAH gene. Among these SNPs, -495C>T in 5’UTR was detected for the first time as heterozygous in type A and AB cats, and homozygous and heterozygous in type B cats. The remaining 13 that have been detected in previous studies were also found as homozygous or heterozygous. Homozygous form (T/T) of the -495C>T polymorphism was found among only type B cats. Among the polymorphisms previously determined in the literature, homozygous form of the -371C>T polymorphism was found among only type B cats whereas heterozygous form (A/C) of the 327A>C polymorphism was detected in only type AB cats. Both Neu5Gc and Neu5Ac were detected in type A and AB cats. In type B cats, only Neu5Ac was detected. Among two type AB cats, the level of Neu5Ac was found higher in cat carrying heterozygous form (T/C) of 1392T>C. Mitotypes A, A6, D, E and 1 were detected among stray cats analysed for the characterisation of CMAH gene. The prevalence of type B cats (67.1%) was higher than others. As a result, the presence of a new SNP as well as previous SNPs indicates that more variations can be found in stray cats with a more comprehensive study in the future. Also, the high prevalence of type B cats demonstrates the high risk of neonatal isoerythrolysis among stray cats living in İzmir, Turkey.

Detection of a Novel Mutation on the Gene ESCO2 in a Pediatric Patient with Syndactyly

Syndactyly is a congenital disease caused by the limb formation abnormalities during fetal development. In this research, we studied the genetic mutations in a pediatric patient with 3rd and 4th fingers were fused together, symmetrically using the whole exome sequencing techniques based on Next generation sequencing. The obtained data revealed a novel mutation located in exon 11 of the gene ESCO2: c.1745A>G: p.582K>R. Sequence verification by Sanger sequencing confirmed the existence of this mutation in the patient as heterozygous form. In silico prediction using PredictSNP, PhD-SNP, PROVEAN or Polyphen-2 tools indicated that the mutation was likely to affect the structure and function of Acetyltransferase? (encoded by ESCO2 gene). Further studies will be performed to analyze the effect of this mutations on the intracellular protein network associated with syndactyly.