Balkan Journal of Medical Genetics最新文献

Purpose: Recent studies have addressed the association between lung development and long-noncoding RNAs (lncRNAs). But few studies have investigated the role of lncRNAs in neonatal respiratory distress syndrome (RDS). Thus, this study aimed to compare the expression profile of circulating lncRNAs between RDS infants and controls.

Methods: 10 RDS infants and 5 controls were enrolled. RDS patients were further divided into mild and severe RDS subgroups. Blood samples were collected for the lncRNA expression profile. Subsequently, differentially expressed lncRNAs were screened out. Bioinformatics analysis was applied to establish a co-expression network of differential lncRNAs and mRNAs, and predict the underlying biological functions.

Results: A total of 135 differentially expressed lncRNAs were identified, including 108 upregulated and 27 downregulated lncRNAs (fold-change>2 and P<0.05) among the three groups (non-RDS, mild RDS and severe RDS groups). Of these lncRNAs, four were selected as showing higher fold changes and validated by qRT-PCR. ENST00000470527.1, ENST00000504497.1, ENST00000417781.5, and ENST00000440408.5 were increased not only in the plasma of total RDS patients but also in the severe RDS subgroup. Gene Ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) analyses showed that differentially expressed lncRNAs may play important roles in RDS through regulating PI3KAkt, RAS, MAPK, and TGF-β signaling pathways.

Conclusion: The present results found that ENST00000470527.1, ENST00000504497.1, ENST00000417781.5, and ENST00000440408.5 may be invol ved in RDS. This could provide new insight into research of the potential pathophysiological mechanisms of preterm RDS.

Sexual development (SD) is a complex process with strict spatiotemporal regulation of gene expression. Despite advancements in molecular diagnostics, disorders of sexual development (DSD) have a diagnostic rate of ~50%. Androgen insensitivity syndrome (AIS) represents the most common form of 46,XY DSD, with a spectrum of defects in androgen action. Considering the importance of very strict regulation of the SD, it is reasonable to assume that the genetic cause for proportion of the DSD lies in the non-coding part of the genome that regulates proper gene functioning. Here we present a patient with partial AIS (PAIS) due to a mosaic de novo c.-547C>T pathogenic variant in the 5'UTR of androgen receptor (AR) gene. The same mutation was previously described as inherited, in two unrelated patients with complete AIS (CAIS). Thus, our case further confirms the previous findings that variable gene expressivity could be attributed to mosaicism. Mutations in 5'UTR could create new upstream open reading frames (uORFs) or could disrupt the existing one. A recent systematic genome-wide study identified AR as a member of a subset of genes where modifications of uORFs represents an important disease mechanism. Only a small number of studies are reporting non-coding mutations in the AR gene and our case emphasizes the importance of molecular testing of the entire AR locus in AIS patients. The introduction of new methods for comprehensive molecular testing in routine genetic diagnosis, accompanied with new tools for in sillico analysis could improve the genetic diagnosis of AIS, and DSD in general.

Objectives: Chromosomal abnormalities are an important cause of especially early miscarriages. The aim of this study was to analyze the chromosomal aberrations and determine the frequencies of numerical and structural chromosome abnormalities in spontaneous abortion materials.

Methods: This was a prospective research and ninety two abortion samples obtained from women who had one or more miscarriages were included in the study. Conventional karyotype analysis was performed on each sample to identify possible chromosomal abnormalities.

Results: By karyotype analysis, 11 polyploidy cases, (9 triploids and 2 tetraploids), 8 trisomies (one of which was mosaic), 2 monosomies (monosomy X), 1 isochromosome, 1 Xq deletion, and 4 translocations were detected in abortion materials. Isochromosome and Xq deletion cases were also mosaic. In addition, five polymorphic variants were revealed. We found higher paternal age in polyploidy cases.

Conclusion: The most common anomaly we found in abortion materials was polyploidy. This was followed by aneuploidy (trisomy and monosomy). Polyploidy (triploidy or tetraploidy) emerged as an important cause in cases of spontaneous abortion. Paternal age may be associated with polyploidy especially triploidy.

Fabry disease (FD) is an X-linked, lysosomal glycosphingolipid storage disorder that occurs very rarely. Cardiac involvement may comprise of left ventricular hypertrophy (LVH), arrhythmias, conduction abnormalities, heart failure and valvular abnormalities. The goal of this study was to conduct gene analysis for FD in patients suffering from unexplained LVH. 120 patients over the age of 30 who were diagnosed by echocardiography with idiopathic LVH were included in the study. Patients with severe hypertension, intermediate valve disease such as moderate aortic stenosis, known FD, and a family history of autosomal dominant hypertrophic cardiomyopathy were excluded from the study. GLA gene mutations were studied by Sanger sequence analysis in all patients. Of the 120 total patients included in this study, 69 were female (58%) and 51 were male (42%). The mean age was 60.3 ± 15.7. GLA gene mutations were detected in three male patients. The detected mutations are as follows: NM_000169.2:IVS6-10G>A (c.1000-10G>A), NM_000169.2:c.937G>T (p.D313Y) (p.Asp313Tyr) and NM_000169.2:c.941A>T (p.K314M) (p.Lys314Met). Early diagnosis is of vital importance in FD, which can be treated with enzyme replacement. Genetic screening in patients diagnosed with idiopathic LVH by echocardiography is important in the early diagnosis and treatment of FD. Patients over 30 years of age with idiopathic LVH should be screened for FD. Various new polymorphisms can be detected in genetic screening. Identifying new polymorphisms is important for knowing the true mutations in FD.

Type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS) are diseases caused by the interaction of genetic and non-genetic factors. Therefore, the aim of our study was to investigate the association between six common genetic polymorphisms and T2DM and MetS in males. A total of 120 T2DM, 75 MetS, and 120 healthy controls (HC) were included in the study. ACE ID, eNOS 4a/b, ATR1 A1166C, OXTR (A>G), SOD1 +35A/C, CAT-21A/T gene polymorphisms were genotyped by PCR or PCR-RFLP techniques. T2DM was diagnosed at an earlier age compared to MetS (54 vs 55 years old, p=0.0003) and the difference was greater in carriers of the OXTR G allele (54 vs 56 years old, p=0.0002) or both OXTR G and eNOS b alleles (54 vs 56, p=0.00016). The SOD1 AA genotype (O.R.=0.11, p=0.0006) and the presence of both ACE I and OXTR1 A (O.R.=0.39, p=0.0005) alleles revealed to be protective for T2DM. SOD1 AA and AC genotypes were protective factors for triglyceride (p=0.0002 and p=0.0005, respectively) and HDL cholesterol (p=0.0002 and p=0.0004, respectively) levels in T2DM patients. ACE DD was identified more frequently in hypertensive T2DM patients (O.R.=3.77, p=0.0005) and in those who reported drinking alcohol (p=0.0001) comparing to HC and T2DM patients who did not drink alcohol, respectively. We observed that T2DM patients who reported drinking alcohol had an increased frequency of ACE DD and eNOS bb (p<0.0001), or ACE DD and OXTR G (p<0.0001) compared to non-drinkers. No gene polymorphisms were associated with MetS.

Gitelman syndrome (GS) is a rare renal tubulopathy with an autosomal recessive mode of inheritance, caused by biallelic pathogenic variants in the SLC12A3 gene. The clinical features may overlap with other disorders, such as Bartter syndrome type 3, HNF1B nephropathy or even mitochondrial disease, but can be distinguished by molecular genetic analysis. Here we report on two preschool brothers, who presented with a several months' history of episodes of carpopedal spasms and muscle aches. The biochemical analyses revealed hypokalemia and hypomagnesemia without metabolic alkalosis. A 24-h urine sample demonstrated hypocalciuria. The molecular analyses showed that both patients were heterozygous for 3 (likely) pathogenic variants in SLC12A3: c.1805_1806del; p. (Tyr602Cysfs*31), c.2660+1G>A and c.2944 A>T; p. (Ile982Phe). Analysis of the parents showed that the mother was heterozygous for the c.2944 A>T p.(Ile982Phe) variant, and the father carried the other 2 variants (c.1805_1806del and c.2660+1G>A). Herein we present two children in a family from N. Macedonia with clinical manifestations and electrolyte imbalances suggestive of GS. The results of the tubulopathy next generation sequencing (NGS) panel confirmed the diagnosis. The boys are treated with a high salt diet and oral potassium and magnesium supplements.

Pre-implantation genetic diagnosis (PGD) is not often performed when donor gametes are used, due to its high cost. This is with the presumption that the donors are healthy. We report on five cases of babies with confirmed cystic fibrosis (CF), being the result from in vitro fertilization (IVF) with donor (4 cases) or own gametes (one case). There has been no family history for CF in any of the families affected. The clinical presentation in the children ranged from meconium ileus to recurrent respiratory infections and severe nasal polyposis. The age of diagnosis also varied from birth until 9 years. Since one of the presented cases was discovered in a very renowned private IVF clinic, the clinic changed their own protocol, and currently they test every donor for CF carriership. The percentage of CF carriers in the donor population is roughly the same as the one predicted in the general population of Bulgaria - 1/33. Although PGD is costly, the costs for proper care for a CF patient are currently much higher. The more economical option would to screen every donor for CF carriership. IVF requires a lot of physical and psychological stamina. The couples that go through this procedure also require a great deal of hope. It is essential to be more preconscious for possible congenital diseases. We advocate every IVF center to test the donors for CF carriership or to provide PGD for their clients.

Noninvasive prenatal testing (NIPT) is commonly used to screen for fetal trisomy 13, 18, and 21 and often for sex chromosomal aneuploidies (SCAs). Although the testing is also used for sex chromosomal aneuploidies, it is not as efficient as it is for common trisomies. In this particular study, we present a case for whom the NIPT diagnosis was originally 45,X and who was diagnosed with mixed gonadal dysgenesis 45,X/46,XY after birth. A 38-year-old [G3P3] pregnant woman underwent NIPT at 15 weeks' gestation and was found to be at probable risk for 45,X. Because cordocentesis is an invasive procedure, the pregnant woman did not want to undergo cordocentesis. Consequently, postnatal cytogenetic analysis was performed and the baby's karyotype was shown to be 45,X/46,X,+mar?. No numerical and/or structural anomalies were observed in the karyotypes of parents and siblings. Based on the microarray analysis of the analyzed sample, one copy of the X chromosome was detected in all cells and the presence of one copy of the Y chromosome was detected in a ~40% mosaic state: arr(X) x1,(Y)x1[0.4]. SRY gene duplication on Y chromosome was confirmed by fluorescence in situ hybridization (FISH) and microarray analysis. The patient's clinical examination showed ambiguous genitalia (clitoromegaly) and dysmorphic facial features. The baby underwent surgery for aortic coarctation. The results were consistent with a genetic diagnosis of 45,X/46,XY mixed gonadal dysgenesis. Genetic counselling was offered to the family. In conclusion, NIPT still has potential limitations in correctly identifying sex chromosomes and mosaicism that may mislead clinicians and families.

Wolf-Hirschhorn syndrome is a rare condition caused by terminal deletions, of variable size, in the short arm of chromosome 4. The syndrome displays the combination of typical morphological facial variations, intellectual disability, language delay, and various malformations. This report describes the clinical aspect and developmental evolution of a male patient with Wolf-Hirschhorn syndrome, from infancy to adolescence. The patient was first examined and diagnosed at 11 months, with follow-up at the ages of 4 and 16.

Diastrophic dysplasia (DTD) is an uncommon pathology which falls under the group of skeletal dysplasias with its first symptoms observed from birth. The pathology is often featured by short stature and abnormally short extremities (also known as short-limbed dwarfism); the osseous structures of the body (bones and joints) are characterized through defective development in many body regions. More than 300 genes were reported to be involved in DTD etiology with autosomal recessive, autosomal dominant and X-linked manner. We describe clinical case of a 42-year-old woman from the west of Ukraine with diastrophic dysplasia and two pathogenic variants c.1020_1022del (p.Val341del) and c.1957T>A (p.Cys653Ser) identified in SLC26A2 gene. SLC26A2-related diastrophic dysplasia was confirmed based on the presence of pathogenic variants in SLC26A2, which is associated with autosomal recessive forms of skeletal dysplasia, combined with phenotypic symptoms and radiographic findings.