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BACKGROUND: ISG15 deficiency is a mixed syndrome of Mendelian susceptibility to mycobacterial infections (MSMD), a rare inherited condition characterized primarily by recurrent infections from low-virulence mycobacteria and monogenic type I interferonopathy. OBJECTIVE: To characterize the laboratory and molecular features of two patients from different families affected by the same ISG15 variant. METHODS: We began with clinical characterization and investigation, assessed IL-12/IFN-γ production, performed genetic characterization through WES and Sanger sequencing, conducted an in silico molecular analysis of the genetic ISG15 variant's protein impact, and utilized RNAseq for transcriptome analysis to understand pathway impacts on ISG15-deficient subjects from unrelated families. RESULTS: A mutation in the ISG15 gene was identified, affecting two patients treated in different hospitals and cities in Brazil (Fortaleza and Sao Paulo), who are also members of unrelated families. Both patients showed low IFN-γ production when stimulated with BCG or BCG + IL-12. ISG15 deficiency presented with two distinct clinical phenotypes: infectious and neurological. It was identified that both patients are homozygous for the variant (c.83 T > A). Furthermore, it was observed that the mutant protein p.L28Q results in an unstable protein with increased flexibility (ΔΔG: -2.400 kcal/mol). Transcriptome analysis revealed 1321 differentially expressed genes, with significant upregulation in interferon pathways, showing higher expression in patients compared to controls. CONCLUSION: This study describes the first reported cases in Brazil of two unrelated patients with the same ISG15 mutation c.83 T > A, exhibiting infectious features such as mycobacterial infections and systemic candidiasis, neurological findings, and skin lesions, without adverse reactions to the BCG vaccine. CLINICAL IMPLICATIONS: Reporting ISG15 gene mutations in Brazilian patients enhances understanding of genetic susceptibilities, guiding effective diagnostics and treatment. Identifying high-risk individuals aids clinical practices, genetic counseling, and influences public health policies. We have identified the first case in Brazil of the same ISG15 variant c.83 T > A that was identified in two unrelated patients with distinct clinical phenotypes, infectious and neurological.
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Citocinas , Mutación , Ubiquitinas , Humanos , Citocinas/metabolismo , Ubiquitinas/genética , Brasil , Mutación/genética , Masculino , Femenino , Linaje , Predisposición Genética a la Enfermedad , Interferón gamma/genética , Lactante , Infecciones por Mycobacterium/genética , Infecciones por Mycobacterium/diagnóstico , Infecciones por Mycobacterium/etiología , Preescolar , Fenotipo , NiñoRESUMEN
BACKGROUND: Nelore cattle play a key role in tropical production systems due to their resilience to harsh conditions, such as heat stress and seasonally poor nutrition. Monitoring their genetic diversity is essential to manage the negative impacts of inbreeding. Traditionally, inbreeding and inbreeding depression are assessed by pedigree-based coefficients (F), but recently, genetic markers have been preferred for their precision in capturing the inbreeding level and identifying animals at risk of reduced productive and reproductive performance. Hence, we compared the inbreeding and inbreeding depression for productive and reproductive performance traits in Nelore cattle using different inbreeding coefficient estimation methods from pedigree information (FPed), the genomic relationship matrix (FGRM), runs of homozygosity (FROH) of different lengths (> 1 Mb (genome), between 1 and 2 Mb - FROH 1-2; 2-4 Mb FROH 2-4 or > 8 Mb FROH >8) and excess homozygosity (FSNP). RESULTS: The correlation between FPed and FROH was lower when the latter was based on shorter segments (r = 0.15 with FROH 1-2, r = 0.20 with FROH 2-4 and r = 0.28 with FROH 4-8). Meanwhile, the FPed had a moderate correlation with FSNP (r = 0.47) and high correlation with FROH >8 (r = 0.58) and FROH-genome (r = 0.60). The FROH-genome was highly correlated with inbreeding based on FROH>8 (r = 0.93) and FSNP (r = 0.88). The FGRM exhibited a high correlation with FROH-genome (r = 0.55) and FROH >8 (r = 0.51) and a lower correlation with other inbreeding estimators varying from 0.30 for FROH 2-4 to 0.37 for FROH 1-2. Increased levels of inbreeding had a negative impact on the productive and reproductive performance of Nelore cattle. The unfavorable inbreeding effect on productive and reproductive traits ranged from 0.12 to 0.51 for FPed, 0.19-0.59 for FGRM, 0.21-0.58 for FROH-genome, and 0.19-0.54 for FSNP per 1% of inbreeding scaled on the percentage of the mean. When scaling the linear regression coefficients on the standard deviation, the unfavorable inbreeding effect varied from 0.43 to 1.56% for FPed, 0.49-1.97% for FGRM, 0.34-2.2% for FROH-genome, and 0.50-1.62% for FSNP per 1% of inbreeding. The impact of the homozygous segments on reproductive and performance traits varied based on the chromosomes. This shows that specific homozygous chromosome segments can be signs of positive selection due to their beneficial effects on the traits. CONCLUSIONS: The low correlation observed between FPed and genomic-based inbreeding estimates suggests that the presence of animals with one unknown parent (sire or dam) in the pedigree does not account for ancient inbreeding. The ROH hotspots surround genes related to reproduction, growth, meat quality, and adaptation to environmental stress. Inbreeding depression has adverse effects on productive and reproductive traits in Nelore cattle, particularly on age at puberty in young bulls and heifer calving at 30 months, as well as on scrotal circumference and body weight when scaled on the standard deviation of the trait.
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Genómica , Depresión Endogámica , Endogamia , Linaje , Animales , Bovinos/genética , Genómica/métodos , Homocigoto , Femenino , Masculino , Polimorfismo de Nucleótido SimpleRESUMEN
The purpose of this study was to analyze and molecularly describe the largest group of patients with ABCA4-associated retinal degeneration in Latin America. Pathogenic variants in ABCA4, a member of the ATP Binding Cassette (ABC) transporters superfamily, is one of the most common causes of inherited visual deficiency in humans. Retinal phenotypes associated with genetic defects in ABCA4 are collectively known as ABCA4-associated retinal degenerations (ABCA4R), a group of recessively inherited disorders associated with a high allelic heterogeneity. While large groups of Caucasian and Asiatic individuals suffering from ABCA4R have been well characterized, molecular information from certain ethnic groups is limited or unavailable, precluding a more realistic knowledge of ABCA4-related mutational profile worldwide. In this study, we describe the molecular findings of a large group of 211 ABCA4R index cases from Mexico. Genotyping was performed using either next generation sequencing (NGS) of a retinal dystrophy genes panel or exome. ABCA4 targeted mutation testing was applied to a subgroup of subjects in whom founder mutations were suspected. A total of 128 different ABCA4 pathogenic variants were identified, including 22 previously unpublished variants. The most common type of genetic variation was single nucleotide substitutions which occurred in 92.7% (408/440 alleles). According to the predicted protein effect, the most frequent variant type was missense, occurring in 83.5% of disease-causing alleles (368/440). Mutations such as p.Ala1773Val are fully demonstrated as a founder effect in native inhabitants of certain regions of Mexico. This study also gives us certain indications of other founder effects that need to be further studied in the near future. This is the largest molecularly characterized ABCA4R Latin American cohort, and our results supports the value of conducting genetic screening in underrepresented populations for a better knowledge of the mutational profile leading to monogenic diseases.
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Transportadoras de Casetes de Unión a ATP , Genotipo , Degeneración Retiniana , Humanos , Transportadoras de Casetes de Unión a ATP/genética , México , Masculino , Femenino , Degeneración Retiniana/genética , Niño , Mutación , Adulto , Adolescente , Persona de Mediana Edad , Secuenciación de Nucleótidos de Alto Rendimiento , Alelos , Fenotipo , Preescolar , Adulto Joven , LinajeRESUMEN
Background: Multiple Endocrine Neoplasia type 1 (MEN1) is an autosomal dominant disorder marked by pathogenic variants in the MEN1 tumor suppressor gene, leading to tumors in the parathyroid glands, pancreas, and pituitary. The occurrence of ACTH-producing pancreatic neuroendocrine carcinoma is exceedingly rare in MEN1. Case presentation: This report details a Colombian family harboring a novel MEN1 variant identified through genetic screening initiated by the index case. Affected family members exhibited primary hyperparathyroidism (PHPT) symptoms from their 20s to 50s. Uniquely, the index case developed an ACTH-secreting pancreatic neuroendocrine carcinoma, a rarity in MEN1 syndromes. Proactive screening enabled the early detection of pituitary neuroendocrine tumors (PitNETs) as microadenomas in two carriers, with subsequent surgical or pharmacological intervention based on the clinical presentation. Conclusion: Our findings underscore the significance of cascade screening in facilitating the early diagnosis and individualized treatment of MEN1, contributing to better patient outcomes. Additionally, this study brings to light a novel presentation of ACTH-producing pancreatic neuroendocrine carcinoma within the MEN1 spectrum, expanding our understanding of the disease's manifestations.
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Hormona Adrenocorticotrópica , Carcinoma Neuroendocrino , Neoplasia Endocrina Múltiple Tipo 1 , Neoplasias Pancreáticas , Linaje , Humanos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/diagnóstico , Masculino , Carcinoma Neuroendocrino/genética , Carcinoma Neuroendocrino/patología , Colombia , Neoplasia Endocrina Múltiple Tipo 1/genética , Neoplasia Endocrina Múltiple Tipo 1/complicaciones , Femenino , Persona de Mediana Edad , Estudios de Seguimiento , Hormona Adrenocorticotrópica/sangre , Hormona Adrenocorticotrópica/metabolismo , Adulto , Proteínas Proto-Oncogénicas/genéticaRESUMEN
BACKGROUND: 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. MATERIAL AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
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Distrofias Hereditarias de la Córnea , Linaje , Fosfatidilinositol 3-Quinasas , Humanos , Masculino , Adulto Joven , Distrofias Hereditarias de la Córnea/genética , Distrofias Hereditarias de la Córnea/diagnóstico , Fosfatidilinositol 3-Quinasas/genética , Persona de Mediana Edad , Eliminación de Gen , Femenino , Adulto , Eliminación de Secuencia , Secuenciación de Nucleótidos de Alto RendimientoRESUMEN
Limb-girdle muscular dystrophy type 2G/R7 (LGMD2G/R7) is an ultra-rare condition initially identified within the Brazilian population. We aimed to expand clinical and genetic information about this disease, including its worldwide distribution. A multicenter historical cohort study was performed at 13 centers in Brazil in which data from index cases and their affected relatives from consecutive families with LGMD2G/R7 were reviewed from July 2017 to August 2023. Additionally, a systematic literature review was conducted to identify case reports and series of the disease worldwide. Forty-one LGMD2G/R7 cases were described in the Brazilian cohort, being all subjects homozygous for the c.157C>T/(p.Gln53*) variant in TCAP. Survival curves showed that the median disease duration before individuals required walking aids was 21 years. Notably, women exhibited a slower disease progression, requiring walking aids 13 years later than men. LGMD2G/R7 was frequently reported not only in Brazil but also in China and Bulgaria, with 119 cases identified globally, with possible founder effects in the Brazilian, Eastern European, and Asian populations. These findings are pivotal in raising awareness of LGMD2G/R7, understanding its progression, and identifying potential modifiers. This can significantly contribute to the development of future natural history studies and clinical trials for this disease.
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Distrofia Muscular de Cinturas , Mutación , Humanos , Distrofia Muscular de Cinturas/genética , Distrofia Muscular de Cinturas/epidemiología , Distrofia Muscular de Cinturas/diagnóstico , Masculino , Brasil/epidemiología , Femenino , Adulto , Adolescente , Persona de Mediana Edad , Niño , Estudios de Cohortes , Adulto Joven , Linaje , Conectina/genética , Fenotipo , Predisposición Genética a la Enfermedad , PreescolarRESUMEN
BACKGROUND: Albinism is a heterogeneous condition in which patients present complete absence, reduction, or normal pigmentation in skin, hair and eyes in addition to ocular defects. One of the heterogeneous forms of albinism is observed in Hermansky-Pudlak syndrome (HPS) patients. HPS is characterized by albinism and hemorrhagic diathesis due to the absence of dense bodies in platelets. METHODS: In this report, we describe a case of a pair of Puerto Rican siblings with albinism that were clinically diagnosed with HPS during childhood. Since they did not harbor the founder changes in the HPS1 and HPS3 genes common in Puerto Ricans, as adults they wanted to know the type of albinism they had. We performed exome sequencing, validation by PCR, and cloning of PCR products followed by Sanger sequencing in the family members. RESULTS: We discovered no mutations that could explain an HPS diagnosis. Instead, we found the siblings were compound heterozygotes for 4 variants in the Tyrosinase gene: c.-301C>T, c.140G>A (rs61753180; p.G47D), c.575C>A (rs1042602; p.S192Y), and c.1205G>A (rs1126809; p.R402Q). Our results show that the correct diagnosis for the siblings is OCA1B. CONCLUSION: Our study shows the importance of molecular testing when diagnosing a rare genetic disorder, especially in populations were the disease prevalence is higher.
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Albinismo Oculocutáneo , Síndrome de Hermanski-Pudlak , Monofenol Monooxigenasa , Humanos , Síndrome de Hermanski-Pudlak/genética , Síndrome de Hermanski-Pudlak/diagnóstico , Síndrome de Hermanski-Pudlak/patología , Albinismo Oculocutáneo/genética , Albinismo Oculocutáneo/diagnóstico , Monofenol Monooxigenasa/genética , Masculino , Femenino , Adulto , Linaje , Pruebas Genéticas/métodos , Mutación , HeterocigotoRESUMEN
BACKGROUND: Ion channels, vital transmembrane protein complexes, regulate ion movement within cells. Germline variants in channel-encoding genes lead to channelopathies. The sodium channels in cardiac cells exhibit a structure of an alpha subunit and one to two beta subunits. The alpha subunit, encoded by the SCN5A gene, comprises four domains. CASE PRESENTATION: A fifteen-year-old Ecuadorian female with atrial flutter and abnormal sinus rhythm with no familial history of cardiovascular disease underwent NGS with the TruSight Cardio kit (Illumina). A likely pathogenic SCN5A gene variant (NM_188056.2:c.2677 C > Tp. Arg893Cys) was identified, associated with arrhythmias, long QT, atrial fibrillation, and Brugada syndrome. Ancestral analysis revealed a predominant European component (43.9%), followed by Native American (35.7%) and African (20.4%) components. CONCLUSIONS: The participant presents atrial flutter and conduction disorders, despite lacking typical cardiovascular risk factors. The proband carries a SCN5A variant that has not been previously reported in Latin America and may be associated to her phenotype. The documented arginine-to-cysteine substitution at position 893 in the protein is crucial for various cellular functions. The subject's mixed genetic composition highlights potential genetic contributors to atrial flutter, emphasizing the need for comprehensive genetic studies, particularly in mixed populations like Ecuadorians. This case underscores the importance of genetic analysis for personalized treatment and the significance of studying diverse genetic backgrounds in understanding cardiovascular diseases.
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Aleteo Atrial , Predisposición Genética a la Enfermedad , Canal de Sodio Activado por Voltaje NAV1.5 , Fenotipo , Humanos , Femenino , Canal de Sodio Activado por Voltaje NAV1.5/genética , Ecuador , Adolescente , Aleteo Atrial/genética , Aleteo Atrial/diagnóstico , Aleteo Atrial/fisiopatología , Mutación , LinajeRESUMEN
The exact accuracy of estimated breeding values can be calculated based on the prediction error variances obtained from the diagonal of the inverse of the left-hand side (LHS) of the mixed model equations (MME). However, inverting the LHS is not computationally feasible for large datasets, especially if genomic information is available. Thus, different algorithms have been proposed to approximate accuracies. This study aimed to: 1) compare the approximated accuracies from 2 algorithms implemented in the BLUPF90 suite of programs, 2) compare the approximated accuracies from the 2 algorithms against the exact accuracy based on the inversion of the LHS of MME, and 3) evaluate the impact of adding genotyped animals with and without phenotypes on the exact and approximated accuracies. Algorithm 1 approximates accuracies based on the diagonal of the genomic relationship matrix (G). In turn, algorithm 2 combines accuracies with and without genomic information through effective record contributions. The data were provided by the American Angus Association and included 3 datasets of growth, carcass, and marbling traits. The genotype file contained 1,235,930 animals, and the pedigree file contained 12,492,581 animals. For the genomic evaluation, a multi-trait model was applied to the datasets. To ensure the feasibility of inverting the LHS of the MME, a subset of data under single-trait models was used to compare approximated and exact accuracies. The correlations between exact and approximated accuracies from algorithms 1 and 2 of genotyped animals ranged from 0.87 to 0.90 and 0.98 to 0.99, respectively. The intercept and slope of the regression of exact on approximated accuracies from algorithm 2 ranged from 0.00 to 0.01 and 0.82 to 0.87, respectively. However, the intercept and the slope for algorithm 1 ranged from -0.10 to 0.05 and 0.98 to 1.10, respectively. In more than 80% of the traits, algorithm 2 exhibited a smaller mean square error than algorithm 1. The correlation between the approximated accuracies obtained from algorithms 1 and 2 ranged from 0.56 to 0.74, 0.38 to 0.71, and 0.71 to 0.97 in the groups of genotyped animals, genotyped animals without phenotype, and proven genotyped sires, respectively. The approximated accuracy from algorithm 2 showed a closer behavior to the exact accuracy when including genotyped animals in the analysis. According to the results, algorithm 2 is recommended for genetic evaluations since it proved more precise.
The genomic estimated breeding value (GEBV) represents an animal's genetic merit calculated using a combination of phenotypes, pedigree, and genomic information through a procedure known as single-step genomic best linear unbiased prediction (ssGBLUP). The accuracy of a GEBV reflects how closely it correlates with the true breeding value. However, calculating accuracies is not computationally feasible for large datasets with genomic information. In this context, methods for approximating accuracies have been proposed and implemented into genetic evaluations. This study aimed to compare 2 algorithms to approximate accuracies for ssGBLUP. In algorithm 1, genomic contributions are based on the diagonal of the genomic relationship matrix (G), combined with contributions from animal records and pedigrees. In turn, algorithm 2 combines accuracies with and without genomic information through effective record contributions. The data for this study were provided by the American Angus Association and included datasets of growth, carcass, and marbling traits. Genotypes were available for 1,235,930 animals, and the pedigree had 12,492,581 animals. We showed that algorithm 2 is better suited for approximating accuracies, as its approximations closely matched the exact accuracy values obtained from the inverse of the mixed model equations.
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Algoritmos , Cruzamiento , Genotipo , Modelos Genéticos , Animales , Genómica , Bovinos/genética , Masculino , Femenino , Fenotipo , LinajeRESUMEN
BACKGROUND: The selection of individuals based on their predicted breeding values and mating of related individuals can increase the proportion of identical-by-descent alleles. In this context, the objectives of this study were to estimate inbreeding coefficients based on alternative metrics and data sources such as pedigree (FPED), hybrid genomic relationship matrix H (FH), and ROH of different length (FROH); and calculate Pearson correlations between the different metrics in a closed Nellore cattle population selected for body weight adjusted to 378 days of age (W378). In addition to total FROH (all classes) coefficients were also estimated based on the size class of the ROH segments: FROH1 (1-2 Mb), FROH2 (2-4 Mb), FROH3 (4-8 Mb), FROH4 (8-16 Mb), and FROH5 (> 16 Mb), and for each chromosome (FROH_CHR). Furthermore, we assessed the effect of each inbreeding metric on birth weight (BW), body weights adjusted to 210 (W210) and W378, scrotal circumference (SC), and residual feed intake (RFI). We also evaluated the chromosome-specific effects of inbreeding on growth traits. RESULTS: The correlation between FPED and FROH was 0.60 while between FH and FROH and FH and FPED were 0.69 and 0.61, respectively. The annual rate of inbreeding was 0.16% for FPED, 0.02% for FH, and 0.16% for FROH. A 1% increase in FROH5 resulted in a reduction of up to -1.327 ± 0.495 kg in W210 and W378. Four inbreeding coefficients (FPED, FH, FROH2, and FROH5) had a significant effect on W378, with reductions of up to -3.810 ± 1.753 kg per 1% increase in FROH2. There was an unfavorable effect of FPED on RFI (0.01 ± 0.0002 kg dry matter/day) and of FROH on SC (-0.056 ± 0.022 cm). The FROH_CHR coefficients calculated for BTA3, BTA5, and BTA8 significantly affected the growth traits. CONCLUSIONS: Inbreeding depression was observed for all traits evaluated. However, these effects were greater for the criterion used for selection of the animals (i.e., W378). The increase in the genomic inbreeding was associated with a higher inbreeding depression on the traits evaluated when compared to pedigree-based inbreeding. Genomic information should be used as a tool during mating to optimize control of inbreeding and, consequently, minimize inbreeding depression in Nellore cattle.
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Fertilidad , Endogamia , Linaje , Animales , Bovinos/genética , Bovinos/crecimiento & desarrollo , Fertilidad/genética , Genómica/métodos , Femenino , Masculino , Fenotipo , Carácter Cuantitativo Heredable , Peso Corporal/genéticaRESUMEN
RASopathies encompass a diverse set of disorders affecting genes that encode proteins within the RAS-MAPK pathway. RASA1 mutations are the cause of an autosomal dominant disorder called capillary malformation-arteriovenous malformation type 1 (CM-AVM1). Unlike other RASopathies, facial dysmorphism has not been described in these patients. We phenotypically delineated a large family of individuals with multifocal fast-flow capillary malformations, severe lymphatic anomalies of perinatal onset, and dysmorphic features not previously described. Sequencing studies were performed on probands and related family members, confirming the segregation of dysmorphic features in affected members of a novel heterozygous variant in RASA1 (NM_002890.3:c.2366G>A, p.(Arg789Gln)). In this work, we broaden the phenotypic spectrum of CM-AVM type 1 and propose a new RASA1 variant as likely pathogenic.
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Malformaciones Arteriovenosas , Mutación de Línea Germinal , Linaje , Mancha Vino de Oporto , Proteína Activadora de GTPasa p120 , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Capilares/anomalías , Capilares/patología , Facies , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal/genética , Proteína Activadora de GTPasa p120/genética , Fenotipo , Mancha Vino de Oporto/genética , Mancha Vino de Oporto/patología , Malformaciones Arteriovenosas/genéticaRESUMEN
INTRODUCTION: Neurodevelopmental disorders (NDDs) are diverse and can be explained by either genomic aberrations or single nucleotide variants. Most likely due to methodological approaches and/or disadvantages, the concurrence of both genetic events in a single patient has hardly been reported and even more rarely the pathogenic variant has been regarded as the cause of the phenotype when a chromosomal alteration is initially identified. CASE PRESENTATION: Here, we describe a NDD patient with a 6p nonpathogenic paracentric inversion paternally transmitted and a de novo pathogenic variant in the GRIN2B gene. Molecular-cytogenetic studies characterized the familial 6p inversion and revealed a paternal 9q inversion not transmitted to the patient. Subsequent whole-genome sequencing in the patient-father dyad corroborated the previous findings, discarded inversions-related cryptic genomic rearrangements as causative of the patient's phenotype, and unveiled a novel heterozygous GRIN2B variant (p.(Ser570Pro)) only in the proband. In addition, Sanger sequencing ruled out such a variant in her mother and thereby confirmed its de novo origin. Due to predicted disturbances in the local secondary structure, this variant may alter the ion channel function of the M1 transmembrane domain. Other pathogenic variants in GRIN2B have been related to the autosomal dominant neurodevelopmental disorder MRD6 (intellectual developmental disorder, autosomal dominant 6, with or without seizures), which presents with a high variability ranging from mild intellectual disability (ID) without seizures to a more severe encephalopathy. In comparison, our patient's clinical manifestations include, among others, mild ID and brain anomalies previously documented in subjects with MRD6. CONCLUSION: Occasionally, gross chromosomal abnormalities can be coincidental findings rather than a prime cause of a clinical phenotype (even though they appear to be the causal agent). In brief, this case underscores the importance of comprehensive genomic analysis in unraveling the wide-ranging genetic causes of NDDs and may bring new insights into the MRD6 variability.
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Inversión Cromosómica , Trastornos del Neurodesarrollo , Receptores de N-Metil-D-Aspartato , Femenino , Humanos , Masculino , Cromosomas Humanos Par 6/genética , Trastornos del Neurodesarrollo/genética , Linaje , Fenotipo , Receptores de N-Metil-D-Aspartato/genética , Secuenciación Completa del GenomaRESUMEN
Leber congenital amaurosis (LCA)/early-onset severe retinal dystrophy (EOSRD) stand as primary causes of incurable childhood blindness. This study investigates the clinical and molecular architecture of syndromic and non-syndromic LCA/EOSRD within a Chilean cohort (67 patients/60 families). Leveraging panel sequencing, 95.5% detection was achieved, revealing 17 genes and 126 variants (32 unique). CRB1, LCA5, and RDH12 dominated (71.9%), with CRB1 being the most prevalent (43.8%). Notably, four unique variants (LCA5 p.Glu415*, CRB1 p.Ser1049Aspfs*40 and p.Cys948Tyr, RDH12 p.Leu99Ile) constituted 62.7% of all disease alleles, indicating their importance for targeted analysis in Chilean patients. This study underscores a high degree of inbreeding in Chilean families affected by pediatric retinal blindness, resulting in a limited mutation repertoire. Furthermore, it complements and reinforces earlier reports, indicating the involvement of ADAM9 and RP1 as uncommon causes of LCA/EOSRD. These data hold significant value for patient and family counseling, pharmaceutical industry endeavors in personalized medicine, and future enrolment in gene therapy-based treatments, particularly with ongoing trials (LCA5) or advancing preclinical developments (CRB1 and RDH12).
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Mutación , Distrofias Retinianas , Humanos , Distrofias Retinianas/genética , Distrofias Retinianas/terapia , Distrofias Retinianas/diagnóstico , Chile/epidemiología , Masculino , Femenino , Niño , Preescolar , Oxidorreductasas de Alcohol/genética , Proteínas de la Membrana/genética , Proteínas del Ojo/genética , Amaurosis Congénita de Leber/genética , Amaurosis Congénita de Leber/terapia , Amaurosis Congénita de Leber/diagnóstico , Linaje , Proteínas del Tejido Nervioso/genética , Adolescente , Alelos , Variación Genética , Enfermedades Hereditarias del OjoRESUMEN
A six-year-old girl with restrictive cardiomyopathy and hypertrabeculation, due to the early onset of her disease, whole exome sequencing was conducted, revealing the presence of a novel heterozygous missense variant in the FLNC gene. The same gene variant was also identified in her father, who, at an adult age, displayed normal imaging results and was symptom-free. This variant has not been reported in population databases or current medical literature and is classified as likely pathogenic.
Menina de seis anos com cardiomiopatia restritiva e hipertrabeculação na qual, devido ao início precoce da doença, foi realizado sequenciamento completo do exoma, revelando a presença de uma nova variante heterozigótica missense no gene FLNC. A mesma variante genética também foi identificada em seu pai, que, já adulto, apresentava resultados de imagem normais e não apresentava sintomas. Esta variante não foi relatada em bancos de dados populacionais ou na literatura médica atual e é classificada como provavelmente patogênica.
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Cardiomiopatía Restrictiva , Mutación Missense , Humanos , Femenino , Cardiomiopatía Restrictiva/genética , Niño , Secuenciación del Exoma , LinajeRESUMEN
Primary congenital glaucoma (PCG) is one of the leading causes of visual damage and blindness, severely affecting the quality of life of affected children. It is characterized by cupping of the optic disc and loss of ganglion cells due to elevated intraocular pressure. While most PCG patients exhibit epiphora, photophobia, and buphthalmos with corneal opacity, variability in phenotypic manifestations is not uncommon. Prompt diagnosis and treatment of PCG affected individuals becomes relevant to preserve visual function throughout their lives. Most PCG cases are sporadic or autosomal recessive; however, an incompletely dominant autosomal dominant form arising from mutations in the TEK gene has recently been demonstrated. Here, we describe the clinical and mutational features of a cohort of Mexican patients with TEK-related PCG. Our results support the involvement of the TEK gene as an important cause of the disease in our ethnic group and expand the mutational spectrum causing PCG by reporting 10 novel disease-causing variants.
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Glaucoma , Mutación , Linaje , Fenotipo , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Estudios de Cohortes , Análisis Mutacional de ADN , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Glaucoma/genética , Glaucoma/patología , Glaucoma/congénito , México/epidemiología , Mutación/genéticaRESUMEN
BACKGROUND: Exploring the expression of X linked disorders like haemophilia A (HA) in females involves understanding the balance achieved through X chromosome inactivation (XCI). Skewed XCI (SXCI) may be involved in symptomatic HA carriers. We aimed to develop an approach for dissecting the specific cause of SXCI and verify its value in HA. METHODS: A family involving three females (two symptomatic with severe/moderate HA: I.2, the mother, and II.1, the daughter; one asymptomatic: II.2) and two related affected males (I.1, the father and I.3, the maternal uncle) was studied. The genetic analysis included F8 mutational screening, multiplex ligation-dependent probe amplification, SNP microarray, whole exome sequencing (WES) and Sanger sequencing. XCI patterns were assessed in ectoderm/endoderm and mesoderm-derived tissues using AR-based and RP2-based systems. RESULTS: The comprehensive family analysis identifies I.2 female patient as a heterozygous carrier of F8:p.(Ser1414Ter) excluding copy number variations. A consistent XCI pattern of 99.5% across various tissues was observed. A comprehensive filtering algorithm for WES data was designed, developed and applied to I.2. A Gly58Arg missense variant in VMA21 was revealed as the cause for SXCI.Each step of the variant filtering system takes advantage of publicly available genomic databases, non-SXCI controls and case-specific molecular data, and aligns with established concepts in the theoretical background of SXCI. CONCLUSION: This study acts as a proof of concept for our genomic filtering algorithm's clinical utility in analysing X linked disorders. Our findings clarify the molecular aspects of SXCI and improve genetic diagnostics and counselling for families with X linked diseases like HA.
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Hemofilia A , Linaje , Inactivación del Cromosoma X , Humanos , Inactivación del Cromosoma X/genética , Femenino , Hemofilia A/genética , Masculino , Algoritmos , Secuenciación del Exoma/métodos , Factor VIII/genética , Cromosomas Humanos X/genética , Genómica/métodos , Variaciones en el Número de Copia de ADN/genética , Mutación/genética , AdultoRESUMEN
The conservation of animal genetic resources refers to measures taken to prevent the loss of genetic diversity in livestock populations, including the protection of breeds from extinction. Creole cattle populations have suffered a drastic reduction in recent decades owing to absorbent crosses or replacement with commercial breeds of European or Indian origin. Genetic characterization can serve as a source of information for conservation strategies to maintain genetic variation. The objective of this work was to evaluate the levels of inbreeding and kinship through the use of genomic information. A total of 903 DNAs from 13 cattle populations from Argentina, Bolivia and Uruguay were genotyped using an SNP panel of 48 K. Also, a dataset of 76 K SNPs from Peruvian Creole was included. Two inbreeding indices (FROH and Fhat2) and kinship relationships were calculated. In addition, effective population size (Ne), linkage disequilibrium, population composition and phylogenetic relationships were estimated. In Creole cattle, FROH ranged from 0.14 to 0.03, and Fhat2 was close to zero. The inferred Ne trends exhibited a decline toward the present for all populations, whereas Creole cattle presented a lower magnitude of Ne than foreign breeds. Cluster analysis clearly differentiated the taurine and Zebu components (K2) and showed that Bolivian Creole cattle presented Zebu gene introgression. Despite the population reduction, Creole populations did not present extreme values of consanguinity and kinship and maintain high levels of genetic diversity. The information obtained in this work may be useful for planning conservation programmes for these valuable local animal genetic resources.
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Endogamia , Polimorfismo de Nucleótido Simple , Animales , Bovinos/genética , Uruguay , Bolivia , Cruzamiento , Desequilibrio de Ligamiento , Filogenia , Genotipo , Argentina , Linaje , Variación Genética , Genética de Población , Densidad de PoblaciónRESUMEN
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease usually associated with severe weakness and death within 2-5 years. SOD1 mutations cause hereditary ALS in autosomal dominant and rarely in recessive pattern. We describe a new phenotype of slowly progressive fALS due to homozygous SOD1 mutations (c.358G > C, p.Val120Leu) in a Brazilian family. We reviewed the medical chart and interviewed the index patient and other relatives. A 41-year-old man developed weakness in his legs, leading to frequent falls, followed over the next few months with progressive arm fasciculations and muscle atrophy. The SOD1 enzymatic activity in erythrocytes was slightly decreased. A genetic test panel disclosed homozygous SOD1 mutations (c.358G > C, p.Val120Leu). His asymptomatic parents also carried one mutant allele and 2 brothers and a sister had died with ALS. We reported a new family with homozygous SOD1 mutation and slowly progressive ALS course. Further studies are necessary to confirm whether this mutation can also lead to disease in heterozygosis with incomplete penetrance.
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Esclerosis Amiotrófica Lateral , Progresión de la Enfermedad , Mutación , Superóxido Dismutasa-1 , Humanos , Masculino , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/diagnóstico , Adulto , Superóxido Dismutasa-1/genética , Brasil , Mutación/genética , Linaje , Superóxido Dismutasa/genética , Homocigoto , Femenino , Persona de Mediana Edad , Valina/genética , Leucina/genéticaRESUMEN
INTRODUCTION: Genetic mutations or inflammatory, degenerative, or neoplastic conditions can trigger amyloidosis. Hereditary gelsolin amyloidosis is a genetic disorder primarily marked by amyloid fibrils composed of misfolded gelsolin fragments. CASE REPORT: We present three sisters with AGel amyloidosis, illustrating its clinical diversity. Patient 1, a 51-year-old, had bilateral ptosis, ocular discomfort, and dry eye syndrome due to cranial nerve involvement. Patient 2, a 53-year-old, experienced progressive bilateral visual impairment. Patient 3, a 50-year-old, exhibited right eye ectropion. Genetic analysis, with the identical mutation, heterozygous c.640G > A (p.Asp214Asn) mutation, confirmed AGel amyloidosis diagnoses, with common findings including lattice corneal amyloidosis, reduced corneal sensitivity, and recurrent corneal erosions. Neurological manifestations included ataxia and peripheral neuropathy, with skin abnormalities observed in patient 1. Ocular involvement severity and distribution varied among patients. DISCUSSION: Common ocular and neurological manifestations validated AGel amyloidosis diagnoses, reinforcing its hereditary basis. Neurological symptoms highlighted the disorder's impact on various organ systems, while skin abnormalities contributed to ocular discomfort. Variable ocular involvement emphasized the disorder's heterogeneity. These patients emphasize hereditary gelsolin amyloidosis's clinical diversity and suggest potential environmental influences on disease expression. Genetic confirmation and confocal microscopy findings reaffirm the genetic basis while raising questions about assessing systemic disease severity, necessitating further investigation in larger cohorts. Ophthalmologists' specialized care is crucial for managing ocular symptoms, given the absence of a universal cure.