Homozygosity of the Z-2 polymorphic variant in the aldose reductase gene promoter confers increased risk for neuropathy in children and adolescents with Type 1 diabetes.

BACKGROUND: Diabetic neuropathy (DN) is the least recognized complication of diabetes mellitus and may start early in the course of the disease. Aldose reductase (AKR1B1) gene promoter Z-2/Z-2 polymorphism increases the expression of AKR1B1 enzyme and may contribute to DN. SUBJECTS: We evaluated 108 Type 1 diabetes (T1D) children and adolescents (mean ± SD age: 13.5 ± 3.46 years, disease duration: 5.3 ± 3.4 years) and 150 healthy controls (age: 11.9 ± 2.7 years). METHODS: In both groups, pupillary dilation (PD) in darkness, postural blood pressure test (PBPT), and vibration sensation thresholds (VST) in upper and lower limbs were estimated as indices of autonomic and peripheral neuropathy, respectively. Nerve conduction studies (NCS) were performed in patients as peripheral neuropathy index. The polymorphisms of AKR1B1 gene were evaluated using microsatellite (AC)n sequence Z. RESULTS: PBPT, PD, and VST impairments were more frequent in patient group compared with controls, while 38.6% of patients exhibited NCS abnormality. Gender, age, pubertal status, height, body mass index, diabetes duration, HbA1c, and anti-GAD titers were associated with neuropathy indices in patients. There was a strong correlation between PD and NCS in patients, while homozygous patients for Z-2 AKR1B1 gene polymorphism had higher prevalence of abnormal NCS (83.3% vs. 34.6%), PD (62.5% vs. 31.5%), and PBPT values compared with heterozygous or negative patients. Homozygous AKR1B1 status predicted PD, NCS, and PBPT variance, while PD, VST, NCS, and PBPT parameters accurately discriminated homozygous AKR1B1 patients. CONCLUSIONS: Impaired indices of peripheral and autonomic DN were present in a significant proportion of young T1D patients. PD, VST, NCS, and PBPT parameters were simultaneously associated with homozygous state of AKR1B1 Z-2 gene polymorphism, implicating polyol metabolism with both autonomic and peripheral neuropathies.

The lysine-specific methyltransferase KMT2C/MLL3 regulates DNA repair components in cancer.

Genome-wide studies in tumor cells have indicated that chromatin-modifying proteins are commonly mutated in human cancers. The lysine-specific methyltransferase 2C (KMT2C/MLL3) is a putative tumor suppressor in several epithelia and in myeloid cells. Here, we show that downregulation of KMT2C in bladder cancer cells leads to extensive changes in the epigenetic status and the expression of DNA damage response and DNA repair genes. More specifically, cells with low KMT2C activity are deficient in homologous recombination-mediated double-strand break DNA repair. Consequently, these cells suffer from substantially higher endogenous DNA damage and genomic instability. Finally, these cells seem to rely heavily on PARP1/2 for DNA repair, and treatment with the PARP1/2 inhibitor olaparib leads to synthetic lethality, suggesting that cancer cells with low KMT2C expression are attractive targets for therapies with PARP1/2 inhibitors.

Diabetic neuropathy in children and adolescents with type 1 diabetes mellitus: Diagnosis, pathogenesis, and associated genetic markers.

Diabetic neuropathy (DN) is a common long-term complication of type 1 (T1D) and type 2 (T2D) diabetes mellitus, with significant morbidity and mortality. DN is defined as impaired function of the autonomic and/or peripheral nervous system, often subclinical, particularly in children and adolescents with T1D. Nerve conduction studies (NCS) and skin biopsies are considered gold-standard methods in the assessment of DN. Multiple environmental and genetic factors are involved in the pathogenesis of DN. Specifically, the role of metabolic control and glycemic variability is of paramount importance. A number of recently identified genes, including the AKR1B1, VEGF, MTHFR, APOE, and ACE genes, contribute significantly in the pathogenesis of DN. These genes may serve as biomarkers to predict future DN development or treatment response. In addition, they may serve as the basis for the development of new medications or gene therapy. In this review, the diagnostic evaluation, pathogenesis, and associated genetic markers of DN in children and adolescents with T1D are presented and discussed.

Application of high-resolution array comparative genomic hybridization in children with unknown syndromic microcephaly.

BackroundMicrocephaly can either be isolated or it may coexist with other neurological entities and/or multiple congenital anomalies, known as syndromic microcephaly. Although many syndromic cases can be classified based on the characteristic phenotype, some others remain uncertain and require further investigation. The present study describes the application of array-comparative genomic hybridization (array-CGH) as a diagnostic tool for the study of patients with clinically unknown syndromic microcephaly.MethodsFrom a cohort of 210 unrelated patients referred with syndromic microcephaly, we applied array-CGH analysis in 53 undiagnosed cases. In all the 53 cases except one, previous standard karyotype was negative. High-resolution 4 × 180K and 1 × 244K Agilent arrays were used in this study.ResultsIn 25 out of the 53 patients with microcephaly among other phenotypic anomalies, array-CGH revealed copy number variations (CNVs) ranging in size between 15 kb and 31.6 Mb. The identified CNVs were definitely causal for microcephaly in 11/53, probably causal in 7/53, and not causal for microcephaly in 7/53 patients. Genes potentially contributing to brain deficit were revealed in 16/53 patients.ConclusionsArray-CGH contributes to the elucidation of undefined syndromic microcephalic cases by permitting the discovery of novel microdeletions and/or microduplications. It also allows a more precise genotype-phenotype correlation by the accurate definition of the breakpoints in the deleted/duplicated regions.

Diagnostic exome sequencing to elucidate the genetic basis of likely recessive disorders in consanguineous families.

Rare, atypical, and undiagnosed autosomal-recessive disorders frequently occur in the offspring of consanguineous couples. Current routine diagnostic genetic tests fail to establish a diagnosis in many cases. We employed exome sequencing to identify the underlying molecular defects in patients with unresolved but putatively autosomal-recessive disorders in consanguineous families and postulated that the pathogenic variants would reside within homozygous regions. Fifty consanguineous families participated in the study, with a wide spectrum of clinical phenotypes suggestive of autosomal-recessive inheritance, but with no definitive molecular diagnosis. DNA samples from the patient(s), unaffected sibling(s), and the parents were genotyped with a 720K SNP array. Exome sequencing and array CGH (comparative genomic hybridization) were then performed on one affected individual per family. High-confidence pathogenic variants were found in homozygosity in known disease-causing genes in 18 families (36%) (one by array CGH and 17 by exome sequencing), accounting for the clinical phenotype in whole or in part. In the remainder of the families, no causative variant in a known pathogenic gene was identified. Our study shows that exome sequencing, in addition to being a powerful diagnostic tool, promises to rapidly expand our knowledge of rare genetic Mendelian disorders and can be used to establish more detailed causative links between mutant genotypes and clinical phenotypes.

A variant of uncertain significance of the HMGA2 gene in a child with Silver-Russell syndrome-like phenotype: a case report.

Silver-Russell syndrome 5 (SRS5) is characterized by asymmetric intrauterine growth restriction (IUGR), poor postnatal growth, macrocephaly at birth, and feeding difficulties. Other possible features include triangular shaped face, prominent forehead, hypertelorism, epicanthus, micrognathia, brachydactyly, clinodactyly of the 5th finger, and syndactyly of the 2nd and 3rd toes. Pathogenic variants of the HMGA2 (high mobility group AT-hook 2) gene, on chromosome 12q14, which regulates the transcription of growth factor IGF2, have recently been associated with this syndrome. Herein, we present a 2.5-year-old boy with growth delay, SRS-like phenotype, and a variant of uncertain significance in the HMGA2 gene, which has not, to the best of our knowledge, been described to date in the medical literature. So far, 28 pathogenic variants of the HMGA2 gene in patients with clinical SRS phenotype have recently been reported. Therefore, HMGA2 gene testing should always be done in SRS patients who are found to be negative for the typical 11p15 (epi)mutations and matUPD7, while the mutations should also be added to growth retardation disorder panels.

Association of NADPH oxidase p22phox gene C242T, A640G and -930A/G polymorphisms with primary knee osteoarthritis in the Greek population.

Osteoarthritis (OA) is the most common form of arthritis with still unknown pathogenic etiology and considerable contribution of genetic factors. Recently, a new emerging role of oxidative stress in the pathology of OA has been reported, lacking however elucidation of the underlying mechanism. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase being a complex enzyme produced by chondrocytes, presents the major source of reactive oxygen species and main contributor of increased oxidative stress. The present study aims to evaluate the association of NADPH oxidase p22phox gene C242T, A640G and -A930G polymorphisms with primary knee OA in the Greek population. One hundred fifty five patients with primary symptomatic knee OA participated in the study along with 139 matched controls. Genotypes were determined using polymerase chain reaction and restriction fragment length polymorphism technique. Allelic and genotypic frequencies were compared between both study groups. NADPH p22phox -A930G polymorphism was significantly associated with knee OA in the crude analysis (P = 0.018). No significant difference was detected for C242T and A640G polymorphisms (P > 0.05). The association between -A930G polymorphism and knee OA disappeared when the results were adjusted for obesity (P = 0.078, odds ratio 0.54, 95 % CI 0.272-1.071). The interaction between all three polymorphisms was not significant. The present study shows that NADPH oxidase p22phox gene C242T, A640G and -A930G polymorphisms are not risk factors for knee OA susceptibility in the Greek population. Further studies are needed to give a global view of the importance of this polymorphism in the pathogenesis of OA.

Retrocollis as the cardinal feature in a de novo ITRP1 variant.

BACKGROUND: ITPR1 gene encodes inositol 1,4,5-trisphosphate-receptor-type 1, a Ca2+ channel highly expressed in cerebellar Purkinje cells. ITPR1 gene variants, through a loss-of-function mechanism, have been found to be related with the manifestation of spinocerebellar ataxia (SCA) 15, an adult-onset slow progressive cerebellar ataxia, SCA 29, a rare non-progressive congenital cerebellar ataxia and Gillepsie syndrome (SCA 29 phenotype plus aniridia). They share an heterogeneity of additional phenotypic features while no genotype-phenotype correlation has ever been found. CASE REPORT: Here we report the case of a boy with cerebellar ataxia who came to our clinic due to his cervical dystonia in the form of retrocollis. He presented an early-onset, non-progressive cerebellar ataxia, with cognitive impairment and delayed motor milestones. Whole exome sequencing (WES) revealed an heterozygous nucleotide variation, c.829A > C (p.Ser277Arg) in ITPR1 gene (NM_001168272.1), a de novo ITPR1 variant, as his parents came up with negative genetic testing. Due to his clinical presentation and genetic result, we came up with the diagnosis of SCA 29. CONCLUSION: We described cervical dystonia as a phenotypic feature of ITPR1 related SCA 29, found in a new de novo ITPR1-variant.

Melanocortin receptor-1 gene polymorphisms and the risk of cutaneous melanoma in a low-risk southern European population.

Individuals with melanocortin 1 receptor (MC1R) gene variants have been shown to carry an increased risk for the development of melanoma. In this study, we investigated the relationship of MC1R gene variants and the risk of melanoma in 123 melanoma patients and 155 control subjects from Greece. The entire MC1R gene was sequenced for polymorphisms and the results were correlated with host factors and pigmentary characteristics. MC1R polymorphisms were present in 59.4% of melanoma patients compared to 37.5% of controls, yielding an odds ratio (OR) of 2.43 (95% confidence interval (CI) = 1.50-3.96, P < 0.001) for melanoma among MC1R carriers. The risk of melanoma was enhanced in individuals carrying multiple variant alleles (OR = 6.97; 95% CI = 1.86-26.12, P = 0.004). Only the Val60Leu, Arg142His, and Arg151Cys variants were significantly associated with melanoma risk. In stratified analysis, the risk of melanoma among MC1R carriers was not influenced by skin phototype, skin color, or hair color. No association was found between MC1R genotype and the age of onset of melanoma, the tumor location, or the tumor thickness. In conclusion, MC1R polymorphisms are a predisposing factor of melanoma in a southern European population with a relatively low incidence of the disease.

Association of MMP-1 -1607 1G/2G (rs1799750) polymorphism with primary knee osteoarthritis in the Greek population.

Osteoarthritis is the most common form of arthritis with still unknown pathogenic etiology and considerable contribution of genetic factors. One of the mechanisms of cartilage degradation in osteoarthritis is enzymatic proteolysis of the extracellular matrix by metalloproteinases. MMP-1, produced by chondrocytes and synovial cells, is a major proteinase of the MMPs family. The present study aims at evaluating the association of MMP1 gene -1607 1G/2G (rs1799750) polymorphism with primary knee osteoarthritis in the Greek population. One hundred fifty five patients with primary symptomatic knee osteoarthritis participated in the study along with 139 controls. Genotypes were determined using PCR-RLFP technique. Allelic and genotypic frequencies were compared between both study groups. There was no significant association between MMP1 -1607 1G/2G polymorphism and knee osteoarthritis, in crude analysis; however, after multiple logistic regression analysis, 1G/2G was associated with reduced odds of knee osteoarthritis by 75% in males, compared to genotypes 1G/1G + 2G/2G, adjusting for age and BMI (adjusted OR: 0.25, 95% CI: 0.069, 0.910, p = 0.035). The present study shows that MMP1 -1607 1G/2G (rs1799750) polymorphism might be a risk factor for knee osteoarthritis susceptibility in the Greek population. Further investigations are needed to confirm this association in the pathogenesis of osteoarthritis.

Jérôme Lejeune (1926-1994): father of modern genetics.

Jérôme Lejeune's greatest achievement was the discovery of the genetic basis of Down's syndrome, which he named trisomy 21. His important research in human genetics, as well as his humanitarian spirit and fight against therapeutic abortion, rightly led to his recognition as the founder of modern genetics.