Carmen Alaez-Verson

Background: Thyroid hormones (TH) regulate skeletal development, central nervous system maturation, and energy homeostasis, primarily through the nuclear receptors TRα and TRβ, encoded by the THRA and THRB genes. Pathogenic variants in THRA lead to resistance to thyroid hormone alpha (RTHα), a rare and diagnostically challenging condition. Methods: A 36-year-old woman and her 12-year-old son were studied to characterize the clinical, biochemical, radiological, and exploratory cerebral metabolic findings associated with a previously unreported, likely pathogenic variant in THRA . Both individuals underwent a comprehensive clinical evaluation. Thyroid function tests included TSH, fT4, fT3, TT3, TT4, and rT3, along with additional biochemical assessments. Molecular analysis included whole-exome sequencing in proband 1, which identified a variant in THRA (NM_199334.5:c.662T>C; p.Ile221Thr), subsequently confirmed in the second case. Additionally, the adult patient underwent brain positron emission tomography with 18F-fluorodeoxyglucose (18F-FDG PET) to assess regional cerebral metabolism with exploratory visual and ROI-based comparison with an age- and sex-matched control subject. Results: Both patients exhibited a phenotype consistent with RTHα, characterized by hypotonia, macrocephaly, dysmorphic features, chronic constipation, and normocytic anemia. The fT3/fT4 ratio was elevated (high-normal), and rT3 levels were decreased in both cases. The THRA variant was located in the ligand-binding domain and segregated with the familial phenotype. Exploratory brain ^18F-FDG PET assessment in Proband 1 showed symmetrically higher FDG uptake in the prefrontal cortex, basal ganglia, and lateral temporal cortex compared with the control subject, with consistently higher SUVmax values across the evaluated ROIs. These findings represent an exploratory single-subject comparison and have not previously been reported in RTHα. Conclusions: This study expands the clinical, biochemical, radiological, and metabolic spectrum associated with THRA variants and suggests that cerebral metabolic evaluation may provide additional diagnostic insights in RTHα. Further studies, including larger cohorts and functional analyses, will be necessary to confirm the proposed mechanisms and the clinical relevance of the observed metabolic findings.

Mexico has one of the highest incidences of childhood acute lymphoblastic leukemia worldwide and also reports one of the lowest 5-year overall survival rates; one cause is elevated treatment-related mortality from severe hematologic toxicity, a critical side effect during chemotherapy. Although association studies have identified common genetic variants linked to toxicity, the Mexican population remains incompletely explored. We performed targeted next-generation sequencing of genes involved in methotrexate and mercaptopurine metabolism in 96 Mexican children with ALL, stratified by hematologic toxicity severity according to CTCAE v5.0. Logistic regression revealed nominally significant associations between the TSER*3/TSER*2 genotype (rs45445694) in the 5′ UTR of TYMS severe hematologic toxicity (overdominant model: OR = 3.21; 95% CI = 1.23–8.38; p = 0.014 and codominant model: OR = 3.31; 95% CI = 1.17–9.34; p = 0.047). Additionally, the CCND1 LD block (rs678653/rs7177) also showed nominal associations (overdominant model: OR = 2.60; 95% CI = 1.01–6.71; p = 0.044). None of these associations remained statistically significant after Bonferroni correction for multiple testing (corrected α = 0.000588). Patients with severe toxicity had lower 5-year overall survival than those without severe toxicity (70.2% vs. 90.5%; p = 0.0609), although the difference was not statistically significant. Variants in 5′ and 3′ UTRs regions were markedly enriched compared to coding sequences, underscoring the importance of regulatory region analysis.

Background/Objectives: Multiple Sclerosis (MS) is a chronic immune-mediated disorder characterized by neuroinflammation and neurodegeneration. Increasing evidence implies the kynurenine pathway (KP) in the MS pathophysiology; however, data from Mexican populations are lacking. This exploratory study aimed to characterize central and circulating KP metabolites in Mexican patients with MS and to investigate potential genetic variants in KP-related genes. Methods: Serum concentrations of kynurenic acid (KYNA) and 3-hydroxykynurenine (3-HK), as well as cerebrospinal fluid (CSF) levels of KYNA, quinolinic acid (QUIN), interleukin-4 (IL-4), and interleukin-6 (IL-6), were determined in treatment-naïve relapsing-remitting MS (RRMS), primary progressive MS (PPMS), and treated PMS patients. Serum levels were compared with those of healthy controls, and CSF findings contrasted with those of non-MS neurological patients and individuals with neurocysticercosis (NCC). Public whole-exome datasets were analyzed for variants in KP-related genes, and target exome sequencing was performed in three Mexican patients with MS. Results: Serum concentrations of KYNA and 3-HK were decreased in MS patients compared with healthy controls. CSF KYNA and QUIN levels did not differ significantly among MS subtypes or the non-MS neurological group, but they were lower than those observed in NCC. IL-4 and IL-6 were detectable in MS CSF samples, supporting the presence of intrathecal inflammation. Genetic and bioinformatic analyses identified variants in genes encoding KP enzymes in both public MS datasets and in Mexican patients with MS. Conclusions: These findings indicate an altered KP metabolism in Mexican MS patients, particularly during the relapse phase, and suggest a possible contribution of genetic variability. Further large-scale studies are needed to confirm these observations and to determine the functional implications of KP-related genetic variants in MS.

Objective: To characterize the allelic and diplotype variability of TPMT and NUDT15 in pediatric patients with B-cell acute lymphoblastic leukemia from the central-southern region of Mexico. Methods: Samples from 275 pediatric B-cell acute lymphoblastic leukemia patients were analyzed. Next-generation sequencing was used for TPMT and NUDT15 genotyping. Alleles and diplotypes were assessed according to the Clinical Pharmacogenetics Implementation Consortium guidelines. Their geographic distribution was compared across Mexican states and global populations. In-silico analyses were conducted to assess the structural and functional impact of TPMT variants not associated with star alleles. Results: The wild-type *1 allele, associated with normal enzymatic activity, was predominant in both genes: TPMT (94.15%) and NUDT15 (90.45%). TPMT showed greater allelic diversity compared with previous studies in Mexican populations. Alleles conferring absent or indeterminate enzymatic activity in TPMT were distributed across six diplotypes (11.62%), with *3A allele (4.73%) and *1 / *3A diplotype (9.45%) being the most frequent. Additionally, two unclassified TPMT variants, p.G126A and p.D137Y, were identified. For NUDT15 , three non-wild-type diplotypes were observed (19.09%), with the *2 allele (6.74%) and *1* / 2 diplotype (13.48%) being the most prevalent. Conclusion: Approximately 28% of patients carried TPMT and/or NUDT15 variants associated with non-wild-type enzymatic activity, increasing the risk of mercaptopurine-induced myelotoxicity. Preemptive genotyping is essential to reduce toxicity, optimize treatment, and advance precision medicine in this population. Additionally, the two TPMT variants p.G126A and p.D137Y, currently not classified within Clinical Pharmacogenetics Implementation Consortium-defined star alleles, highlight the need for functional validation and potential clinical classification to improve pharmacogenetic interpretation in diverse populations.

This study aimed to characterize, for the first time, the cancer spectrum associated with the most frequent pathogenic CHEK2 variant—NM_007194.4(CHEK2):c.707T > C p.(Leu236Pro)—in Mexican individuals. Although this variant is frequently detected through multi-gene panel testing, limited data on its associated cancer risks complicates genetic counseling and surveillance strategies. We retrospectively analyzed 5,759 patients who underwent multi-gene panel testing between August 2015 and August 2024 due to suspected hereditary cancer syndromes. Among them, 58 CHEK2 p.(Leu236Pro) carriers with confirmed cancer diagnoses were identified. Geographical clustering was observed, with 81% of patients originating from central Mexico, suggesting a possible founder effect. Ten distinct clinical indications for genetic testing were identified, with hereditary breast and ovarian cancer (HBOC) syndrome being the most common (74.1%). The mean age at first diagnosis among carriers was 43.8 ± 12 years, and 61.1% of them reported a family history of cancer in first- or second-degree relatives. A second or third primary cancer occurred in 20.7% of cases. Tumors were identified in 12 anatomical sites. Breast cancer predominated (67.6%, including one male case), followed by ovarian (8.1%), prostate (6.7%), gastric (4.1%), thyroid (2.7%), and endometrial (2.7%) cancers. Lymphoma, lung, sacrococcygeal bone, colorectal, and non-melanoma skin cancers each occurred in a single patient. Significant risk association was identified only for breast, ovarian, and gastric cancers. These results highlight the need for personalized surveillance, especially for breast cancer. Incorporating CHEK2 p.(Leu236Pro) into clinical decision-making tools may enhance risk assessment in the Mexican population, but larger studies are needed to refine risk estimates and to clarify the possible founder effect.

Cystic fibrosis (CF) is a rare autosomal recessive disease most commonly affecting the Caucasian population. CF diagnosis can be a challenge due to the large spectrum of pathogenic variants in the CFTR gene and the effects of complex alleles. Next-generation sequencing has improved our understanding of the contribution of these complex alleles to the wide spectrum of CF clinical symptoms and to the response to medications. Herein, we studied nine CF patients from six unrelated families carrying the complex allele p.[Ile148Thr;Ile1023_Val1024del] with a frequency of 0.18%. All patients were from Central Mexico. This complex allele was found in trans with Class I and II pathogenic variants such as p.(Phe508del), and p.(Phe1078Profs*77)]. A targeted search of a dataset of 2217 exomes from healthy individuals revealed that eight individuals (0.18%) carried the p.(Ile148Thr) variant, but only one (0.022%), who was also born in Central Mexico, was a carrier of the complex allele. These findings show an enrichment of this p.[Ile148Thr;Ile1023_Val1024del] complex allele in Mexican CF patients in this region of Mexico. Finally, protein modeling revealed that this complex allele disrupts the secondary structure of the CFTR protein and might alter the ion flow.

Cystic fibrosis (CF) diagnosis can be a challenge due to the large spectrum of pathogenic variants in the CFTR gene and the effects of complex alleles. Next-generation sequencing has improved our understanding of the contribution of these complex alleles to the wide spectrum of CF clinical symptoms and to the response to medications. Herein, we studied nine CF patients from six unrelated families carrying the complex allele p.[Ile148Thr;Ile1023_Val1024del] with a frequency of 0.18%. All the patients were from Central Mexico. This complex allele was found in trans with Class I and II pathogenic variants (PVs) such as [c.1521_1523del, p.(Phe508del), and c.3231_3232del, p.(Phe1078Profs*77)]. A targeted search of a dataset of 2,217 exomes from healthy individuals revealed that eight individuals (0.18%) carried the p.(Ile148Thr) variant, but only one (0.022%), who was also born in Central Mexico, was a carrier of the complex allele. These findings led us to hypothesize a founder effect for the p.[Ile148Thr;Ile1023_Val1024del] complex allele in Mexican patients with CF, probably through migration from the French-Canadian population in Mexico. Finally, protein modeling revealed that this complex allele disrupts the secondary structure of the CFTR protein and might alter the ion flow.