The Role of DNA Repair (XPC, XPD, XPF, and XPG) Gene Polymorphisms in the Development of Myeloproliferative Neoplasms.

Background and Objectives: Several polymorphisms have been described in various DNA repair genes. Nucleotide excision DNA repair (NER) detects defects of DNA molecules and corrects them to restore genome integrity. We hypothesized that the XPC, XPD, XPF, and XPG gene polymorphisms influence the appearance of myeloproliferative neoplasms (MPNs). Materials and Methods: We investigated the XPC 1496C>T (rs2228000, XPC Ala499Val), XPC 2920A>C (rs228001, XPC Lys939Gln), XPD 2251A>C (rs13181, XPD Lys751Gln), XPF-673C>T (rs3136038), XPF 11985A>G (rs254942), and XPG 3507G>C (rs17655, XPG Asp1104His) polymorphisms by polymerase chain reaction-restriction fragment length polymorphism analysis in 393 MPN patients [153 with polycythemia vera (PV), 201 with essential thrombocythemia (ET), and 39 with primary myelofibrosis (PMF)] and 323 healthy controls. Results: Overall, we found that variant genotypes of XPD 2251A>C were associated with an increased risk of MPN (OR = 1.54, 95% CI = 1.15-2.08, p = 0.004), while XPF-673C>T and XPF 11985A>G were associated with a decreased risk of developing MPN (OR = 0.56, 95% CI = 0.42-0.76, p < 0.001; and OR = 0.26, 95% CI = 0.19-0.37, p < 0.001, respectively). Conclusions: In light of our findings, XPD 2251A>C polymorphism was associated with the risk of developing MPN and XPF-673C>T and XPF 11985A>G single nucleotide polymorphisms (SNPs) may have a protective role for MPN, while XPC 1496C>T, XPC 2920A>C, and XPG 3507G>C polymorphisms do not represent risk factors in MPN development.

Influence of XPC, XPD, XPF, and XPG gene polymorphisms on the risk and the outcome of acute myeloid leukemia in a Romanian population.

XPC, XPD, XPF, and XPG genes are implicated in the nucleotide excision repair (NER) system. Gene polymorphisms in NER repair system may influence the individual's capacity to recognize and repair DNA lesions, thus increasing the cancer risk. We hypothesized that these gene polymorphisms might influence the probability of developing acute myeloid leukemia (AML). We investigated the XPC, XPD, XPF, and XPG gene polymorphisms in 108 AML cases and 163 healthy controls. Also cytogenetic analyses besides FLT3 and DNMT3A mutations status were investigated. We found that variant genotypes (heterozygous and homozygous) of XPD 2251A > C and 22541A > C and the heterozygous genotype of XPG 3507G > C were associated with the risk of developing AML (OR = 2.55; 95% CI = 1.53-4.25; p value <0.001; OR = 1.66, 95 % CI = 1.02-2.72; p value = 0.047, and OR = 2.36; 95 % CI = 1.32-4.21; p value = 0.004, respectively). No association was found between white blood cell counts, FLT3, DNMT3A mutations, cytogenetic risk group, and variant genotypes of none of the analyzed polymorphisms. Variant homozygous XPF 673C > T genotype was associated with higher dose of cytosine arabinoside treatment administrated to AML patients (p value = 0.04). No differences were found regarding survival time and variant genotype in the investigated gene polymorphisms with the exception of XPD 2251A > C. In conclusion, XPD 22541A > C, XPD 2251A > C, and XPG 3507G > C gene polymorphisms confer susceptibility to AML, while XPC 2920A > C, XPF-673C > T, XPF 11985A > G are not associated with AML.

Compound heterozygous FAM20C gene variants in a patient with severe Raine syndrome: a case report.

Raine syndrome is a congenital disorder caused by biallelic mutations in the FAM20C gene. While most diagnosed cases of the syndrome are lethal in the first few months of life, there are also reports of non-lethal cases with Raine syndrome. The characteristic of this syndrome is typical facial dysmorphism and generalized osteosclerosis, as well as possible intracranial calcification, hearing loss, and seizures. We report a case of a 4-day-old patient at the time of examination, born with a distinct facial dysmorphism, short neck, narrow chest, and curved tibia. The parents, affirmative gypsy and non-consanguineous, had a previous male child born with the same phenotype who died at 4 months old. The computed tomography scan revealed choanal atresia, while transfontanelar ultrasound showed hypoplasia of the frontal and temporal lobes, corpus callosum dysgenesis, and multiple areas of intracranial hyperechogenicity. The chest X-Ray revealed generalized increased bone density. A skeletal disorders gene panel was performed which identified two variants in the FAM20C gene: a pathogenic variant c.1291C>T (p.Gln431*) and a likely pathogenic variant (c.1135G>A) (p.Gly379Arg), confirming the clinical diagnosis. The parents were also tested, and each was found to carry one of the variants. The particularity of this case is the severe phenotype in a compound heterozygous case that consists of FAM20C c.1291C>T (p.Gln431*) variant that has recently been reported in the literature. Also, our case is one of the few compound-heterozygous mutations in the FAM20C gene that has been described in a non-consanguineous marriage.

Pathogenic Biallelic Mutations in ECHS1 in a Case with Short-Chain Enoyl-CoA Hydratase (SCEH) Deficiency-Case Report and Literature Review.

ECHS1 gene mutations are known to cause mitochondrial short-chain enoyl-CoA hydratase 1 deficiency, a neurodegenerative disorder characterized by psychomotor development delay, lactic acidosis, and basal ganglia lesions resembling Leigh syndrome. Short-chain enoyl-CoA hydratase 1 (ECHS1) deficiency is a very rare and new disorder, with a wide phenotypic spectrum and different outcomes ranging from neonatal death to survival into adulthood. Since the identification of ECHS1 deficiency in 2014, almost 63 patients with pathogenic mutations in the ECHS1 gene have been described to date. This paper focuses on the clinical and molecular findings as well as the evolution of a Caucasian girl diagnosed with ECHS1 deficiency who carries a new compound heterozygous mutation in the ECHS1 gene. Polymorphic symptoms, namely failure to thrive, significant global developmental delay/regression, movement disorders, ocular abnormalities, hearing loss, seizure, and cardiac myopathy, may be a challenge in mitochondrial disorder suspicion. Early diagnosis, an appropriate diet with valine restriction, and trigger avoidance are essential, as there is no effective therapy for the disease. This disorder influences life quality in these patients and their caregivers, and it has the potential to be fatal.

Pitt-Hopkins Syndrome: Clinical and Molecular Findings of a 5-Year-Old Patient.

Pitt Hopkins syndrome (PTHS) is a very rare condition and until now, approximately 500 patients were reported worldwide, of which not all are genetically confirmed. Usually, individuals with variants affecting exons 1 to 5 in the TCF4 gene associate mild intellectual disability (ID), between exons 5 to 8, moderate to severe ID and sometimes have some of the characteristics of PTHS, and variants starting from exon 9 to exon 20 associate a typical PTHS phenotype. In this report, we describe the clinical and molecular findings of a Caucasian boy diagnosed with PTHS. PTHS phenotype is described including craniofacial dysmorphism with brachycephaly, biparietal narrowing, wide nasal bridge, thin and linear lateral eyebrows, palpebral edema, full cheeks, short philtrum, wide mouth with prominent and everted lips, prominent Cupid's bow, downturned corners of the mouth, microdontia and also the clinical management of the patient. The previously and the current diagnosis scores are described in this report and also the challenges and their benefits for an accurate and early diagnosis.

Presence of copy number aberration and clinical prognostic factors in patients with acute myeloid leukemia: an analysis of effect modification.

INTRODUCTION: Acute myeloid leukemia (AML) is characterized by multiple acquired genetic events, chromosomal abnormalities such as copy number aberrations (CNAs), disease progression, and low survival rates. OBJECTIVES: We assessed the utility of a multiplex ligation-dependent probe amplification (MLPA) assay in AML as well as correlations of CNAs with various biological and clinical features of patients with AML, including somatic mutations in the FLT3, NPM1, and DNMT3A genes and survival. PATIENTS AND METHODS: The study included 283 patients with AML. The MLPA was used for investigation of CNAs. The status of somatic mutations was analyzed in all cases. RESULTS: The presence of CNAs was associated with the adverse (high) risk category according to the European LeukemiaNet (ELN) classification (PFDR <0.0001). The significant predictors of mortality were age of 65 years or older (hazard ratio [HR], 2.30; 95% CI, 1.71-3.09), ELN high­risk category (HR, 1.71; 95% CI, 1.15-2.56), and the Eastern Cooperative Oncologic Group Scale (ECOG) performance status grade of 3 or higher (HR, 2.43; 95% CI, 1.80-3.30), but not the presence of CNA. An interaction between CNAs and the ECOG performance status was shown (HRinteraction, 2.24; 95% CI, 1.09-4.57, P = 0.02). The presence of CNAs was positively correlated with the risk of death in patients with an ECOG grade of 3 or higher (HR, 2.02; 95% CI, 1.30-3.12), while for patients with the performance status of 2 or lower, the presence of CNAs was a protective factor against the risk of death. CONCLUSIONS: The presence of CNAs may modify the effect of the ECOG performance status on survival. Independent predictors of mortality in patients with AML include age, ELN adverse risk category, and the ECOG grade of at least 3.