First family with Perry syndrome from Mexico.

Perry syndrome (PS) is a rare autosomal dominant disease characterized by parkinsonism, central hypoventilation, weight loss and depression and is caused by pathogenic mutations in the dynactin subunit 1 (DCTN1) gene (encoding p150glued protein). To date, only two cases have been reported in Latin America, specifically in Colombia and Argentina. The present study, to the best of our knowledge, reports the first recorded Mexican family with PS. The clinical features of the proband and a family history of early parkinsonism led to the suspicion of PS. The pathogenic variant NM_004082:c.212G>A, causing a (p.Gly71Glu) mutation in the p150glued protein, was identified in exon 2 of the DCTN1 gene by exome sequencing, confirming the diagnosis of PS. (p.Gly71Glu) has been previously identified in at least 4 cases of PS from different ethnic backgrounds. Genetic counseling was provided to the available family members. To clarify the impact of the (p.Gly71Glu) variant on the structure and function of the cytoskeleton-associated protein Gly rich (CAP-Gly) domain of p150glued, Glu71 mutated CAP-Gly domains were modeled and compared with the wild-type. It was hypothesized that the larger and more charged side chain of Glu may induce conformational and electrostatic changes, imposing a conformational restriction on the peptide backbone that would affect interaction with the p150glued protein partners, causing dysfunction in the dynactin protein complex.

Prevalence of pathogenic or likely pathogenic germline variants in cancer predisposition genes among selected patients with lung adenocarcinoma: The GERMLUNG study.

INTRODUCTION: Pathogenic or likely pathogenic germline variants (PGVs) in cancer predisposition genes may play a role in lung cancer (LC) susceptibility. However, determining an eligible population for genetic testing remains uncertain. This study aimed to assess the prevalence of PGVs in a selected cohort of individuals with lung adenocarcinoma. METHODS: A cross-sectional cohort study was conducted to assess the PGVs rate in lung adenocarcinoma patients with a family history of LC, young-onset presentation, history of never/light smoking, or actionable genomic alterations (AGAs). Sequencing was performed using Sophia Hereditary Cancer Solution panel F, including 144 cancer predisposition genes. Variants classified as pathogenic or likely pathogenic were included for further analysis. RESULTS: Of 201 patients, 43 (21.4 %) exhibited PGVs, among which 64.5 % were DNA damage repair genes, and 86.1 % were clinically actionable. The main PGVs were in ATM (9.3 %), TP53 (6.9 %), BRCA2 (6.9 %), and CHEK2 (6.9 %) genes. PGVs were associated with male sex (adjusted odds ratio [aOR] 2.46, 95 % CI 1.15-5.32, p = 0.021), along with a trend toward association with AGAs (aOR 6.04, 95 % CI 0.77-49.74, p = 0.094). CONCLUSIONS: In this study, a high PGVs prevalence was identified based on our selection criteria, which represents an effective strategy to identify candidates for germline genomic testing, potential screening strategies in close relatives, and personalized therapeutic modalities. Our results warrant further exploration in other populations to confirm them.

Case report: A familial B-acute lymphoblastic leukemia associated with a new germline pathogenic variant in PAX5. The first report in Mexico.

B-cell acute lymphoblastic leukemia (B-ALL) is one of the most common childhood cancers worldwide. Although most cases are sporadic, some familial forms, inherited as autosomal dominant traits with incomplete penetrance, have been described over the last few years. Germline pathogenic variants in transcription factors such as PAX5, IKZF1, and ETV6 have been identified as causal in familial forms. The proband was a 7-year-old Mexican girl diagnosed with high-risk B-ALL at five years and 11 months of age. Family history showed that the proband's mother had high-risk B-ALL at 16 months of age. She received chemotherapy and was discharged at nine years of age without any evidence of recurrence of leukemia. The proband's father was outside the family nucleus, but no history of leukemia or cancer was present up to the last contact with the mother. We performed exome sequencing on the proband and the proband's mother and identified the PAX5 variant NM_016734.3:c.963del: p.(Ala322LeufsTer11), located in the transactivation domain of the PAX5 protein. The variant was classified as probably pathogenic according to the ACMG criteria. To the best of our knowledge, this is the first Mexican family with an inherited increased risk of childhood B-ALL caused by a novel germline pathogenic variant of PAX5. Identifying individuals with a hereditary predisposition to cancer is essential for modern oncological practice. Individuals at high risk of leukemia would benefit from hematopoietic stem cell transplantation, but family members carrying the pathogenic variant should be excluded as hematopoietic stem cell donors.

IKZF1plus is a frequent biomarker of adverse prognosis in Mexican pediatric patients with B-acute lymphoblastic leukemia.

Background: Recurrent genetic alterations contributing to leukemogenesis have been identified in pediatric B-cell Acute Lymphoblastic Leukemia (B-ALL), and some are useful for refining classification, prognosis, and treatment selection. IKZF1plus is a complex biomarker associated with a poor prognosis. It is characterized by IKZF1 deletion coexisting with PAX5, CDKN2A/2B, or PAR1 region deletions. The mutational spectrum and clinical impact of these alterations have scarcely been explored in Mexican pediatric patients with B-ALL. Here, we report the frequency of the IKZF1plus profile and the mutational spectrum of IKZF1, PAX5, CDKN2A/2B, and ERG genes and evaluate their impact on overall survival (OS) in a group of patients with B-ALL. Methods: A total of 206 pediatric patients with de novo B-ALL were included. DNA was obtained from bone marrow samples at diagnosis before treatment initiation. A custom-designed next-generation sequencing panel was used for mutational analysis. Kaplan-Meier analysis was used for OS estimation. Results: We identified the IKZF1plus profile in 21.8% of patients, which was higher than that previously reported in other studies. A significantly older age (p=0.04), a trend toward high-risk stratification (p=0.06), and a decrease in 5-year Overall Survival (OS) (p=0.009) were observed, although heterogeneous treatment protocols in our cohort would have impacted OS. A mutation frequency higher than that reported was found for IKZF1 (35.9%) and CDKN2A/2B (35.9%) but lower for PAX5 (26.6%). IKZF1MUT group was older at diagnosis (p=0.0002), and most of them were classified as high-risk (73.8%, p=0.02), while patients with CDKN2A/2BMUT had a higher leukocyte count (p=0.01) and a tendency toward a higher percentage of blasts (98.6%, >50% blasts, p=0.05) than the non-mutated patients. A decrease in OS was found in IKZF1MUT and CDKN2A/2BMUT patients, but the significance was lost after IKZF1plus was removed. Discussion: Our findings demonstrated that Mexican patients with B-ALL have a higher prevalence of genetic markers associated with poor outcomes. Incorporating genomic methodologies into the diagnostic process, a significant unmet need in low- and mid-income countries, will allow a comprehensive identification of relevant alterations, improving disease classification, treatment selection, and the general outcome.

CFTR pathogenic variants spectrum in a cohort of Mexican patients with cystic fibrosis.

Background: Molecular diagnosis of cystic fibrosis (CF) is challenging in Mexico due to the population's high genetic heterogeneity. To date, 46 pathogenic variants (PVs) have been reported, yielding a detection rate of 77%. We updated the spectrum and frequency of PVs responsible for this disease in mexican patients. Methods: We extracted genomic DNA from peripheral blood lymphocytes obtained from 297 CF patients and their parents. First, we analyzed the five most frequent PVs in the Mexican population using PCR-mediated site-directed mutagenesis. In patients with at least one identified allele, CFTR sequencing was performed using next-generation sequencing tools and multiplex ligation-dependent probe amplification. For variants not previously classified as pathogenic, we used a combination of in silico prediction, CFTR modeling, and clinical characteristics to determine a genotype-phenotype correlation. Results: We identified 95 PVs, increasing the detection rate to 87.04%. The most frequent variants were p.(PheF508del) (42.7%), followed by p.(Gly542*) (5.6%), p.(Ser945Leu) (2.9%), p.(Trp1204*) and p.(Ser549Asn) (2.5%), and CFTRdel25-26 and p.(Asn386Ilefs*3) (2.3%). The remaining variants had frequencies of <2.0%, and some were exclusive to one family. We identified 10 novel PVs localized in different exons (frequency range: 0.1-0.8%), all of which produced structural changes, deletions, or duplications in different domains of the protein, resulting in dysfunctional ion flow. The use of different in silico software and American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) criteria allowed us to assume that all of these PVs were pathogenic, causing a severe phenotype. Conclusions: In a highly heterogeneous population, combinations of different tools are needed to identify the variants responsible for CF and enable the establishment of appropriate strategies for CF diagnosis, prevention, and treatment.

Mutational profile by targeted next generation sequencing of non-small cell lung cancer in the Mexican population / Perfil mutacional por secuenciación de nueva generación en cáncer de pulmón de células no pequeñas en población mexicana

Abstract: Objective: Targeted next-generation sequencing (t-NGS) has revolutionized clinical diagnosis allowing multiplexed detection of genomic alterations. This study evaluated the profile of somatic mutations by t-NGS in Mexican patients with non-small cell lung cancer (NSCLC). Materials and methods: Genomic DNA was extracted from 90 lung adenocarcinomas and sequences were generated for a panel of 48 cancer genes. Epidermal Growth Factor Receptor (EGFR) mutations were detected in parallel by quantitative PCR. Results: The mutational profile of NSCLC revealed alterations in 27 genes, where TP53 (47.8%) and EGFR (36.7%) exhibited the highest mutation rates. EGFR Q787 mutations were present in 14 cases (15.6%), 10 cases had exon 19 deletions (11.1%), seven cases had L858R (7.8%). The mutational frequency for genes like EGFR, MET, HNF1A, HER2 and GUSB was different compared to caucasian population. Conclusion: t-NGS improved NSCLC treatments efficacy due to its sensitivity and specificity. A distinct pattern of somatic mutations was found in Mexican population.

Resumen: Objetivo: La secuenciación dirigida de nueva generación (SNG) permite la detección múltiple de mutaciones. Este estudio evalúa el perfil de mutaciones somáticas por SNG en pacientes mexicanos con cáncer de pulmón de células no pequeñas (CPCNP). Material y métodos: Se aisló ADN de 90 muestras de pacientes con CPCNP y se analizarón 48 genes relacionados con cáncer. Las mutaciones del receptor del factor de crecimiento epidérmico (EGFR) se detectaron por PCR cuantitativa. Resultados. Se detectaron alteraciones en 27 genes. Las mutaciones más frecuentes fueron TP53 (47.8%) y EGFR (36.7%). En el gen EGFR, 14 casos fueron mutaciones Q787 (15.6%), 10 presentaron microdeleciones en el exón 19 (11.1%), y siete en L858R (7.8%). La frecuencia de mutación en EGFR, MET, HNF1A, HER2 y GUSB fue diferente en comparación con población caucásica. Conclusión: NGS modifica el tratamiento del paciente con CPCNP por su sensibilidad y especificidad para detectar mutaciones. La población mexicana presenta un perfil mutacional particular.

Linfoma linfocitico intermedio rn fase leucemica. Características citomorfológicas e inmunofenotipicas / Interediate lymphocytic lymphoma in leukemic phase. Cytomorphological and immunophenotypic features

Se describen las alteraciones citomorfológicas e inmunofenotípicas de las células leucémicas en un caso de linfoma linfocítico intermedio en fase leucémica. Las células linfoides circulantes eran en su mayoría de mediano tamaño, muy pleomórficas y con irregularidades nucleares. En su membrana expresaban inmunoglubulinas de superficie, HLA-DR, CD19 y CD76, pero no el CD5, ni formaban rosetas de ratón. En general, las células leucémicas presentaban algunas características semejantes a las del manto folicular normal (AU)

Linfoma linfocitico intermedio rn fase leucemica. Características citomorfológicas e inmunofenotipicas / Intermediate lymphocytic lymphoma in leukemic phase. Cytomorphological and immunophenotypic features

Se describen las alteraciones citomorfológicas e inmunofenotípicas de las células leucémicas en un caso de linfoma linfocítico intermedio en fase leucémica. Las células linfoides circulantes eran en su mayoría de mediano tamaño, muy pleomórficas y con irregularidades nucleares. En su membrana expresaban inmunoglubulinas de superficie, HLA-DR, CD19 y CD76, pero no el CD5, ni formaban rosetas de ratón. En general, las células leucémicas presentaban algunas características semejantes a las del manto folicular normal

Estudio molecular de la leucemia mieloide crónica / Molecular study of chronic yeloid leukemia

El cromosoma filadelfia (Ph) es el resultado de la translocación reciproca entre los cromosomas 9 y 22, [t (9,22) (q34.q11)]. Esta anormalidad citogenética esta presente en más del 90

de los pacientes con leucemia mieloide crónica (LMC) y ocasionalmente en otros tipos de hemopatías. Las técnicas de biología molecular permitieron dilucidar los eventos genómicos relacionados con la formación del cromosoma Ph y demostraron qye cuando esto ocurre el c-abl se traslada del cromosoma 9 al gen bcr en el cromosoma 22 y se sintetiza una proteina hibrida bcr-abl. La aplicación más importante del estudio del reordenamiento del gen bcr ha sido la demostración de que existe un grupo de pacientes Ph negativos (Ph) que tienen reordenamiento del bcr y que evolucionan de forma similar a los casos Ph positivos (Ph), En este trabajo se estudió el reordenamiento del gen bcr por la técnica de Southern, en 26 pacientes con LMC: 23 en fase crónica. 1 en fase acelerada y 2 en crisis blástica. De ellos 23 eran Ph+ y 3 Ph-. Todos los pacientes Ph+ reordenaron el bcr, mientras que en los Ph- no se observó reordenamiento (AU)

Aplicación de la reacción en cadena de la polimerasa (PCR) en medicina / Application of polyerase chain reaction (PCR) in medicine

La técnica de reacción en cadena de la polimerasa (PCR) permite amplificar selectivamente secuencias específicas en el ADN en poco tiempo. con gran eficiencia y sensibilidad, por lo que constituye un valioso instrumento en el campo de la medicina. Este método se ha empleado con éxito en el diagnóstico prenatal de enfermedades hereditarias, en la detección de infecciones virales y en el estudio de hemopatias malignas (AU)

Aplicación de la reacción en cadena de la polimerasa (PCR) en medicina / Application of polymerase chain reaction (PCR) in medicine

La técnica de reacción en cadena de la polimerasa (PCR) permite amplificar selectivamente secuencias específicas en el ADN en poco tiempo. con gran eficiencia y sensibilidad, por lo que constituye un valioso instrumento en el campo de la medicina. Este método se ha empleado con éxito en el diagnóstico prenatal de enfermedades hereditarias, en la detección de infecciones virales y en el estudio de hemopatias malignas

Estudio molecular de la leucemia mieloide crónica / Molecular study of chronic myeloid leukemia

El cromosoma filadelfia (Ph) es el resultado de la translocación reciproca entre los cromosomas 9 y 22, [t (9,22) (q34.q11)]. Esta anormalidad citogenética esta presente en más del 90 % de los pacientes con leucemia mieloide crónica (LMC) y ocasionalmente en otros tipos de hemopatías. Las técnicas de biología molecular permitieron dilucidar los eventos genómicos relacionados con la formación del cromosoma Ph y demostraron qye cuando esto ocurre el c-abl se traslada del cromosoma 9 al gen bcr en el cromosoma 22 y se sintetiza una proteina hibrida bcr-abl. La aplicación más importante del estudio del reordenamiento del gen bcr ha sido la demostración de que existe un grupo de pacientes Ph negativos (Ph) que tienen reordenamiento del bcr y que evolucionan de forma similar a los casos Ph positivos (Ph), En este trabajo se estudió el reordenamiento del gen bcr por la técnica de Southern, en 26 pacientes con LMC: 23 en fase crónica. 1 en fase acelerada y 2 en crisis blástica. De ellos 23 eran Ph+ y 3 Ph-. Todos los pacientes Ph+ reordenaron el bcr, mientras que en los Ph- no se observó reordenamiento