Rett syndrome (RTT) is a severe neurological disorder usually caused by mutations in the MECP2 gene. Since the MECP2 gene is located on the X chromosome, X chromosome inactivation (XCI) could play a role in the wide range of phenotypic variation of RTT patients; however, classical methylation-based protocols to evaluate XCI could not determine whether the preferentially inactivated X chromosome carried the mutant or the wild-type allele. Therefore, we developed an allele-specific methylation-based assay to evaluate methylation at the loci of several recurrent MECP2 mutations. We analyzed the XCI patterns in the blood of 174 RTT patients, but we did not find a clear correlation between XCI and the clinical presentation. We also compared XCI in blood and brain cortex samples of two patients and found differences between XCI patterns in these tissues. However, RTT mainly being a neurological disease complicates the establishment of a correlation between the XCI in blood and the clinical presentation of the patients. Furthermore, we analyzed MECP2 transcript levels and found differences from the expected levels according to XCI. Many factors other than XCI could affect the RTT phenotype, which in combination could influence the clinical presentation of RTT patients to a greater extent than slight variations in the XCI pattern.
Physiological and pathological processes differ in men and women, depending on factors such as sex and sociological and anthropological characteristics. However, many diseases are still approached from a masculine point of view. In this respect, ischemic heart disease is one of the diseases that most clearly reflects biological differences and social inequalities. In women, the disease presents at a more advanced age, and presentation is frequently atypical with a higher prevalence of comorbidities and greater severity. Consequently, treatment and outcome differ from those in men. Additionally, women differ in their knowledge, and beliefs regarding ischemic heart disease, as well as in their attitudes at symptom onset. Therefore, clinical practice should place significant emphasis on all these aspects in order to avoid inequalities between men and women in the correct diagnosis, treatment, prevention, and rehabilitation of ischemic heart disease.
BACKGROUND AND AIMS The approach to Alport syndrome is a difficult task due to the phenotypic variability of its symptomatology, incomplete penetrance and its different forms of inheritance [1]. It presents a high degree of underdiagnosis, both because of erratic diagnosis as well as the existence of undiagnosed patients [2]. This study shows a patient carrying two pathogenic variants in COL4A3 and COL4A4 genes, respectively. The interest of the case lies in the low reported frequency of this type of inheritance, of which there are still no prevalence studies, but which may help to better understand this entity, as well as aid future diagnoses [3, 4]. METHOD Our index case is a 55-year-old male (IV.1). His medical history dates back to childhood when the disease began with microhematuria, repeated urinary tract infections, proteinuria and a progressive decrease in glomerular filtration rate until he required hemodialysis at 23 years. He received a living-renal transplantation from his mother, restarting hemodialysis at 49 years; a second engraftment was carried out 3 years later that was working for 5 years until a clear cell renal cancer was diagnosed and transplantectomy was required. There was no evidence of hearing or ocular impairment. Throughout the patient's follow-up, the existence of other relatives on the paternal side with kidney disease became known, and with the suspicion of hereditary origin, a genogram of the family was constructed with five generations [Figure 1]. A genetic study was performed using a next-generation sequencing (NGS) panel (Sophia Genetics) covering the coding and splicing regions of 44 genes related to HRE (Table 1). Subsequently, the study was extended to other relatives. RESULTS Molecular analysis identified two probably pathogenic variants in our index case and other relative at the moment, both in heterozygosis, one in exon 48 of the COL4A3 gene: c.4421T > C, p.(Leu1474Pro). This is a missense-type change in which thymine is replaced by cytosine at position 4421 of the coding sequence and predicts the substitution of the amino acid leucine by proline at position 1474 of the protein, affecting two functional domains. This variant is described and reported in the databases as pathogenic. On the other hand, it presents a deletion, also in heterozygosis, of exon 9 of the COL4A4 gene. Both variants were confirmed by Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA), respectively. In this family, the variants co-segregate with the disease, although the analysis of other cases would be useful; furthermore, both variants co-segregate together, which indicates that the variants are in cis and both come from the same branch and neither has a de novo origin. CONCLUSION We have identified a case of digenic inheritance, two pathogenic variants in COL4A3 and COL4A4 genes respectively, thanks to the NGS techniques, of which very few cases have been described in the literature. Genetic analysis is the only way to confirm the diagnosis, often even to establish it after uncertain diagnoses; it is also the way to determine the mode of transmission and can often avoid the use of other invasive and not risk-free techniques such as skin or kidney biopsy. Although there is currently no curative treatment, early diagnosis is important to slow its progression, so that after the identification of a pathogenic variant, the family implications should be of special interest, to carry out adequate genetic counseling where family members at risk are informed and genetic study is offered, as well as the existing reproductive options for affected patients, such as preimplantation genetic testing or gamete donation. Otherwise, the offspring should be included in a program for early detection and monitoring of the disease.
Background and Aims Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary nephropathy that causes kidney failure and the need for renal replacement therapy (RRT). It has recently been established that there is a genotype-phenotype relationship for this disease, with differences in the age of access to TRS if the involvement occurs in the PKD1 or PKD2 gene and if the variant is truncating or not. Identifying patients at high risk for rapid progression has become increasingly important given the emergence of potential new treatments such as tolvaptan. Method Studies are carried out in 23 families affected in which a genetic study has previously been the variant identified. For the survival analysis, the Kaplan-Meier test was performed. Data are expressed in terms of mean ± SD, median and %. Results The data described in Table 1 show that there is huge variability of access to RRT according to the type of variant found in the family. We found families in which the age at which kidney failure occurred ranged from 48.03 (28.38-67.68) years to families in which RRT began with 78.04 (65.06-91.03). We observed that those families that present a variant with a stop or frameshift codon suffer a loss of kidney function before those that present a missense variant. In the variants with a stop or frameshift codon, we observed that they ranged from 48.03 (28.38-67.68) for the variant c.7480G> T (p.Glu2494 *) to 73.75 (61.52-85, 98) in variant c.9616C> T p.Gln3203 *. In those missense variants, the age of access to RRT ranges from 62.17 (60.43-63.91) to 77.13 (71.56-82.71) Conclusion Advances in studies of the genes involved in ADPKD are expanding the identification of new variants and the knowledge about their involvement in the progression of the disease. The correlation between genotype and kidney disease will provide a useful clinical prognosis for ADPKD and will allow us to establish current and future treatments.
Background and Aims Hereditary renal disease (HRD) is still underdiagnosed: although we know aspects related to autosomal dominant polycystic kidney disease (ADPKD), we know little about the incidence and prevalence of other entities such as Alport syndrome. Altogether, HRD can represent 15% of individuals undergoing renal replacement therapy (RRT) or could even be higher. The advancement of genetics at the healthcare level let to achieve accurate and early renal diagnoses, as well as the incorporation of genetic counseling to families, all of which will result in better management of the disease in its initial stages and the possibility of offering reproductive options that avoid transmission to offspring. Our objective is to know the performance offered by the implementation of the ERH panel through Next Generation Sequencing (NGS) in our healthcare area. Method Observational-descriptive study of 259 probands (141 men / 118 women), mean age of 46 years (30 pediatric / 123 over 50 years), with chronic kidney disease and suspected hereditary cause attended in the specialized consultation of our centers from October 2018 to October 2020. The DNA extracted from leukocytes obtained by venipuncture was processed with Nephropathies Solution version 3 panel (SOPHiA Genetics) according to the manufacturer's protocol. This panel covers the coding regions and splicing junctions of 44 HRD-related genes such as nephrotic syndromes, polycystic kidney diseases, Bartter syndromes, Alport syndrome, CAKUT or tubulopathies (table 1). The sequencing of the libraries was done in a MiSeq (Illumina Inc), the bioinformatic analysis of the data and annotation of variants was performed using the SOPHiA DDM 5.8.0.3 software, and the revision of variants by consulting the main databases (ClinVar, Exac, HGMD, NCBI, PKD Foundation, LOVD). Results The panel was informative (pathogenic or probably pathogenic) in 80/259 patients (31%) and 56/259 cases (21.66%) of variants of uncertain significance (VSI) were detected. Autosomal dominant polycystic kidney disease accounted for 76.2% of the variants identified (56.2% PKD1, 20% PKD2), following Alport syndrome with 15% and the alterations in the PKHD1 gene associated with renal polycystic disease in its recessive form with about 4% (Figure 1). We have also identified a case of autosomal dominant tubulointerstitial kidney disease associated with the UMOD gene that was not suspected until the genetic study was performed. We highlight that 45% (36/80) of the variants identified as responsible for the renal disease are not yet described. Overall, the most prevalent type of mutation is that which produces displacement in the reading frame or frameshift (Figure 2). Individually, frameshift is the most frequent alteration in PKD1, PKD2 and COL4A5, while for PKHD1, COL4A3 and COL4A4 it is missense. Conclusion Our NGS HRD panel a) offers an adequate diagnostic performance at the healthcare level, with definitive results in 1 out of 3 cases and has also allowed the performance of many carrier studies among family members b) is able of diagnosing the most frequent disease, ADPKD and Alport syndrome, as well as unresolved or poorly characterized cases, and c) opens the horizon for new diagnoses, all without increasing costs by outsourcing services. All this makes the genetic study of renal pathology a useful and efficient strategy. These results encourage us to enhance the resources in this area that we consider to be of strategic value.
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