RESUMO
Dear Editor, We have read the article "The usefulness of the genetic panel in the classification and refinement of diagnostic accuracy of Mexican patients with Marfan syndrome and other connective tissue disorders", recently published in your esteemed journal. We are a team dedicated to diagnosing, approaching, and managing patients with connective tissue disorders, particularly hypermobile spectrum disorders (HSD) and Ehlers-Danlos syndromes (EDS). We appreciate the research group's effort to address the complexity of connective tissue disorders using a multi-panel genetic approach and their analysis of genotype-phenotype associations in a cohort of Mexican patients. However, we would like to express our concern regarding two specific points that we consider crucial for the comprehensive understanding and management of these disorders. Read more in the PDF.
Assuntos
Doenças do Tecido Conjuntivo , Síndrome de Marfan , Humanos , Síndrome de Marfan/genética , Síndrome de Marfan/diagnóstico , México , Doenças do Tecido Conjuntivo/genética , Doenças do Tecido Conjuntivo/diagnóstico , Testes Genéticos/métodos , Estudos de Associação Genética/métodosRESUMO
Adrenal hypoplasia congenita, attributed to NR0B1 pathogenic variants, accounts for more than 50% of the incidence of primary adrenal insufficiency in children. Although more than 250 different deleterious variations have been described, no genotype-phenotype correlation has been defined to date. We report a case of an adopted boy who reported the onset of an adrenal crisis at 2 weeks of age, requiring replacement therapy with mineralocorticoids and glucocorticoids for 4 months. For 3 years, he did well without treatment. At almost 4 years of age, the disorder was restarted. A long follow-up showed the evolution of hypogonadotropic hypogonadism. Molecular studies on NR0B1 revealed a novel and deleterious deletion-insertion-inversion-deletion complex rearrangement sorted in the 5'-3' direction, which is described as follows: (1) deletion of the intergenic region (between TASL and NR0B1 genes) and 5' region, (2) insertion of a sequence containing 37 bp at the junction of the intergenic region of the TASL gene and a part of exon 1 of the NR0B1 gene, (3) inversion of a part of exon 1, (4) deletion of the final portion of exon 1 and exon 2 and beginning of the 3'UTR region, (5) maintenance of part of the intergenic sequence (between genes MAGEB1 and NR0B1, telomeric sense), (6) large posterior deletion, in the same sense. The path to molecular diagnosis was challenging and involved several molecular biology techniques. Evaluating the breakpoints in our patient, we assumed that it was a nonrecurrent rearrangement that had not yet been described. It may involve a repair mechanism known as nonhomologous end-joining (NHEJ), which joins two ends of DNA in an imprecise manner, generating an "information scar," represented herein by the 37 bp insertion. In addition, the local Xp21 chromosome architecture with sequences capable of modifying the DNA structure could impact the formation of complex rearrangements.
Assuntos
Insuficiência Adrenal , Receptor Nuclear Órfão DAX-1 , Pré-Escolar , Humanos , Masculino , Insuficiência Adrenal/genética , Insuficiência Adrenal/patologia , Insuficiência Adrenal/diagnóstico , Insuficiência Adrenal/congênito , Receptor Nuclear Órfão DAX-1/genética , Seguimentos , Estudos de Associação Genética/métodos , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Hipoadrenocorticismo Familiar/genética , Mutação/genética , Fenótipo , Recém-Nascido , AdolescenteRESUMO
BACKGROUND: Glutathione S-transferase Pi (GSTP1) enzyme has a major antioxidant effect on the central nervous system (CNS), where it acts against oxidative damage, an established risk factor for amyotrophic lateral sclerosis (ALS). Hence, the purpose of this study was to evaluate a possible relationship between GSTP1 rs1695 polymorphism and the survival rate of male ALS patients, which is the gender more affected by the disease. METHODS AND RESULTS: A case-control study was performed with 56 male ALS patients and 70 healthy male individuals from Midwestern Brazil, which were age-adjusted. GSTP1 rs1695 polymorphism molecular analysis was carried out with restriction fragment length polymorphism. The relationship between ALS patients and GSTP1 rs1695 polymorphism was analyzed using cumulative survival rate as the major outcome, where differences in survival were evaluated through the log-rank test. Our results revealed that mutant genotype (G/G) did not influence the cumulative survival rate of male ALS patients regarding the age of diagnosis (p = 0.5) and time from symptom to diagnosis (p = 0.3). On the other hand, mutant carriers exhibited a significant survival of fewer than 25 months compared to A/A and A/G genotypes that survive more than 100 months (p = 7-E10) in comparison with symptom onset to outcome (p = 0.00006). CONCLUSIONS: In summary, our findings revealed that mutant genotype carriers' male patients had a reduced lifetime, which probably may be resulted from oxidative stress exposure in CNS.
Assuntos
Esclerose Lateral Amiotrófica/genética , Glutationa S-Transferase pi/metabolismo , Adulto , Esclerose Lateral Amiotrófica/metabolismo , Brasil/epidemiologia , Estudos de Casos e Controles , Estudos de Associação Genética/métodos , Predisposição Genética para Doença , Genótipo , Glutationa S-Transferase pi/genética , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Fragmento de Restrição , Polimorfismo de Nucleotídeo Único/genética , Fatores de RiscoRESUMO
Objectives and Methods: Erdheim-Chester disease (ECD) is a rare histiocytic neoplasm with a heterogeneous clinical course, ranging from localized and asymptomatic bone lesions to a multisystem disease, causing significant morbidity and mortality. There are few cohorts published, mainly from North America and Europe. We retrospectively collected clinical data on sixteen biopsy-proven ECD patients diagnosed and treated at two Brazilian reference centres for histiocytic disorders from January 2006 to February 2020.Results: Median time from onset of symptoms to diagnosis was 13 months (0.1-142). The main organ involved in ECD was bone (75%) and also 75% of the patients presented involvement of more than one organ, characterizing a multi-organic form. BRAF status was available in 81.2% of patients and BRAF V600E mutation was detected by Sanger sequencing in only 18.8%, which can be explained by the low sensitivity of this technique. All patients were treated due to symptomatic disease and a median of two lines (range: 1-7) of therapy were needed. The most common first-line therapy used was α-interferon (75%). The median progression-free survival was 7.5 months, and the median OS was not reached.Discussion and Conclusion: In the largest Latin American cohort of patients with ECD reported to date, we observed findings which resemble demographic characteristics, sites of involvement and treatment choices reported by other groups. The outcomes may be better with target therapies such as BRAF and MEK inhibitors in patients with mutation and with the adoption of recently published consensus recommendations for the management of ECD patients.
Assuntos
Biomarcadores Tumorais , Doença de Erdheim-Chester/diagnóstico , Doença de Erdheim-Chester/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Biópsia , Medula Óssea/patologia , Brasil , Doença de Erdheim-Chester/terapia , Estudos de Associação Genética/métodos , Humanos , América Latina , Mutação , Estadiamento de Neoplasias , Fenótipo , Estudos RetrospectivosRESUMO
Patients with inherited retinal dystrophies (IRDs) were recruited from two understudied populations: Mexico and Pakistan as well as a third well-studied population of European Americans to define the genetic architecture of IRD by performing whole-genome sequencing (WGS). Whole-genome analysis was performed on 409 individuals from 108 unrelated pedigrees with IRDs. All patients underwent an ophthalmic evaluation to establish the retinal phenotype. Although the 108 pedigrees in this study had previously been examined for mutations in known IRD genes using a wide range of methodologies including targeted gene(s) or mutation(s) screening, linkage analysis and exome sequencing, the gene mutations responsible for IRD in these 108 pedigrees were not determined. WGS was performed on these pedigrees using Illumina X10 at a minimum of 30X depth. The sequence reads were mapped against hg19 followed by variant calling using GATK. The genome variants were annotated using SnpEff, PolyPhen2, and CADD score; the structural variants (SVs) were called using GenomeSTRiP and LUMPY. We identified potential causative sequence alterations in 61 pedigrees (57%), including 39 novel and 54 reported variants in IRD genes. For 57 of these pedigrees the observed genotype was consistent with the initial clinical diagnosis, the remaining 4 had the clinical diagnosis reclassified based on our findings. In seven pedigrees (12%) we observed atypical causal variants, i.e. unexpected genotype(s), including 4 pedigrees with causal variants in more than one IRD gene within all affected family members, one pedigree with intrafamilial genetic heterogeneity (different affected family members carrying causal variants in different IRD genes), one pedigree carrying a dominant causative variant present in pseudo-recessive form due to consanguinity and one pedigree with a de-novo variant in the affected family member. Combined atypical and large structural variants contributed to about 20% of cases. Among the novel mutations, 75% were detected in Mexican and 50% found in European American pedigrees and have not been reported in any other population while only 20% were detected in Pakistani pedigrees and were not previously reported. The remaining novel IRD causative variants were listed in gnomAD but were found to be very rare and population specific. Mutations in known IRD associated genes contributed to pathology in 63% Mexican, 60% Pakistani and 45% European American pedigrees analyzed. Overall, contribution of known IRD gene variants to disease pathology in these three populations was similar to that observed in other populations worldwide. This study revealed a spectrum of mutations contributing to IRD in three populations, identified a large proportion of novel potentially causative variants that are specific to the corresponding population or not reported in gnomAD and shed light on the genetic architecture of IRD in these diverse global populations.
Assuntos
Etnicidade/genética , Degeneração Retiniana/genética , Consanguinidade , Análise Mutacional de DNA/métodos , Exoma/genética , Proteínas do Olho/genética , Feminino , Estudos de Associação Genética/métodos , Ligação Genética/genética , Genótipo , Humanos , Masculino , México , Mutação/genética , Paquistão , Linhagem , Retina/patologia , Sequenciamento do Exoma/métodos , Sequenciamento Completo do Genoma/métodosRESUMO
Congenital limb deficiency (CLD), one of the most common congenital anomalies, is characterized by hypoplasia/aplasia of one or more limb bones and can be isolated or syndromic. The etiology in CLD is heterogeneous, including environmental and genetic factors. A fraction remains with no etiological factor identified. We report the study of 44 Brazilian individuals presenting isolated or syndromic CLD, mainly with longitudinal defects. Genetic investigation included particularly next-generation sequencing (NGS) and/or chromosomal microarray. The overall diagnostic yield was 45.7%, ranging from 60.9% in the syndromic to 16.7% in the non-syndromic group. In TAR syndrome, a common variant in 3´UTR of RBM8A, in trans with 1q21.1 microdeletion, was detected, corroborating the importance of this recently reported variant in individuals of African ancestry. NGS established a diagnosis in three individuals in syndromes recently reported or still under delineation (an acrofacial dysostosis, Coats plus and Verheij syndromes), suggesting a broader phenotypic spectrum in these disorders. Although a low rate of molecular detection in non-syndromic forms was observed, it is still possible that variants in non-coding regions and small CNVs, not detected by the techniques applied in this study, could play a role in the etiology of CLD.
Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Deformidades Congênitas dos Membros/diagnóstico , Deformidades Congênitas dos Membros/genética , Fenótipo , Brasil , Pré-Escolar , Consanguinidade , Feminino , Estudos de Associação Genética/métodos , Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Recém-Nascido , Masculino , Linhagem , Análise de Sequência de DNA , SíndromeRESUMO
INTRODUCTION: Non-classical class I human leukocyte antigens (HLA) molecules are known to modulate the function of cytotoxic cells (NK and T CD8+) during viral infection by interacting with inhibitory/activating receptors. However, little is known about the HLA-E/-F genetic variability on arbovirus infections. METHODS: We evaluated by massive parallel sequencing the full HLA-E/-F genetic diversity among patients infected during the arbovirus (ZIKV, DENV, and CHIKV) outbreak leading to a broad range of neurological complications in the Brazilian State of Pernambuco. In parallel, healthy blood donors from the same area were also studied. Plink and R software were used for genetic association study. To limit the false-positive results and enhance the reliability of the results, we adopted P-values <0.01 as significant levels. RESULTS: Compared to controls, the HLA-F alleles: -1610 C (rs17875375), +1383 G (rs17178385), and +3537 A (rs17875384), all in complete linkage disequilibrium with each other (r2 = 1), were overrepresented in patients presenting peripheral spectrum disorders (PSD). The HLA-F*Distal-D haplotype that harbored the -1610 C allele exhibited a trend increase in PSD group. No associations were found for HLA-E. CONCLUSIONS: Our findings showed that the HLA-F genetic background seems to be more important than HLA-E on the susceptibility to PSD complications.
Assuntos
Infecções por Arbovirus/genética , Infecções por Arbovirus/virologia , Predisposição Genética para Doença/genética , Variação Genética/genética , Antígenos de Histocompatibilidade Classe I/genética , Doenças do Sistema Nervoso/genética , Doenças do Sistema Nervoso/virologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Arbovírus/patogenicidade , Brasil , Criança , Feminino , Frequência do Gene/genética , Estudos de Associação Genética/métodos , Haplótipos/genética , Humanos , Desequilíbrio de Ligação/genética , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Many genes associated with familial forms of the amyotrophic lateral sclerosis (fALS) have been identified in European and North American cohorts. However, little is known about the genetic bases of fALS in Latin America and Brazil, in particular. To address this question, we recruited 107 patients with fALS from 93 unrelated families from Southeastern, Southern, and Northeastern regions of the country. A 3-step diagnostic approach was used: 1) Triplet repeat primed polymerase chain reaction to search for C9orf72 expansions, then 2) fragment digestion to search for the c.166 C>T VAPB variant, and finally, 3) whole exome sequencing for those who tested negative. We identified the genetic cause for fALS in 70% of the families. VAPB and C9orf72 were the most frequent genes (30% and 22%, respectively), followed by SOD1, TARDBP, ANXA11, and FUS. Five novel variants in known ALS genes were found, including the SOD1 Val120Leu and ANXA11 Asp40Tyr, which were seen in 2 unrelated families each. In conclusion, VAPB and then C9orf72 are the genes most commonly related to fALS in Brazil.
Assuntos
Esclerose Lateral Amiotrófica/epidemiologia , Esclerose Lateral Amiotrófica/genética , Proteína C9orf72/genética , Estudos de Associação Genética/métodos , Variação Genética/genética , Proteínas de Transporte Vesicular/genética , Brasil/epidemiologia , Estudos de Coortes , Proteínas de Ligação a DNA/genética , Reação em Cadeia da Polimerase , Proteína FUS de Ligação a RNA/genética , Superóxido Dismutase-1/genética , Sequenciamento do ExomaRESUMO
Aim: We conducted a retrospective analysis in 71 Mexican Mestizo patients to evaluate the breast cancer-free survival (BCFS) among the inferred genetic phenotypes (GP) of CYP2D6. Patients & methods:CYP2D6 was genotyped through Taqman-probe analysis; GP were inferred according to international guidelines. The BCFS was estimated through Kaplan-Meier method and analyzed with a log-rank test; hazard ratios were calculated with 95% CI and p < 0.05. Results: The BCFS did not differ among CYP2D6 GP (p = 0.45) and recurrence risk was similar between gNM + gUM and gPM + gIM groups (hazard ratio: 1.54, 95% CI: 0.37-6.38; p = 0.55). Conclusion: The findings do not support any impact of CYP2D6 on BCFS. Evaluation of other genetic/nongenetic biomarkers is needed in Mexican Mestizo patients under tamoxifen treatment.