Environmental and Genetic Risk Factors in Developmental Dysplasia of the Hip for Early Detection of the Affected Population.

Diagnosis of developmental dysplasia of the hip (DDH) mostly relies on physical examination and ultrasound, and both methods are operator-dependent. Late detection can lead to complications in young adults. Current evidence supports the involvement of environmental and genetic factors, such as single nucleotide variants (SNVs). Incorporating genetic factors into diagnostic methods would be useful for implementing early detection and management of affected individuals. Our aim was to analyze environmental factors and SNVs in DDH patients. We included 287 DDH cases and 284 controls. Logistic regression demonstrated an association for sex (OR 9.85, 95% CI 5.55-17.46, p = 0.0001), family history (OR 2.4, 95% CI 1.2-4.5, p = 0.006), fetal presentation (OR 3.19, 95% CI 1.55-6.54, p = 0.002), and oligohydramnios (OR 2.74, 95%CI 1.12-6.70, p = 0.026). A model predicting the risk of DDH including these variables showed sensitivity, specificity, PPV, and NPV of 0.91, 0.53, 0.74, and 0.80 respectively. The SNV rs1800470 in TGFB1 showed an association when adjusted for covariables, OR 0.49 (95% CI 0.27-0.90), p = 0.02. When rs1800470 was included in the equation, sensitivity, specificity, PPV and NPV were 0.90, 0.61, 0.84, and 0.73, respectively. Incorporating no-operator dependent variables and SNVs in detection methods could be useful for establishing uniform clinical guidelines and optimizing health resources.

Administration of Tamoxifen Can Regulate Changes in Gene Expression during the Acute Phase of Traumatic Spinal Cord Injury.

Traumatic spinal cord injury (SCI) causes irreversible damage leading to incapacity. Molecular mechanisms underlying SCI damage are not fully understood, preventing the development of novel therapies. Tamoxifen (TMX) has emerged as a promising therapy. Our aim was to identify transcriptome changes in the acute phase of SCI and the effect of Tamoxifen on those changes in a rat model of SCI. Four groups were considered: (1) Non-injured without TMX (Sham/TMX-), (2) Non-injured with TMX (Sham/TMX+), (3) injured without TMX (SCI/TMX-), and (4) injured with TMX (SCI/TMX+). Tamoxifen was administered intraperitoneally 30 min after injury, and spinal cord tissues were collected 24 h after injury. Clariom S Assays Array was used for transcriptome analysis. After comparing Sham/TMX- versus SCI/TMX-, 708 genes showed differential expression. The enriched pathways were the SCI pathway and pathways related to the inflammatory response. When comparing SCI/TMX- versus SCI/TMX+, only 30 genes showed differential expression, with no pathways enriched. Our results showed differential expression of genes related to the inflammatory response after SCI, and Tamoxifen seems to regulate gene expression changes in Ccr2 and Mmp12. Our study contributes data regarding the potential value of tamoxifen as a therapeutic resource for traumatic SCI during the acute phase.

Association of the EPAS1 rs7557402 Polymorphism with Hemodynamically Significant Patent Ductus Arteriosus Closure Failure in Premature Newborns under Pharmacological Treatment with Ibuprofen.

Patent ductus arteriosus (PDA) is frequent in preterm newborns, and its incidence is inversely associated with the degree of prematurity. The first choice of pharmacological treatment is ibuprofen. Several genes, including EPAS1, have been proposed as probable markers associated with a genetic predisposition for the development of PDA in preterm infants. EPAS 1 NG_016000.1:g.84131C>G or rs7557402 has been reported to be probably benign and associated with familial erythrocytosis by the Illumina Clinical Services Laboratory. Other variants of EPAS1 have been previously reported to be benign for familial erythrocytosis because they decrease gene function and are positive for familial erythrocytosis because the overexpression of EPAS1 is a key factor in uncontrolled erythrocyte proliferation. However, this could be inconvenient for ductal closure, since for this process to occur, cell proliferation, migration, and differentiation should take place, and a decrease in EPAS1 gene activity would negatively affect these processes. Single-nucleotide polymorphisms (SNPs) in EPAS1 and TFAP2B genes were searched with high-resolution melting and Sanger sequencing in blood samples of preterm infants with hemodynamically significant PDA treated with ibuprofen at the National Institute of Perinatology. The variant rs7557402, present in the EPAS1 gene eighth intron, was associated with a decreased response to treatment (p = 0.007, OR = 3.53). The SNP rs7557402 was associated with an increased risk of pharmacological treatment failure. A probable mechanism involved could be the decreased activity of the product of the EPAS1 gene.

Blood Type Associated with the Risk of COVID-19 Infection in Pregnant Women.

COVID-19 forced us to investigate risk factors to provide the best medical attention, especially in vulnerable groups, such as pregnant patients. Studies in other populations have analyzed blood groups in relation to infection, complications, and death. The present study aimed to analyze the association of blood groups with the risk of infection and complications in pregnant women and newborns from the Mexican-Mestizo population. We studied 1906 individuals. Quantitative variables were analyzed through the Student's t-test. Categorical variables were analyzed through Pearson's chi-square test, and logistic regression was used to analyze the association between categorical variables and outcomes. No significant association was observed between blood groups and infection risk. Individuals with the AB blood type are at higher risk for developing severe disease, although blood groups do not seem to be involved in the risk of SARS-CoV-2 infection. However, the AB blood group could be considered a risk factor for developing severe COVID-19 in the Mexican population.

Genetic polymorphisms rs1800871 and rs1800872 of IL-10 gene are associated with dengue infection, especially with serotype 1 and DwoWS in Mexican population.

INTRODUCTION: Dengue infection is generated by a complex interaction between DENV (Dengue Virus) and the host's immune response. Interleukin-10 is an immunoregulatory cytokine during DENV infection. The objective of this study was to investigate whether genetic variants in IL-10 could be useful as a predictive and susceptibility marker in the prognosis of DENV infection, particularly with serotype 1, and in participants with dengue without warning signs. MATERIAL AND METHODS: A study of cases (n = 365) and controls (n = 364) was carried out. Genotyping was performed by real-time PCR using TaqMan probes. Sample size power was calculated using Quanto software RESULTS: This is the first report showing the independent association of the T allele of rs1800871 (P = 0.023) and the A allele of rs1800872 (P = 0.010) with the risk of dengue infection. Statistical analysis established the genotypic association of IL-10 SNPs with DENV infection under different inheritance models. Our results also showed the association of the CC, TC, and CA haplotypes (P = 0.0064, P = 0.0032, and P = 0.0010 respectively) with infection. Furthermore, both polymorphic sites were associated with the risk of DwoWS and serotype 1 (Den-1) under different inheritance models. Finally, under the dominant model, we identified a positive correlation between IL-10 levels vs. IFN-γ and IL-8. CONCLUSION: Our results show the first independent association of the T and A alleles of the polymorphic sites rs1800871 and rs1800872, with dengue infection, particularly with Den-1, and in participants with DwoWs.

Unraveling the role of relative telomere length and CAG expansion on initial symptoms of juvenile Huntington disease.

BACKGROUND AND PURPOSE: Juvenile-onset Huntington disease (JHD) is defined when symptoms initiate before 20 years of age. Mechanisms explaining differences between juvenile and adult onset are not fully understood. Our aim was to analyze the distribution of initial symptoms in a cohort of JHD patients and to explore its relationship with CAG expansion and relative telomere length (RTL). METHODS: A total of 84 JHD patients and 54 neurologically healthy age and sex matched individuals were recruited. CAG length was measured by southern blot or triplet repeat primed polymerase chain reaction. RTL was measured using the Cawthon method. RESULTS: Psychiatric symptoms were most frequent when considering the entire cohort. When divided into onset before or after 10 years, cognitive symptoms were more frequent in the youngest, whilst in the older group psychiatric symptoms prevailed. Motor symptoms were rare in the youngest and epilepsy was observed only in this group as well as a larger CAG expansion. RTL analysis revealed shorter telomeres in JHD patients compared to controls. This difference is not influenced by age, initial symptoms, time of disease or CAG expansion. CONCLUSIONS: To the best of our knowledge this is the largest cohort of JHD patients reported. Psychiatric manifestations deserve special attention when JHD is suspected and epilepsy is especially important in the youngest patients. Initial symptoms seem to be influenced by CAG expansion and therefore age of onset. RTL is significantly reduced in JHD patients which can influence the characteristic neurodegeneration of JHD and contribute to the clinical discrepancy between adult and juvenile forms of Huntington disease.

Plasma Total Antioxidant Capacity and Carbonylated Proteins Are Increased in Pregnant Women with Severe COVID-19.

Oxidative stress (OS) induced by SARS-CoV-2 infection may play an important role in COVID-19 complications. However, information on oxidative damage in pregnant women with COVID-19 is limited. Objective: We aimed to compare lipid and protein oxidative damage and total antioxidant capacity (TAC) between pregnant women with severe and non-severe COVID-19. Methods: We studied a consecutive prospective cohort of patients admitted to the obstetrics emergency department. All women positive for SARS-CoV-2 infection by reverse transcription-polymerase chain reaction (RT-qPCR) were included. Clinical data were collected and blood samples were obtained at hospital admission. Plasma OS markers, malondialdehyde (MDA), carbonylated proteins (CP), and TAC; angiogenic markers, fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF); and renin-angiotensin system (RAS) markers, angiotensin-converting enzyme 2 (ACE-2) and angiotensin-II (ANG-II) were measured. Correlation between OS, angiogenic, and RAS was evaluated. Results: In total, 57 pregnant women with COVID-19 were included, 17 (28.9%) of which had severe COVID-19; there were 3 (5.30%) maternal deaths. Pregnant women with severe COVID-19 had higher levels of carbonylated proteins (5782 pmol vs. 6651 pmol; p = 0.024) and total antioxidant capacity (40.1 pmol vs. 56.1 pmol; p = 0.001) than women with non-severe COVID-19. TAC was negatively correlated with ANG-II (p < 0.0001) and MDA levels (p < 0.0001) and positively with the sFlt-1/PlGF ratio (p = 0.027). Conclusions: In pregnant women, severe COVID-19 is associated with an increase in protein oxidative damage and total antioxidant capacity as a possible counterregulatory mechanism.

AZFa, AZFb, AZFc and gr/gr Y-chromosome microdeletions in azoospermic and severe oligozoospermic patients, analyzed from a neural network perspective.

AIM: Analysis of male infertility by molecular methods has increased since recognition of genetic risk factors. The AZFa, AZFb, AZFc, and gr/gr regions on the Y-chromosome can cause male infertility. The aim of this study was to determine the prevalence of Y-chromosome microdeletions in these regions in infertile Mexican patients. MATERIAL AND METHODS: We recruited 57 infertile patients with abnormal sperm count (26 azoospermic and 31 oligozoospermic) and 55 individuals with normal sperm count. Analysis of the regions of interest was performed by PCR. RESULTS: 15.8% of infertile patients presented Y-chromosome microdeletions, whereas no deletions were found in the control group. Deletions were observed in all the analyzed regions except in AZFa. Additionally, the neural network model revealed a mild genotype-phenotype correlation between deletion of the sY1191, sY1291 and sY254 markers with oligozoospermia, azoospermia and cryptozoospermia, respectively. CONCLUSIONS: Our data show that AZFb, AZFc, and gr/gr microdeletions are significantly associated with infertility in Mexican population. In addition, the neural network model revealed a discrete genotype-phenotype correlation between specific deletions and a particular abnormality. Our results reinforce the importance of the analysis of AZF regions as part of the clinical approach of infertile men.

OBJETIVO: La utilización de técnicas moleculares para estudiar la infertilidad masculina se ha incrementado desde el reconocimiento de factores genéticos. Las regiones AZFa, AZFb, AZFc, y gr/gr del cromosoma Y son causa de infertilidad masculina. El objetvo de este estudio fue determinar la prevalencia de microdeleciones en estas regiones en pacientes infértiles Mexicanos. MATERIAL Y MÉTODOS: Reclutamos 57 pacientes infértiles con cuentas espermáticas anormales (26 con azoospermia y 31 con oligozoospermia) y 55 individuos con cuentas espermáticas normales. El análisis de las regiones se realizó mediante PCR. RESULTADOS: 15.8% de los pacientes infértiles presentó microdeleciones, no se encontraron microdeleciones en el grupo control. Las microdeleciones fueron observadas en todas las regiones excepto en AZFa. Adicionalmente, el modelo de red neuronal reveló una leve correlación genotipo-fenotipo entre microdeleciones de los marcadores sY1191, Sy1291 y sY254 con oligozoospermia, azoospermia y criptozoospermia, respectivamente. CONCLUSIONES: Nuestros datos muestran que las microdeleciones en AZFb, AZFc, y gr/gr se asocian significativamente con infertilidad en la población Mexicana. Además, el modelo de red neuronal reveló una discreta correlación genotipo-genotipo entre microdeleciones específicas con una anormalidad en particular. Nuestros resultados refuerzan la importancia del análisis de las regiones AZF en el abordaje de la infertilidad masculina.

circRNA Regulates Dopaminergic Synapse, MAPK, and Long-term Depression Pathways in Huntington Disease.

Huntington disease (HD) is the most common neurogenetic disorder caused by expansion of the CAG repeat in the HTT gene; nevertheless, the molecular bases of the disease are not fully understood. Non-coding RNAs have demonstrated to be involved in the physiopathology of HD. However, the role of circRNAs has not been investigated. The aim of this study was to identify the circRNAs with differential expression in a murine cell line model of HD and to identify the biological pathways regulated by the differentially expressed circRNAs. CircRNA expression was analyzed through a microarray, which specifically detects circular species of RNA. The expression patterns between a murine cell line expressing mutant Huntingtin and cells expressing wild-type Huntingtin were compared. We predicted the miRNAs with binding sites for the differentially expressed circRNAs and the corresponding target genes for those miRNAs. Using the target genes, we performed a function enrichment analysis. We identified 23 circRNAs differentially expressed, 19 downregulated and four upregulated. Most of the downregulated circRNAs derive from the Rere gene. The dopaminergic synapse, MAPK, and long-term depression pathways were significantly enriched. The three identified pathways have been previously associated with the physiopathology of HD. The understanding of the circRNA-miRNA-mRNA network involved in the molecular mechanisms driving HD can lead us to identify novel biomarkers and potential therapeutic targets. To the best of our knowledge, this is the first study analyzing circRNAs in a model of Huntington disease.

Unravelling complex mosaicism of sex chromosomes in a patient with primary amenorrhea through cytogenetic analysis on urothelial cells.

OBJECTIVE: Sex chromosome mosaicism remains challenging in the study of disorders of sex development (DSD). Aneuploid cells in the developing gonad play a major role in sex determination. Therefore, it is necessary acknowledge their presence by different methods. Our aim was to stand out the utility of urothelial cells for unravelling complex and hidden cell lines in DSD patients. CASE REPORT: Herein we report on a 19-year-old female with primary amenorrhea, short stature without ambiguous external genitalia. She had a 45,X/46, XY karyotype in leukocytes. Interphase FISH revealed hidden 45,X/47,XYY/47,XXY/46,XY/46, XX mosaicism in leukocytes and urothelial cells. CONCLUSION: These findings highlight the importance of investigating sex chromosome mosaicism in other tissues. Of particular interest in cases of DSD are the cells from the urinary epithelium, which may reflect the cell composition of the urogenital ridge, the analysis of these cells should be considered within the clinical assessment of DSD patients.

Single-nucleotide polymorphism rs10036727 in the SLIT3 gene is associated with osteoporosis at the femoral neck in older Mexican postmenopausal women.

AIMS: Osteoporosis (OP) remains a major public health problem worldwide. The most serious complications of this disease are fragility fractures, which increase morbidity and mortality. Management of OP represents an economic burden for health systems. Therefore, it is necessary to develop new screening strategies to identify the population at risk and implement preventive measures. We previously identified the SNPs rs3801387 in WNT16, rs7108738 in SOX6, rs10036727 in SLIT3 and rs7584262 in PKDCC as associated with bone mineral density in postmenopausal women through a genome-wide association study. The aim of this study was to validate those SNPs in two independent cohorts of non-related postmenopausal women. MATERIALS AND METHODS: We included 1160 women classifying them as normal, osteopenic or osteoporotic and a group with hip fragility fracture. Genotyping was performed using predesigned TaqMan assays. RESULTS: The variants rs10036727 and rs7108738 showed a significant association with BMD at the femoral neck. SLIT3 has been previously proposed as a potential biomarker and therapeutic resource. CONCLUSIONS: Our results provide new evidence regarding a possible involvement of SLIT3 in bone metabolisms and encourage the development of more studies in different populations to support these observations.

Clinical and genetic description of patients with prenatally identified cardiac tumors.

OBJECTIVE: Rhabdomyomas are the most common type of prenatal cardiac tumors. When isolated, 50% to 70% are related to the tuberous sclerosis complex (TSC). The aim of this study was to reinforce the importance of additional clinical data in patients with prenatal heart tumors. METHODS: From 2010 to 2017, 10 prenatally detected cardiac tumors were referred to the Genetics Department, and a complete family history was taken. Postnatal echocardiographic and full clinical evaluation were completed. Next generation sequencing (NGS) of the TSC1 and TSC2 genes was performed. RESULTS: The 10 cases were postnatally confirmed as rhabdomyomas. Four de novo and four family cases were detected, and only one patient was previously aware of the TSC diagnosis. Molecular analysis by NGS was performed in four patients with three TSC2 mutations, two of which were previously reported and one not. DISCUSSION: Prenatal cardiac tumors are associated with TSC in 60% of cases. Prenatal diagnosis of cardiac tumors permits a further analysis of family members using the fetus as a clue for familial disease diagnosis.

Heterogeneous Diagnoses Underlying Radial Ray Anomalies.

OBJECTIVE: To review perinatal Radial Ray Anomaly (RRA) cases born at the National Institute of Perinatology, Mexico, and to reveal the heterogeneous diagnoses of these patients. METHODS: All patients with RRA over a 18 mo period were included; 4/15 were detected prenatally and 11/15 postnatally. Karyotype was performed for all patients with bilateral RRA; and chromosomal breakage analysis, when the karyotype was normal. RESULTS: Fifteen RRA patients were identified: one with trisomy 18, three with an isolated defect, six with monogenic disease, four with a genetic association and one with diabetic embryopathy. Five were stillborn and two died during the early neonatal period; all of whom presented with multiple defects. Three of the live born patients and one stillborn with multiple defects had Fanconi anemia. RRAs carry a high perinatal mortality rate (47%) when they occur in association with other defects. CONCLUSIONS: The assessment of these patients needs to involve the combined use of ultrasound, clinical, genetic, cytogenetic and molecular testing. The present results indicate that the chromosome breakage test should always be performed to rule out Fanconi anemia in this group.

Fenotipo grave en dos medio hermanas con síndrome de Adams Oliver / Severe phenotype in two half-sibs with Adams Oliver syndrome

El síndrome de Adams Oliver (AOS) es una entidad heterogénea con defecto transverso terminal de extremidades (TTLD) y aplasia cutis congénita (ACC) con un amplio espectro fenotípico. Se han descrito diferentes modos de herencia en esta enfermedad; los defectos más graves se han asociado a un patrón autosómico recesivo (AR). Objetivo. presentar a una familia con dos medio hermanas con un fenotipo grave de Adams Oliver, con una madre sana. Reporte del caso: una mujer de 27 años de edad fue referida al Departamento de Genética. Su hija anterior presentó acránea, anillos de constricción y defectos transversos terminales de extremidades. Su hija actual presentaba encefalocele occipital, defecto amplio en huesos del cráneo, aplasia cutis congénita, defecto terminal transverso de extremidades y labio y paladar hendido bilateral. Sugerimos que algunos casos con fenotipo grave del síndrome de Adams Oliver pueden deberse a herencia autosómico dominante con penetrancia incompleta o a la presencia de mosaicismo gonadal.

Adams Oliver syndrome (AOS) is a highly variable entity with terminal transverse limb defects (TTLD) and aplasia cutis congenita (ACC) with a wide phenotypic spectrum. Several inheritance models have been observed; the most severe phenotype has been related to an autosomal recessive (AR) pattern of inheritance. Objective. To present a family with two half siblings with a severe phenotype of Adams Oliver syndrome in which the mother was healthy. Case report: A 27 year-old woman was referred to the Genetics Department. Her previous girl presented acrania, constriction rings and terminal transverse limb defects. The present girl had occipital encephalocele, large scalp defects, aplasia cutis congenita, terminal transverse limb defects and bilateral cleft lip and palate. Autosomal dominant inheritance with reduced penetrance or gonadal mosaicism has to be considered in Adams Oliver syndrome with severe intracranial anomalies.

Severe phenotype in two half-sibs with Adams Oliver syndrome.

UNLABELLED: Adams Oliver syndrome (AOS) is a highly variable entity with terminal transverse limb defects (TTLD) and aplasia cutis congenita (ACC) with a wide phenotypic spectrum. Several inheritance models have been observed; the most severe phenotype has been related to an autosomal recessive (AR) pattern of inheritance. OBJECTIVE. To present a family with two half siblings with a severe phenotype of Adams Oliver syndrome in which the mother was healthy. CASE REPORT: A 27 year-old woman was referred to the Genetics Department. Her previous girl presented acrania, constriction rings and terminal transverse limb defects. The present girl had occipital encephalocele, large scalp defects, aplasia cutis congenita, terminal transverse limb defects and bilateral cleft lip and palate. Autosomal dominant inheritance with reduced penetrance or gonadal mosaicism has to be considered in Adams Oliver syndrome with severe intracranial anomalies.

Pure trisomy 2p syndrome in two siblings with an unbalanced translocation and minimal terminal 12q monosomy characterized by high-density microarray.

Pure partial trisomy 2p patients have rarely been reported. Oligonucleotide array analysis has proved to be important for examining 2p rearrangements to delineate the involved segment and to rule out additional imbalances modifying the phenotype. Here, we report 2 siblings with an unbalanced translocation that led to a partial trisomy 2p (p22.3pter) and a terminal deletion of 12q (q24.33qter). This finding was characterized by the molecular karyotyping of both siblings. The 12q loss spanned approximately 300 kb and did not yield clinical features in our patients. The trisomic region in the short arm of chromosome 2 spanned 32.8 Mb and yielded phenotypic features of pure distal 2p trisomy, notably facial anomalies, growth failure, and psychomotor delay. The clinical features of our patients help to delineate the phenotype of the pure trisomy 2p syndrome. Patient 2 also showed a horseshoe kidney which is a previously unrecognized defect associated with this syndrome.

El papel de la genética en la restricción del crecimiento intrauterino / The role of genetics in fetal growth restriction

Se define como restricción del crecimiento intrauterino (RCIU) a la alteración en el crecimiento fetal que determina un peso por debajo de la percentila 10 para la edad gestacional. Las causas genéticas de RCIU pueden dividirse en: cromosómicas, alteraciones de la epigenética o impronta y síndromes génicos. Se presenta el caso de una paciente con RCIU referida por sospecha de displasia ósea, en la que se descartó disfunción vascular placentaria por ultrasonido prenatal, infecciones, patología materna y displasias óseas por estudio radiológico normal. Se realizó cariotipo en el cordón umbilical y en tres diferentes sitios de la placenta por la posibilidad de un mosaico placentario, obteniéndose un resultado normal. Al nacimiento presentó peso y talla por debajo de la percentila 3, cráneo dolicocéfalo con frontal prominente, fontanela anterior amplia, cara pequeña, triangular con mentón en punta y clinodactilia bilateral. A los dos meses de edad se observó asimetría de extremidades inferiores y se refirió reflujo gastroesofágico. Con base en los criterios clínicos y resultados obtenidos se realizó el diagnóstico de síndrome de Silver-Russell.

Intrauterine growth restriction (IUGR) is an alteration in fetal development in which the fetal weight is below the 10th percentile for gestational age. The genetic causes of IUGR can be classified as: chromosomal, epigenetic and other imprinting disorders and monogenic syndromes. We report a patient with IUGR referred to our hospital with the prenatal diagnosis of achondroplasia. Vascular malfunction of the placentae, maternal pathology, and skeletal dysplasia were discarded. A karyotype in umbilical cord and in three different placental spots was performed, with a normal result in all of them, ruling out placentae mosaicism. At birth, the weight and height were below the 3th percentile. Physical examination showed: dolicocephaly, frontal prominence, large fontanels, small and triangular face, pointed chin and incurved bilateral fifth fingers. Two months later a lower limb asymmetry was noticed and gastroesophageal reflux was referred. With these clinical abnormalities and the studies performed the diagnosis of Silver-Russell syndrome was established.