Carrier Mothers Research Articles

DETERMINISTIC MODEL OF ZIKA-VIRUS WITH CARRIER MOTHER AND RESERVOIRS: A MATHEMATICAL ANALYSIS APPROACH

In this paper, a mathematical model for the Zika virus is suggested to investigate the transmission dynamics of infection based on humans, pregnant carrier mother, infected children and the reservoir (primates) in three connected populations. Vertical and direct transmissions from all people to primates are considered in the proposed model. The Zika virus then spreads from this reservoir of infection via the nonhuman primate population (infected mosquitoes) to other entities. This virus can be passed on to the human population through an infected mosquito. Therefore, the new model with ten compartmental models has been normalized as follows: The normalized model is analyzed in depth to explore linkages between mosquitoes, humans, and primates on the dynamics of Zika-Virus transmission. The mathematical analysis comprises positivity and boundedness of solutions, determination of the basic reproduction number R0 via next-generation matrix approach, existence and stability of all equilibria as well as sensitivity analysis. Local and Global Stability of the Disease-free Equilibrium. Finally, numerical simulations are performed to verify the analytical results obtained and exhibit the contribution of different model parameters on disease transmission dynamics. The results prove that the interaction of forest mosquitoes with primates has a significant effect on human-Zika-Virus transmission dynamics among the susceptible population due to transitions to forested areas. Moreover, the findings suggest that the transmission probabilities and biting rates of mosquitoes on humans and primates are major parameters in transmitting the disease.

Multiple Congenital Anomalies-Hypotonia-Seizures Syndrome 2 Caused by a Novel PIGA Variant Not Associated with a Skewed X-Inactivation Pattern

Germline variants in the phosphatidylinositol glycan class A (PIGA) gene, which is involved in glycosylphosphatidylinositol (GPI) biosynthesis, cause multiple congenital anomalies-hypotonia-seizures syndrome 2 (MCAHS2) with X-linked recessive inheritance. The available literature has described a pattern of almost 100% X-chromosome inactivation in mothers carrying PIGA variants. Here, we report a male infant with MCAHS2 caused by a novel PIGA variant inherited from his mother, who has a non-skewed pattern of X inactivation. Phenotypic evidence supporting the pathogenicity of the variant was obtained by flow-cytometry tests. We propose that the assessment in neutrophils of the expression of GPI-anchored proteins (GPI-APs), especially CD16, should be considered in cases with variants of unknown significance with random X-inactivation in carrier mothers in order to clarify the pathogenic role of PIGA or other gene variants linked to the synthesis of GPI-APs.

Etiological involvement of KCND1 variants in an X-linked neurodevelopmental disorder with variable expressivity

Utilizing trio whole-exome sequencing and a gene matching approach, we identified a cohort of 18 male individuals from 17 families with hemizygous variants in KCND1, including two de novo missense variants, three maternally inherited protein-truncating variants, and 12 maternally inherited missense variants. Affected subjects present with a neurodevelopmental disorder characterized by diverse neurological abnormalities, mostly delays in different developmental domains, but also distinct neuropsychiatric signs and epilepsy. Heterozygous carrier mothers are clinically unaffected. KCND1 encodes the α-subunit of Kv4.1 voltage-gated potassium channels. All variant-associated amino acid substitutions affect either the cytoplasmic N- or C-terminus of the channel protein except for two occurring in transmembrane segments 1 and 4. Kv4.1 channels were functionally characterized in the absence and presence of auxiliary β subunits. Variant-specific alterations of biophysical channel properties were diverse and varied in magnitude. Genetic data analysis in combination with our functional assessment shows that Kv4.1 channel dysfunction is involved in the pathogenesis of an X-linked neurodevelopmental disorder frequently associated with a variable neuropsychiatric clinical phenotype.

Multi-omics in MECP2 duplication syndrome patients and carriers.

MECP2 duplication syndrome (MDS) is an X-linked neurodevelopmental disorder caused by the gain of dose of at least the genes MECP2 and IRAK1 and is characterised by intellectual disability (ID), developmental delay, hypotonia, epilepsy and recurrent infections. It mainly affects males, and females can be affected or asymptomatic carriers. Rett syndrome (RTT) is mainly triggered by loss of function mutations in MECP2 and is a well described syndrome that presents ID, epilepsy, lack of purposeful hand use and impaired speech, among others. As a result of implementing omics technology, altered biological pathways in human RTT samples have been reported, but such molecular characterisation has not been performed in patients with MDS. We gathered human skin fibroblasts from 17 patients with MDS, 10 MECP2 duplication carrier mothers and 21 patients with RTT, and performed multi-omics (RNAseq and proteomics) analysis. Here, we provide a thorough description and compare the shared and specific dysregulated biological processes between the cohorts. We also highlight the genes TMOD2, SRGAP1, COPS2, CNPY2, IGF2BP1, MOB2, VASP, FZD7, ECSIT and KIF3B as biomarker and therapeutic target candidates due to their implication in neuronal functions. Defining the RNA and protein profiles has shown that our four cohorts are less alike than expected by their shared phenotypes.

Origin of pathogenic variant and mosaicism in families with a sporadic case of haemophilia B.

Of newly diagnosed cases of haemophilia B, the proportion of sporadic cases is usually 50% of severe cases and 25% of moderate/mild cases. However, cases presumed to be sporadic due to family history may not always be sporadic. Few case reports have been published on mosaicism in haemophilia B. The present study aimed to trace the origin of the pathogenic variant in a well-defined cohort of sporadic cases of haemophilia B by haplotyping markers. It also aimed to determine the frequency of mosaicism in presumed non-carrier mothers. The study group was 40 families, each with a sporadic case of haemophilia B analysed in two-to-three generations by Sanger sequencing, haplotyping and using the sensitive droplet digital polymerase chain reaction (ddPCR) technique. In 31/40 (78%) of the families, the mother carried the same pathogenic variant as her son, while Sanger sequencing showed that 9/40 (22%) of the mothers did not carry this variant. Of these variants, 2/9 (22%) were shown to be mosaics by using the ddPCR technique. 16/21 carrier mothers, with samples from three generations available, had a de novo pathogenic variant of which 14 derived from the healthy maternal grandfather. The origin of the pathogenic variant in sporadic cases of haemophilia B is most often found in the X-chromosome derived from the maternal grandfather or, less often, from the maternal grandmother. Mosaic females seem to be found at the same frequency as in haemophilia A but at a lower percentage of the pathogenic variant.

Optimization of Mother-to-Child Hepatitis B Virus Prevention Program: Integration of Maternal Screening and Infant Post-Vaccination Serologic Testing.

Evaluation of the impact of a hepatitis B virus (HBV) prevention program that incorporates maternal antiviral prophylaxis on mother-to-child transmission (MTCT) is limited using real-world data. We analyzed data on maternal HBV screening, neonatal immunization, and post-vaccination serologic testing (PVST) for hepatitis B surface antigen (HBsAg) among at-risk infants born to HBV carrier mothers from the National Immunization Information System during 2008-2022. Through linkage with the National Health Insurance Database, information on maternal antiviral therapy was obtained. Multivariate logistic regression was performed to explore MTCT risk in relation to infant-mother characteristics and prevention strategies. In total, 2 460 218 deliveries with maternal HBV status were screened. Between 2008 and 2022, the annual HBsAg and hepatitis B e antigen (HBeAg) seropositivity rates among native pregnant women decreased from 12.2% to 2.6% and from 2.7% to 0.4%, respectively (P for both trends < .0001). Among the 22 859 at-risk infants who underwent PVST, the MTCT rates differed between infants born to HBsAg-positive/HBeAg-negative and HBeAg-positive mothers (0.75% and 6.33%, respectively; P < .001). MTCT risk increased with maternal HBeAg positivity (odds ratio [OR], 9.29; 95% confidence interval [CI], 6.79-12.73) and decreased with maternal antiviral prophylaxis (OR, 0.28; 95% CI, .16-.49). For infants with maternal HBeAg positivity, MTCT risk was associated with mothers born in the immunization era (OR, 1.40; 95% CI, 1.17-1.67). MTCT was related to maternal HBeAg positivity and effectively prevented by maternal prophylaxis in the immunized population. At-risk infants born to maternal vaccinated cohorts might possibly pose further risk.

Descriptive Analysis of Carrier and Affected Hereditary Fructose Intolerance in Women during Pregnancy.

(1) Background: Hereditary fructose intolerance (HFI) is a rare autosomal recessive metabolic disorder resulting from aldolase B deficiency, requiring a fructose, sorbitol and sucrose (FSS)-free diet. Limited information exists on the relationship between pregnancy outcomes and HFI. This study aims to analyze pregnancy-related factors in a cohort of thirty Spanish women, with twenty-three being carriers and seven being HFI-affected (45 pregnancies). (2) Methods: A descriptive, cross-sectional and retrospective study utilized an anonymous questionnaire. (3) Results: Findings encompassed physical and emotional states, nutritional habits, pathology development and baby information. Notable results include improved physical and emotional states compared to the general population, with conventional analyses mostly within normal ranges. Persistent issues after pregnancy included hepatic steatosis, liver adenomas and hemangiomas. Carrier mothers' babies exhibited higher weight than those of patient mothers, while the weights of carrier children born with HFI were similar to disease-affected children. (4) Conclusions: Pregnant women with HFI did not significantly differ in physical and emotional states, except for nausea, vomiting, and cravings. Post-pregnancy, HFI patients and carriers exhibited persistent hepatic issues. Significantly, babies born to HFI-affected mothers had lower weights. This study sheds light on pregnancy outcomes in HFI, emphasizing potential complications and the need for ongoing monitoring and care.

Adherence to universal screening for group B Streptococcus in pregnancy and prevalence of colonised pregnancies in Caserta province, Italy.

Group B Streptococcus (Streptococcus agalactiae; GBS) infection is a significant contributor to neonatal morbidity and mortality. In the early 1970s, the neonatal mortality rate for infants with invasive GBS disease was 55%. With the adoption of the first medical community guidelines to prevent GBS infection in the 1990s, the mortality rate decreased to approximately 5%. The main obstetric procedure for preventing vertical transmission of GBS infection involves universal screening of pregnant women using a vaginal-rectal swab (VRS) to identify those eligible for intrapartum antibiotic prophylaxis (IAP). The study analyzes the adherence of screening and the trend of GBS infection in pregnancy in the province of Caserta, Italy. Data were obtained from pregnant women who gave birth in a first level birthing center in 2022 from birth assistance certificate (CEDAP), obstetric and neonatal record. Postnatal evaluation collected through computer-assisted telephone interviews. 567 women delivered at our center during the study period. The average coverage of GBS testing in pregnancy was 99.2% (562), and the proportion of GBS colonised women was 12.6% (71) according with the national average, which is about 10-20%. The spread of positive cases appears to fluctuate among the various groups of pregnant women studied, indicating no significant statistical variance among presence of a partner, among women who have given birth multiple times, among Italian nationals, or across different ages, but a significant statistical excess is evident among mothers with less education. In 93% (66) of GBS carrier mothers, intrapartum antibiotic prophylaxis (IAP) was administered correctly, regardless of the type of delivery performed. Despite the successful integration of GBS screening, a significant gap remains between the ideal scenario and the actual implementation of IAP. At the three-month assessment, no child required hospitalization, consistent with the relatively low incidence of invasive GBS infection. Nevertheless, for those who are not eligible to VRS screening, such as preterm birth, or IAP, as in precipitous birth, the identification of biomarkers enabling early recognition of invasive GBS disease remains essential. Additionally, the emergence of vaccines administered during gestation, conferring passive immunity to newborns represents a promising possible new direction. Therefore, to ensure the practical application of GBS screening and actual IAP by healthcare providers, periodic audits and regular monitoring should be encouraged.

X-linked chronic granulomatous disease secondary to skewed X-chromosome inactivation in female patients.

Chronic granulomatous disease (CGD) is a heterogeneous primary immunodeficiency. X-linked (XL) CGD caused by gene defects of CYBB is the most prevalent type of CGD. We aim to understand the clinical and molecule features of XL-CGD secondary to skewed X-chromosome inactivation (XCI) in female. We retrospectively reviewed the medical records of a female patient diagnosed with XL-CGD. Flow cytometry was used to detect the respiratory burst function. After restriction enzyme digestion of DNA, XCI was calculated by detecting fluorescent PCR products with capillary electrophoresis. The previously published female XL-CGD cases secondary to skewed XCI was summarized. Clinical data were available for 15 female subjects. The median age of diagnosis was 16 years. Consistent with XL-CGD in males, infection was the most frequent manifestation in the female patients. Catalase-positive pathogens including Serratia marcescens and Staphylococcus aureus infections were the most common pathogens. Autoimmune/autoinflammation manifestations were observed in five patients. Dihydrorhodamine (DHR) assay showed that median %DHR+ values were 6.5% and the values varying with age were observed in 2 patients. All patients had a skewing XCI and there was no consistency between the daughter and carrier mother. Anti-infective treatment was effective in majority and there was no mortality reported in XL-CGD female patients to date. XL-CGD should not be neglected in female patients manifested as CGD phenotype and it is necessary to make periodic clinical evaluation of CGD female carriers as the neutrophil oxidative function may decline with aging and increase the risk for infection.

Female Hemophilia in a Set of Triplets

Female Hemophilia In A Set Of Triplets Introduction: Hemophilia A (HA) and B (HB) are the most common inherited bleeding disorders. Gene sequencing identifies specific mutations and their associations with plasma factor levels and clinical phenotypes. Both HA and HB are X-linked recessive disorders, where the female carriers pass the gene onto their descendants. Males who inherit the mutated gene from their mothers develop the disease, whereas females are carriers due to having one normal gene, they typically do not display the characteristic features of hemophilia and have moderately low factor VIII levels of less than 40%. Female carriers may have bleeding symptoms, yet they do not experience as severe morbidities as the male hemophilia patients, due to having higher plasma factor VIII levels. Rarely female carriers can be severely affected and may have plasma factor VIII activities comparable to those with severe hemophilia. Here we are presenting a set of triplets, where the male infant and one of his sisters have severe hemophilia while the other sister is a hemophilia carrier. Methods: A set of triplets a male and two female neonates were born after 33 weeks of gestation to a healthy mother. Female neonates were dichorionic but shared the same placenta. The male infant had a circumcision at six weeks of age, which was complicated with prolonged bleeding. He was brought to the hospital and was diagnosed with severe HA. (Table.1). Infant #2 was admitted to the hospital for skin rash at age 8 weeks. She had staphylococcal scalded skin syndrome and was treated with vancomycin and cephalexin. She was noted to have prolonged bleeding from needle puncture sites. She was diagnosed with severe HA. The bleeding was controlled with tight packing. After a week of treatment her rash cleared, and she was discharged home. (Table 1). Infant #3 She was a healthy baby with no bleeding problems. (Table 1). Results and conclusions: We presented three infant-triplets-with factor VIII deficiency; infant #1 and infant #2 have severe HA. Infant #3 is an asymptomatic carrier. They all have the same mutation as their asymptomatic carrier mother. Infant #1 the male infant developed severe HA due to having the hemophilia allele on his “X” chromosome. Infant #3 a female infant is an asymptomatic carrier. She inherited the hemophilia allele on the X chromosome from her carrier mother and has an X chromosome bearing the normal allele, thus is able to produce factor VIII of 40%. Infant #2 the other female infant had severe HA, with a factor VIII activity of &amp;lt;0.3%. Female hemophilia is rare occurrence. Hemophilia treatment center (HTT) population profile (PP) reported that of the 1,676 females attending to HTC, 47.6% of them had less than 40% factor level, 0.48% of them had severe, 1.4% had moderate and 17.9% had mild hemophilia[Haemophilia. 2021:27(6):1037-1044. Doi:10.1111}. This can occur, in the setting of monosomy X (Turner syndrome-XO), due to having one X chromosome carrying the hemophilic gene or in the setting of compound heterozygosity: the female product of a father with hemophilia and the mother being a carrier. Similarly, hemizygosity of the hemophilic gene on both parents would result in hemophilia in their daughters. Another mechanism that plays a role in the pathogenesis of female hemophilia is the “X chromosome inactivation (XCI). This has been described as the most common cause of female hemophilia. One of the two X chromosomes in females is randomly and permanently inactivated in cells to ensure the balance with one X chromosome of males and limit the overproduction of potentially toxic gene proteins. The degree of inactivation determines the plasma levels of the gene products, in hemophilia the factor levels. The chromosome analysis of infant #2 revealed normal 46XX. Structural chromosomal abnormality is ruled out as she did not have Turner syndrome “XO”, or “45XY” with androgen insensitivity syndrome, nor did she have compound heterozygosity or hemizygosity of the X chromosome. The father had normal coagulation studies and factor VIII activity. Therefore, we believe infant #2 had extremely skewed XCI and the inactivation is skewed in favor of hemophilic X chromosome. This mechanism resulted in severe HA in this infant. The infants are now seven months old and have no bleeding problems, as infant #1 and #2 are on prophylaxis with emicizumab (Hemlibra), they both have 1% factor activity by chromogenic assay and do not have inhibitors. (Table 1)

Epidermolysis bullosa with col7a1 mutation at Jiangsu university hospital: A Case report and review of the literature

We describe a case of a new born Chinese male baby who was diagnosed with Epidermolysis Bullosa (EB), a rare genetic skin illness that causes particular blisters to appear on the baby's lower limbs immediately after delivery. The flaw results from the skin's reduced ability to adhere to supporting tissue, which makes it brittle. Through carrier mother inheritance, genetic testing identified our case as an EB patient with Aplasia Cutis Congenita after a nucleotide alteration in the COL7A1 gene.

Red Blood Cells from Individuals with Lesch-Nyhan Syndrome: Multi-Omics Insights into a Novel S162N Mutation Causing Hypoxanthine-Guanine Phosphoribosyltransferase Deficiency.

Lesch-Nyhan syndrome (LN) is an is an X-linked recessive inborn error of metabolism that arises from a deficiency of purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT). The disease manifests severely, causing intellectual deficits and other neural abnormalities, hypercoagulability, uncontrolled self-injury, and gout. While allopurinol is used to alleviate gout, other symptoms are less understood, impeding treatment. Herein, we present a high-throughput multi-omics analysis of red blood cells (RBCs) from three pediatric siblings carrying a novel S162N HPRT1 mutation. RBCs from both parents-the mother, a heterozygous carrier, and the father, a clinically healthy control-were also analyzed. Global metabolite analysis of LN RBCs shows accumulation of glycolytic intermediates upstream of pyruvate kinase, unsaturated fatty acids, and long chain acylcarnitines. Similarly, highly unsaturated phosphatidylcholines are also elevated in LN RBCs, while free choline is decreased. Intracellular iron, zinc, selenium, and potassium are also decreased in LN RBCs. Global proteomics documented changes in RBC membrane proteins, hemoglobin, redox homeostasis proteins, and the enrichment of coagulation proteins. These changes were accompanied by elevation in protein glutamine deamidation and methylation in the LN children and carrier mother. Treatment with allopurinol incompletely reversed the observed phenotypes in the two older siblings currently on this treatment. This unique data set provides novel opportunities for investigations aimed at potential therapies for LN-associated sequelae.

Factor VIII Level in the Potential Female Carrier Mothers of Patients with Hemophilia A and Its Impact on Joint Health

Background Hemophilia A is an X-linked bleeding disorder. The characteristic bleeding phenotype in patients with severe hemophilia is recurrent spontaneous hemarthrosis with development of hemophilic arthropathy. Heterozygous female carriers with factor VIII (FVIII) activity level lower than 40% may be at risk for bleeding that is usually comparable to that seen in males with mild hemophilia. Aim of the Work To assess factor VIII level in mothers of known patients of hemophilia A correlating it with the frequency of clinically and radiologically documented arthropathy. Patients and Methods A cross sectional study included 40 mothers of patient with hemophilia A during the period from September 2020 to September 2021. Studied participants were subjected to detailed analysis of bleeding history, six major joints range of motion (ROM) examination, functional independence score in hemophilia (FISH), FVIII level one stage assessment and magnetic resonant imaging (MRI) of the reported affected joints. Results Mean age of mothers is 42.25 ± 7.74 years. Eleven mothers (27.5%) had no bleeding symptoms, 16 (40%) had one bleeding symptoms and 13 (32.5%) had two or more bleeding symptoms. As regard joint pain, 13 (32.5%) had severe pain, 3 (7.5%) had ankle pain and 2 (5%) had elbow pain with a mean pain score of 2.55±3.32, and 7 (17.5%) had bilateral pain. Mean FVIII activity was 43.33 IU (± 22.79), ranging from FVIII (0 &amp;lt; 30 IU) in 13 (32.5%), FVIII (30 &amp;lt;60) in 18 (45.0%) and FVIII ≥ 60 IU in 9 (22.5%) among the studied participants. Knees were the most affected joints with decreased mean ROM (±SD) in right and left knees of (123.25 (±12.06) and 120.00 (±15.81)) respectively. The median MRI scores were studied was 5 (2.6%) with median osteochondral changes of 4 (2.5%) and median soft tissue changes of 1 (0-1), their median FISH score of 8 (8-9). By comparing groups at the level of factor VIII, there was no significant difference according to anthropometric bleeding parameters, pain, and MRI score. None of participants needed hospital admission, factor VIII replacement or packed red cells replacement. Conclusion Potential female hemophilia A carriers are at risk of spontaneous bleeding which may entail bleeding in the joints, causing early joint damage. They showed reduced overall joint ROM and structural osteochondral changes in MRI joint examination which mandates further studies about early detection of potential female hemophilia carriers for the possible need of early medical intervention.

Hemizygous variants in protein phosphatase 1 regulatory subunit 3F (PPP1R3F) are associated with a neurodevelopmental disorder characterized by developmental delay, intellectual disability and autistic features.

Protein phosphatase 1 regulatory subunit 3F (PPP1R3F) is a member of the glycogen targeting subunits (GTSs), which belong to the large group of regulatory subunits of protein phosphatase 1 (PP1), a major eukaryotic serine/threonine protein phosphatase that regulates diverse cellular processes. Here, we describe the identification of hemizygous variants in PPP1R3F associated with a novel X-linked recessive neurodevelopmental disorder in 13 unrelated individuals. This disorder is characterized by developmental delay, mild intellectual disability, neurobehavioral issues such as autism spectrum disorder, seizures and other neurological findings including tone, gait and cerebellar abnormalities. PPP1R3F variants segregated with disease in affected hemizygous males that inherited the variants from their heterozygous carrier mothers. We show that PPP1R3F is predominantly expressed in brain astrocytes and localizes to the endoplasmic reticulum in cells. Glycogen content in PPP1R3F knockout astrocytoma cells appears to be more sensitive to fluxes in extracellular glucose levels than in wild-type cells, suggesting that PPP1R3F functions in maintaining steady brain glycogen levels under changing glucose conditions. We performed functional studies on nine of the identified variants and observed defects in PP1 binding, protein stability, subcellular localization and regulation of glycogen metabolism in most of them. Collectively, the genetic and molecular data indicate that deleterious variants in PPP1R3F are associated with a new X-linked disorder of glycogen metabolism, highlighting the critical role of GTSs in neurological development. This research expands our understanding of neurodevelopmental disorders and the role of PP1 in brain development and proper function.

Dört Aileden Pelizaeus-Merzbacher Sendromlu Altı Hastanın Klinik ve Moleküler Sitogenetik Analizleri

Objective: Pelizaeus-Merzbacher Disease is a rare X-linked recessive leukodystrophy caused by a mutation in the proteolipid protein (PLP) gene on chromosome Xq22. PMD is an early-onset neurological disorder characterized by nystagmus, spastic quadriplegia, ataxia, and developmental delay. Genetic analysis has identified Xq22 microduplications (60-70%), point mutations (10–25%), and deletions (5-10%) within the coding region of the PLP genes in Pelizaeus-Merzbacher Disease. This study evaluated six patients with PLP1 deletion and duplication in four Turkish families. Material and Methods: To detect the duplication and deletion of PLP1, chromosomal microarray analysis, and multiplex ligation-related probe amplification assays were performed. Results: In these four families, two brothers had a hemizygous deletion in the PLP1 gene, their carrier mother had a deletion in the PLP1 gene, and another two unrelated boys and one girl had duplication of the PLP1. Also, we identified the rare case of two brother patients who were found to have a hemizygous deletion in the PLP1 gene. Their carrier mother had unexplained dementia. Conclusion: Genotype-phenotype correlations of the PLP1 mutation in these families were identified in this study while trying to elucidate the genetic etiology of six individuals from four different families.

Health Effects of Sleep Quality in Premutation Carrier Mothers of Individuals With Fragile X Syndrome.

Sleep plays an integral role in supporting well-being, and sleep difficulties are common in mothers of individuals with developmental disabilities, including fragile X syndrome (FXS). This study assessed whether the effects of sleep quality on physical health and depression are exacerbated by genetic risk factors (CGG repeats) in FMR1 premutation carrier mothers of individuals with FXS. Poor sleep quality predicted a greater number of physical health conditions for mothers with CGG repeats in the mid-premutation range (90-110 repeats), but not for those in the lower (< 90 repeats) or higher (> 110 repeats) ends of the range. A significant association between poor sleep quality and maternal depressive symptoms was also observed, but there was no evidence that this effect varied by level of genetic vulnerability. This research extends our understanding of individual differences in the effects of sleep quality among mothers of individuals with FXS.

Assessing the impact of hepatitis B immune globulin (HBIG) on responses to hepatitis B vaccine during co-administration.

A hepatitis B vaccination (HepB) series with an initial dose of hepatitis B immune globulin (HBIG) is the recommended prophylaxis for infants born to mothers with chronic hepatitis B virus (HBV) infection and for HBV-exposed persons without known protection. The HepB and HBIG are administered at different sites (limbs). Instances of HepB and HBIG administered at the same site are documented but the impact on immune responses to HepB remains unanswered. Newborn and adult BALB/c mice received one dose of HepB at time zero alone or with HBIG in the same or different sites, followed by 2 additional doses of HepB at 3 and 10weeks (newborn mice) or 4 and 16weeks (adult mice). To study memory responses mice were given a 4th, booster, dose of HepB at 26weeks and B cells analyzed. Administration of HepB with HBIG resulted in reduced responses to HepB following the first 2 doses, regardless of site, compared to mice that received HepB only. Lower levels of antibody to HBV surface antigen (anti-HBs) were observed at the end of the 3-dose series (p<0.0001) in all groups of newborn mice that received HepB and HBIG. In adult mice, this difference was only seen when HepB and HBIG were delivered at the same site. However, following a HepB booster at 26weeks, HBsAg-specific B-cell expansion and memory phenotype were not impacted by initial HBIG administration CONCLUSION: Administration of HBIG with HepB can delay and reduce responses to HepB in mice. Our findings suggest that the initial circulating levels of HBIG could prevent infection despite an impaired response to vaccine and support the current recommendation of assessing seroprotection after series completion for infants born to HBV carrier mothers, including in cases where vaccine and HBIG are administered incorrectly at the same site.

Preferential Inheritance in Hemophilia

BACKGROUND Hemophilia A and B are X-linked recessive disorders. Each male offspring born of parents with carrier female and an unaffected male have a 50% chance of being affected with hemophilia. We have observed a higher prevalence of affected hemophilia A and B males in our patient families, than expected of classical X-linked inheritance. We investigate the observed inheritance rate (OIR) of hemophilia A and B in males at our institution to determine whether the disease is preferentially inherited compared to the expected rate of inheritance. METHODS All patients with diagnosis of either hemophilia A (89) or B (166) at our institution as of 3/1/2022 were included in the initial pool of patients. Patients ages 18 or younger were excluded. The electronic records were reviewed for family history (FH) of hemophilia, focusing on male inheritance and maternal carrier status. Families with only one son were excluded to reduce selection bias from families with only one son and who had not inherited the mutation. Siblings were identified by chart review and were excluded to avoid duplication. Patients were formed into unique families (UFs) if carrier status of the mother could be reasonably inferred by either 1) presence of two or more children with hemophilia or 2) documentation of the mother's factor deficiency or mutation status or FH of carrier status. Statistical analysis for male inheritance was conducted in two ways. First, UFs were stratified by total number of sons. An adjusted expected inheritance rate (AEIR) was calculated, adjusting for carrier mothers who have no affected sons and thus would be missed by our selection process. This was compared to the OIR with a one-sample t-test. If the sample was too small, UFs were aggregated and compared using the highest AEIR. Second, the total number of brothers of affected patients were aggregated. The OIR of the brothers of affected patients was compared to the 50% expected inheritance rate of classical X-linked inheritance by z-test. Female inheritance was not investigated as carrier status could not be reliably obtained. RESULTS Thirty-six UFs with hemophilia B were identified. 26/36 had >50% of sons affected. The total aggregate prevalence was 103/150 (68.7%). There were 9 UFs with 2 total sons with a mean OIR of 94.4% compared to the 66.7% AEIR (p=0.001, 95% CI LL 83.5%). There were 8 UFs with 3 total sons with a mean OIR of 87.5% compared to the 57.1% AEIR (p=0.001, 95% CI LL 75.1%). There were 7 UFs with 4 total sons with a mean OIR of 64.3% compared to the 53.3% AEIR (p=0.037, 95% CI LL 53.7%). There were 12 UFs with 5 or more sons with a mean OIR of 56.7% compared to the aggregated 51.6% AEIR (p=0.173). There were 115 total brothers of hemophiliacs, 69 of which had hemophilia. The OIR was 60% for brothers (p=0.0147, 95% CI LL 52.4%). 26/36 UFs were of Amish decent, comprising an aggregate prevalence of 81/126 (64.3%). Nine UFs with hemophilia A were identified. 6/9 UFs had >50% of sons affected. The total aggregate prevalence was 16/22 (72.7%). As the sample was small, all 9 UFs were compared to the aggregated AEIR of 66.7%. The mean OIR was 77.8% (p=0.131, 95% CI LL 59.6%). There were 13 brothers of hemophiliacs, 7 of which had hemophilia. The OIR was 53.8% for brothers (p=0.395). CONCLUSION Our data suggests that there is a higher proportion of affected males with hemophilia B than expected from the classical X-linked inheritance pattern. There were no significant differences in our hemophilia A group compared to expected rates of inheritance, though this was limited by our small sample size. We plan to analyze the specific genetic mutations of our patients to further elucidate any links to potential preferential inheritance. A larger dataset is needed to confirm our findings. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Preimplantation genetic testing (PGT) for hemophilia A: Experience from one center

ObjectiveHemophilia A (HA) is an X-linked recessive bleeding disease caused by a deficiency or dysfunction of blood coagulation factor VIII (FVIII). Available treatment to replenish the missing factor may not reach a good outcome for all patients because of potential complications that include the development of inhibitor antibodies directed against factor VIII. Therefore, the prevention of transmitting pathogenic mutations to the next generation is the best solution for this disease. Preimplantation genetic testing for a monogenic disorder (PGT-M) has become a standard method to prevent the transmission of monogenic heritable disease. The gold standard of the molecular technique used for PGT-M nowadays is the co-amplification of the polymorphic microsatellite linkage markers that use microsatellite DNA technique that overcomes the limitation of other methods. The important issue of this technique is the definition of markers that are specific for each allele on different loci. Each gene locus needs a characteristic design to allow accurate diagnosis that can be applied on PGT-M due to the limited quantity of DNA available. Here we present our study of four specific self-designed linked polymorphic markers applied on screening the embryos before implantation for hemophilia A families in Vietnam. Material and methodsIn this study, we investigated the feasibility of application and diagnostic value of 4 STR loci (FXS1108, DXS9897, F8int22, DXS9901) in the intragenic or neighbouring regions of the F8 gene. 35 hemophilia A families were recruited for STR analysis to define at least two characteristic heterologous markers for each family and 12 cases of pre-implantation genetic testing (PGT-M) for carrier mothers were performed. ResultAll 4 of these loci (FXS1108, DXS9897, F8int22, DXS9901) were found practical and useful for preimplantation genetic testing (PGT-M). All 12 cases of PGT-M using the method had informative STR results and correct diagnosis was achieved. 9 out of the 12 mothers (75%) were implanted with 1–2 thawed embryos after the biopsy resulting in the birth of 5 healthy babies (55%). ConclusionWe conclude that specific 4 STR markers for rapid pre-implantation genetic testing of hemophilia A can be successfully applied with high confidence and accuracy in clinical settings. The results of the study provide solid evidence confirming that the microsatellite DNA technique is a highly reliable method, suitable for hemophilia A families wishing to determine carrier status or having healthy babies.

Prevalence of Group B Streptococcus in pregnant women in Kerala and relation to neonatal outcomes: a prospective cross-sectional study.

Early onset sepsis (EOS) in neonates is a scourge that contributes to morbidity and mortality. Prominent stakeholders recommend universal screening of antenatal women for Group B Streptococcus (GBS) and intrapartum antibiotic prophylaxis (IAP) for those who are carriers. However, there are controversies. Other guidelines allow region-specific protocols due to sociodemographic, geographical and ethnic differences. We planned to analyze the prevalence of GBS rectovaginal carriage at 36-37 weeks gestation and its effect on early neonatal status. This prospective multidisciplinary study (Obstetrics, Perinatology, Neonatology, Microbiology and Infectious diseases) was conducted in our tertiary care center between February 2020 and May 2021. In our study group which included 966 mothers who delivered at the hospital, 4.8% of mothers who were screened by genito-rectal swabs were positive for GBS at 36-37 weeks gestation. All these mothers were given IAP as per protocol. Other organisms detected on screening mothers were Candida and Gram-negative bacteria. None of the neonates born to these mothers required any intensive care unit admission or therapy for systemic illness. There was no difference in clinically relevant outcomes between neonates who were born to GBS-positive mothers as compared to those born to negative screen result mothers. GBS prevalence in our cohort was lower than most scientific reports. The neonates born to carrier mothers did not present with signs of early-onset sepsis.