Introduction: PACS1-related neurodevelopmental disorder (PACS1-related NDD) is caused by pathogenic variants in the PACS1 gene and is characterized by a distinctive facial appearance, intellectual disability, speech delay, seizures, feeding difficulties, cryptorchidism, hernias, and structural anomalies of the brain, heart, eye, and kidney. There is a marked facial resemblance and a common multisystem affectation with patients carrying pathogenic variants in the WDR37 and PACS2 genes, although they vary in terms of severity and eye involvement. Case Presentation: Here, we describe 4 individuals with PACS1-related NDD from Mexico, all of them carrying a de novo PACS1 variant c.607C>T; p.(Arg203Trp) identified by exome sequencing. In addition to eye colobomata, this report identified corneal leukoma, cataracts, and tortuosity of retinal vessels as ophthalmic manifestations not previously reported in patients with PACS1-related NDD. Discussion: We reviewed the ocular phenotypes reported in 74 individuals with PACS1-related NDD and the overlaps with WDR37- and PACS2-related syndromes. We found that the 3 syndromes have in common the presence of colobomata, ptosis, nystagmus, strabismus, and refractive errors, whereas microphthalmia, microcornea, and Peters anomaly are found only among individuals with PACS1-related NDD and WDR37 syndrome, being more severe in the latter. This supports the previous statement that the so-called WDR37-PACS1-PACS2 axis might have an important role in ocular development and also that the specific ocular findings could be useful in the clinical differentiation between these related syndromes.

Background. Diabetic retinopathy (DR) risk has been shown to vary depending on ethnic backgrounds, and thus, it is worthy that underrepresented populations are analyzed for the potential identification of DR-associated genetic variants. We conducted a case-control study for the identification of DR-risk variants in Mexican population. Methods. We ascertained 60 type 2 diabetes mellitus (T2DM) patients. Cases ( ) were patients with advanced proliferative DR (PDR) with less than 15 years after a T2DM diagnosis while controls ( ) were patients with no DR 15 years after the diagnosis of T2DM. Exome sequencing was performed in all patients, and the frequency of rare variants was compared. In addition, the frequency of variants occurring in a set of 169 DR-associated genes were compared. Results. Statistically significant differences were identified for rare missense and splice variants and for rare splice variants occurring more than once in either group. A strong statistical difference was observed when the number of rare missense variants with an aggregated prediction of pathogenicity and occurring more than once in either group was compared ( ). Moreover, 8 variants identified more than once in either group, occurring in previously identified DR-associated genes were recognized. The p.Pro234Ser KIR2DS4 variant showed a strong protective effect ( [0.001–0.36]; ). Conclusions. Our study showed an enrichment of rare splice acceptor/donor variants in patients with PDR and identified a potential protective variant in KIR2DS4. Although statistical significance was not reached, our results support the replication of 8 previously identified DR-associated genes.

Several reports have provided evidence that there are genetic variants of genes such as MSTN, BDRKB2, ACTN3 and ADRB2 that are involved in a better response to adaptation during resistance or strength training, while other genes such as GRB14, AGT and END1 are reported to be associated with the risk of suffering from some diseases such as diabetes, hypertension or obesity. A cross-sectional study from a Mexican Mestizo population was performed to estimate the frequency of 10 gene variants in 8 genes involved in athletic performance or chronic degenerative diseases, MSTN (rs1805085, rs1805086), BDKRB2 (rs1799722), FST (rs1423560), ACTN3 (rs1815739), ADRB2 (rs1042713, rs1042714), GRB14 (rs8192673), AGT (rs699) and EDN1 (rs5370), and to compare frequencies from 26 populations reported in the Database of 1000 Genomes project. Genotype frequencies fitted the Hardy–Weinberg equilibrium, except for MST rs1805086 and FST rs1423560, and our study revealed significant differences in the distribution of frequencies of some of these gene variants among populations reported in the 1000 Genomes Project. Our findings provide insights regarding the genetic background of our population, and future case–control studies can be carried out with more accurate sample sizes for genetic association studies. Our results may be also useful in recognizing the roles and mechanisms contributing to athletic performance and/or chronic degenerative diseases in Mexicans.

Fleck corneal dystrophy (FCD) is a rare autosomal dominant disease that affects exclusively the corneal stroma. The disease is caused by heterozygous variants in PIKFYVE, a gene encoding a lipid kinase involved in multiple cellular pathways, primarily participating in membrane dynamics and signaling. This report describes a familial case of FCD caused by a complete deletion of the PIKFYVE gene. A clinical ophthalmic examination was performed on the proband and family members. Genetic testing included next-generation sequencing (multigene panel), and chromosomal microarray analysis. A quantitative PCR assay was designed in order to segregate the deletion. A 19-year-old male, with no family or personal history of ocular disease, presented for evaluation due to an acute illness consisting of burning, foreign body sensation, and red eye. Slit lamp biomicroscopy revealed bilateral small pterygia and scattered bilateral white opacities in the corneal stroma, a very similar corneal phenotype was found in the 47-year-old father, who was asymptomatic. NGS detected a heterozygous deletion of the entire PIKFYVE coding sequence. CMA in DNA from the propositus indicated a 543 kb deletion in 2q33.3q34 spanning the entire PIKFYVE gene. The deletion was confirmed in the father. We add to the molecular spectrum of FCD by describing a familial case of a whole PIKFYVE gene deletion in affected subjects. Our findings support that normal expression of PIKFYVE is necessary for corneal keratocytes homeostasis and normal corneal appearance. We conclude that PIKFYVE haploinsufficiency is the molecular mechanism underlying this familial case of FCD.

Background: Major depressive disorder (MDD) arises from genetic and environmental factors. We evaluated functional variation in methylenetetrahydrofolate reductase (MTHFR), circulating MTHFR protein, and homocysteine (HCY) in Mexican-Mestizo participants. Methods: We analyzed 1507 individuals across four cohorts: a primary case–control sample (358 DSM-IV-TR MDD cases, 170 psychiatrically screened controls), a community cohort (n = 204), and a general population cohort (n = 775) for allele-frequency context. We genotyped rs1801133 (C677T) and rs13306560 using TaqMan assays. Serum MTHFR and HCY were measured by ELISA in available subsamples (n reported where applicable). Primary analyses tested association of genotypes with MDD under codominant, allelic, and recessive models; false discovery rate (FDR) correction accounted for multiple genetic models. Exploratory multivariable logistic regression adjusted for sex, age, and adverse childhood experiences. Results: The rs13306560 A allele was rare (~2.6%) and showed no association with MDD. Under a recessive model, the rs1801133 TT genotype was more frequent among cases (33.3%) than controls (23.5%) (χ² p = 0.036); this association did not survive FDR correction (q = 0.117) and is reported as hypothesis-generating. In an exploratory adjusted logistic regression (N = 446) using the post hoc recessive coding, TT homozygotes had higher odds of MDD versus CC/CT (OR = 1.98, 95% CI 1.23–3.17, p = 0.005). Serum MTHFR concentrations were higher in cases than controls (median 1834.8 vs. 1241.9 pg/mL; Mann–Whitney U = 343, p = 0.017). Serum MTHFR displayed a borderline positive correlation with HAM-D scores (Spearman r = 0.24, p = 0.050). Conclusions: In this Mexican-Mestizo sample, MTHFR C677T (rs1801133) homozygosity and elevated circulating MTHFR emerged as preliminary, hypothesis-generating candidates for MDD risk. The genetic association did not meet multiple-testing correction (q = 0.117) and requires independent replication; the serum MTHFR case–control difference survived correction (q = 0.034) but warrants confirmation given the small biomarker subsample. A mechanistic study is needed to clarify causality and clinical relevance.