Male Carriers Research Articles

Clinical outcomes in carriers of insertional translocation: a retrospective analysis of comprehensive chromosome screening results

To evaluate the clinical outcomes in the carriers of insertional translocation (IT). Retrospective case series. University-affiliated reproductive medical center. Twenty-three couples with ITs. No direct interventions were involved; however, this study included patients who underwent preimplantation genetic testing for structural chromosomal rearrangements (PGT-SR). Outcome of preimplantation genetic testing for structural chromosomal rearrangements and percentage of blastocysts available for transfer. Among 23 IT carriers, 15 were simple interchromosome ITs (type A), 3 were intrachromosome IT carriers (type B), and 5 were interchromosome IT carriers combined with other translocations (type C). A total of 190 blastocysts from 30 cycles were biopsied, 187 embryos were tested successfully, and only 57 blastocysts (30.5%) from 21 patients were available for transfer (normal or balanced). The unbalanced rearrangement rate of type C was 79.2% (42/53), and the proportion of type A was 50.0% (57/114), which was significantly higher than that of type B (5%, 1/20). In type A, the probability of embryos harboring unbalanced rearrangement in female carriers was 56.0% (51/91), which was higher than that in male carriers (26.1%, 6/23). Furthermore, the haploid autosomal length value of the inserted fragment was correlated linearly with the incidence of abnormal embryos. In type A gametes, most gametes produced by 2:2 separation without crossover, and no 3:1 separation gamete was observed. The chance of identifying normal or balanced and mosaic blastocysts per mature oocytes in patients with ITs are 16.6% (67/404). Greater IT complexity results in fewer transferable embryos. For simple interchromosome ITs, female carriers and those with higher haploid autosomal length values have a higher risk of producing embryos with unbalanced rearrangement.

Longitudinal effects of sex on pathology accumulation, neurodegeneration and cognitive decline in Presenilin‐1 E280A mutation carriers: preliminary findings from the Colombia‐Boston (COLBOS) biomarker study

AbstractBackgroundPrevious work showed that females at risk for autosomal dominant Alzheimer’s disease (AD) due to a single mutation (E280A) in the Presenilin‐1 gene (PSEN1) may have greater cognitive resilience to AD‐pathology and neurodegeneration than males. However, more research is needed to clarify the effect of sex on AD risk and progression. We investigated the effects of sex on rates of amyloid and tau accumulation, neurodegeneration, and memory decline in PSEN1 mutation carriers with and without cognitive impairment, who are genetically determined to develop early‐onset dementia.MethodA total of 66 cognitively unimpaired mutation carriers (mean age of 34.41 +/‐ 4.86 years; 38 females), and 23 cognitively impaired mutation carriers (mean age of 44.91 +/‐ 2.83 years; 17 females) from the Colombia‐Boston Biomarker (COLBOS) study completed baseline cognitive assessments. A subset of 52 participants also completed florbetapir‐ and flortaucipir‐PET, and structural MRI. Cognitive and neuroimaging follow‐up visits were completed at 2‐ (n = 29) and 4‐year (n = 13) intervals. We used linear mixed‐effects models, with random intercepts, to predict rate of change in MMSE scores, CERAD word list delayed recall, cortical amyloid burden, tau in the entorhinal, inferior temporal, and precuneus cortices, and hippocampal volume by sex, controlling for education.ResultOver time, carriers exhibited greater cortical amyloid burden (p<.001), inferior temporal tau (p = .019), precuneus tau (p = .003), lower hippocampal volume (p = .005), and showed a trend towards lower MMSE scores (p = .059) and word list delayed recall (p<.080); entorhinal tau did not significantly increase (p = .137). Female carriers showed a steeper decline in word list delayed recall than male carriers (p = .021). There were no sex differences in the rate of accumulation of mean cortical amyloid or regional tau, hippocampal atrophy, or change in MMSE scores (all ps>.05).ConclusionPreliminary findings of this ongoing study suggest that despite similar rates of pathology accumulation or atrophy between female and male PSEN1 E280A carriers, female mutation carriers may have faster memory decline. Future analyses with additional participants and follow‐up intervals are needed to characterize sex differences in ADAD risk and resilience, as well as inform development of treatments and interventions.

Sex‐ and APOE‐Specific Transcriptomic Signatures in Alzheimer’s Disease: An AZ‐ADRC‐Research Education Scholars Team Science Project

AbstractBackgroundAge, female sex and APOEε4 allele are among the top risk factors for developing late‐onset Alzheimer’s disease (LOAD). To enable Precision medicine for AD drug development, it is crucial targeting specific biological pathways driving AD pathology. While individual effects of sex or APOE have been studied, genes and biological pathways commonly or uniquely altered by these two factors are less understood.MethodROSMAP RNA‐Seq data were obtained from AMP‐AD including 369 frontal cortex samples from APOEε3/ε3 and APOEε3/ε4 individuals. Of these, 209 had an AD diagnosis and 160 were controls. Differentially expressed genes (DEGs, pvalue<.05) between LOAD and cognitively normal individuals were identified using a generalized linear regression model. Gene Set Enrichment Analysis (GSEA) was performed using Gene Ontology Biological Processes (GOBP). Redundant GOBP enriched terms were removed computing semantic similarity measures (adjusted pvalue<.05). Comparison analyses were conducted to identify common and unique DEGs and enriched GOBPs across sex‐genotype conditions.ResultAPOEε3/ε3 female brains exhibited the greatest DEG number (n = 11,851) while APOEε3/ε3 males exhibited the least (n = 714). Nine DEGs were shared across all comparisons, which were involved in metabolic processes, synaptic function, myelination, and GPCR signaling. GSEA revealed comparable numbers of LOAD‐enriched pathways in all female groups and male APOEε3/ε4s (n = 144‐155 GOBP terms), whereas APOEε3/ε3 males exhibited the fewest enriched terms (n = 13). Identified GOBP terms included pathways related to metabolism, cellular responses and regulation, and immune response regulation. However, there were no common GOBP terms across all sex‐genotype conditions.ConclusionOur analyses provide evidence of sex‐ and APOE‐ specific transcriptomic signatures and biological processes altered in LOAD brains. The findings suggest significantly greater transcriptomic dysregulation in female APOEε3/ε3 brains despite the similar extent of affected biological pathways as other sex‐APOE conditions. In contrast, a significantly smaller number of affected biological processes were identified in male APOEε3/ε3s despite having comparable transcriptomic dysregulation as the male APOε4 carriers but less than the female groups. These analyses provide rationale to develop risk factor‐specific therapeutics for the prevention and treatment of LOAD by considering the interaction between biological sex and APOE genotype.

Sensorimotor and inhibitory control in aging FMR1 premutation carriers.

Aging FMR1 premutation carriers are at risk of developing neurodegenerative disorders, including fragile X-associated tremor/ataxia syndrome (FXTAS), and there is a need to identify biomarkers that can aid in identification and treatment of these disorders. While FXTAS is more common in males than females, females can develop the disease, and some evidence suggests that patterns of impairment may differ across sexes. Few studies include females with symptoms of FXTAS, and as a result, little information is available on key phenotypes for tracking disease risk and progression in female premutation carriers. Our aim was to examine quantitative motor and cognitive traits in aging premutation carriers. We administered oculomotor tests of visually guided/reactive saccades (motor) and antisaccades (cognitive control) in 22 premutation carriers (73% female) and 32 age- and sex-matched healthy controls. Neither reactive saccade latency nor accuracy differed between groups. FMR1 premutation carriers showed increased antisaccade latencies relative to controls, both when considering males and females together and when analyzing females separately. Reduced saccade accuracy and increased antisaccade latency each were associated with more severe clinically rated neuromotor impairments. Findings indicate that together male and female premutation carriers show a reduced ability to rapidly exert volitional control over prepotent responses and that quantitative differences in oculomotor behavior, including control of visually guided and antisaccades, may track with FXTAS - related degeneration in male and female premutation carriers.

The ENPP1 K121Q polymorphism is associated with obesity-related parameters in Iranian normoglycemic male subjects

Objectives: The K121Q polymorphism of the Ectoenzyme Nucleotide Pyrophosphate Phosphodiesterase 1 (ENPP1) gene has been variably associated with obesity in several populations. However, this association has not been studied in Iranian subjects. It was hypothesized that the K121Q variant might be associated with obesity and related risk factors in subjects with normal glucose tolerance and normal fasting glucose.
 Methods: The K121Q genotypes were determined by PCR-restriction fragment length polymorphism in 377 non-diabetic subjects.
 Results: In males, the frequency of the Q allele was 20.8% and 15.9% (p=0.269) in obese and non-obese subjects, respectively. The ENPP1 genotype (KQ+QQ) was not associated with systolic and diastolic blood pressure, triglyceride, cholesterol, LDL-C, HDL-C, HOMA-IR, or insulin levels in both genders. Male carriers of the KQ+QQ genotype had significantly higher values for BMI (p=0.079), waist (p=0.01), and WHR (p=0.006) than subjects with the KK genotype. Obesity-related parameters were not significantly different between obese and non-obese female subjects.
 Conclusion: Our results suggest that the ENPP1 121Q allele might be associated with obesity and related parameters only among Iranian normoglycemic male subjects.

Influence of left ventricular ejection fraction, type of mutation and sex on malignant ventricular arrhythmias in dsp and flnc mutations

Abstract Introduction Pathogenic mutations in FLNC and DSP are a common cause of arrhythmogenic left ventricular cardiomyopathy and "arrhythmic dilated cardiomyopathy". We aimed to study demographic and clinical differences amongst these carriers. Purpose 1. To study the prevalence of malignant ventricular arrhythmias in DSP and FLNC mutation carriers in the studies and reports published in the literature. 2. To analyse the effect of age, left ventricular ejection fraction (LVEF), and sex on ventricular arrhythmias in both groups. Methods A systematic review of the human studies published in Medline and EMBASE until September 2022 was carried out. "Desmoplakin Mutations", "Filamin Mutations", "Arrhythmogenic Cardiomyopathy" and "Dilated Cardiomyopathy" were the keywords included in the search queries. Studies, family reports, and registries reporting on individual data of pathogenic or likely pathogenic mutation carriers were selected for analysis. Results Twenty-four articles published between 2002 and 2020 were selected from a total of 430 entries. 171 DSP carriers (from 16 studies) and 169 FLNC carriers (from 7 studies) were included in the analysis. Mean age was similar in both groups: 39.45±19.23 years in DSP vs 42.02±16.27 in the FLNC group (p:0.201). The proportion of females was higher among DSP carriers than that found among FLNC carriers: 101 (59%) vs 76 (45%), p: 0.012. Non-missense mutations were more frequent in both groups: 98 DSP carriers (57%) and 157 FLNC carriers (97%). LVEF was slightly more depressed amongst FLNC carriers: 47.75±14.94% vs 52.37±14.64%, p:0.014. A total of 81 major arrhythmic events (sudden death, ventricular fibrillation, sustained ventricular tachycardia were reported. The LVEF of the male patients that had suffered a major event was similar in both groups (39.13±18.20% in DSP vs 39.03±12.24% in FLNC, p:0.987). On the contrary, LVEF was significantly lower in female carriers of DSP mutations (32.33±15.65% in DSP vs 47.60±15.88% in FLNC, p:0.050). Male carriers show a worse prognosis than their female counterparts (log-rank 0.005) (Figure). The difference was not significant after adjusting for LVEF and type of mutation (missense vs non-missense). LVEF (HR 0.94 per percentage unit (0.91-0.96), p <0.001) and non-missense mutations (HR 0.21 (0.07-0.66), p:0.008) were inversely associated with adverse outcomes in DSP carriers in a multivariate analysis. LVEF was also associated with a better outcome in FLNC carriers (HR 0.97 (0.95-0.99), p: 0.019. Conclusion Moderate systolic dysfunction is a risk factor for malignant arrhythmias amongst DSP and FLNC mutation carriers. Female FLNC carriers with mild systolic dysfunction are at risk for sustained ventricular arrhythmias. Missense DSP mutations are associated with poor arrhythmic prognosis.Sex differences in survival

Arrhythmogenic cardiomyopathy phenotype associated with the pathogenic founder variant c.1211dup in PKP2

Abstract Background Arrhythmogenic cardiomyopathy results in life-threatening ventricular arrhythmia and heart failure. Phenotypic features vary according to genetic aetiology. Genotype-phenotype research is therefore crucial for patient counselling and treatment decisions such as implantable cardioverter defibrillator therapy. By collecting data from patient records we characterized the clinical phenotype associated with variant c.1211dup (p.Val406Serfs*4) in the plakophilin-2 gene (PKP2), common in the Dutch population. Purpose We aimed to investigate the incidence of ventricular arrhythmia and heart failure in families carrying the PKP2 c.1211dup variant. Furthermore, we aimed to determine the founder status of this variant, and compare phenotype severity with other truncating PKP2 variants. Methods Clinical data were collected retrospectively from medical records of 106 PKP2 c.1211dup heterozygous carriers (>85% of known carriers in The Netherlands) in a Castor EDC database. Using occurrence of ventricular arrhythmia and heart failure, event-free survival was compared between males and females, and probands and family members, using log-rank tests. Using data from a central curated arrhythmogenic cardiomyopathy database, c.1211dup was compared to three other truncating PKP2 variants (c.235C>T (p.Arg79*), c.397C>T (p.Gln133*) and c.2489+1G>A (p.?)) on ventricular arrhythmia-free survival by a Cox proportional hazards model, corrected for sex and proband status. Results Forty-seven carriers (44%) were diagnosed with arrhythmogenic cardiomyopathy at 41 years on average. As shown in figure 1, 29 participants (27%) experienced episodes of ventricular arrhythmia and 12 (11%) developed heart failure, with male carriers showing significantly higher risks than females on both endpoints (p<0.05). Based on available magnetic resonance imagery and echocardiographic data, 46% of carriers showed either right ventricular dilatation and/or dysfunction, and a substantial minority of 37% showed some form of left ventricular involvement. Both geographical distribution of carriers (figure 2) and haplotype analysis suggested PKP2 c.1211dup to be a founder variant originating from the South-Western coast of the Netherlands. Finally, a Cox proportional hazards model suggested significant differences in ventricular arrhythmia-free survival between four PKP2 truncating founder variants, including c.1211dup. Conclusions The PKP2 c.1211dup variant is a Dutch founder variant associated with a typical right ventricular-dominant arrhythmogenic cardiomyopathy phenotype, but also notable left ventricular involvement. Males were most susceptible to the frequent ventricular arrhythmia, and less frequent heart failure was observed in general. Finally, c.1211dup possibly leads to a more severe phenotype than other Dutch PKP2 founder variants.Phenotype onset stratified by sexGeographic distribution carriers

The suppression of a selfish genetic element increases a male's mating success in a fly.

X chromosome meiotic drive (XCMD) kills Y-bearing sperm during spermatogenesis, leading to the biased transmission of the selfish X chromosome. Despite this strong transmission, some natural XCMD systems remain at low and stable frequencies, rather than rapidly spreading through populations. The reason may be that male carriers can have reduced fitness, as they lose half of their sperm, only produce daughters, and may carry deleterious alleles associated with XCMD. Thus, females may benefit from avoiding mating with male carriers, yielding a further reduction in fitness. Genetic suppressors of XCMD, which block the killing of Y sperm and restore fair Mendelian inheritance, are also common and could prevent the spread of XCMD. However, whether suppressed males are as fit as a wild-type male remains an open question, as the effect that genetic suppressors may have on a male's mating success is rarely considered. Here, we investigate the mating ability of XCMD males and suppressed XCMD males in comparison to wild-type males in the fruit fly Drosophila subobscura, where drive remains at a stable frequency of 20% in wild populations where it occurs. We use both competitive and non-competitive mating trials to evaluate male mating success in this system. We found no evidence that unsuppressed XCMD males were discriminated against. Remarkably, however, their suppressed XCMD counterparts had a higher male mating success compared to wild-type controls. Unsuppressed XCMD males suffered 12% lower offspring production in comparison to wild-type males. This cost appears too weak to counter the transmission advantage of XCMD, and thus the factors preventing the spread of XCMD remain unclear.

10 Female APOE ε4 Carriers with Slow Rates of Biological Aging Have Better Verbal Memory Performance Compared to Female Carriers with Faster Rates of Aging, Independent of Chronological Age, Education, and Depressive Symptoms.

Objective:The presence of an e4 allele of the apolipoprotein E gene (APOE ε4) is considered the strongest genetic risk factor for Alzheimer’s disease (AD) in the US. Evidence suggests that APOE ε4 carriers have worse memory performances compared to APOE ε4 non-carriers in cognitively normal older adults and that female APOE ε4 carriers are at greater risk of AD compared to male carriers. Recent advancements in estimating biological age using DNA methylation markers may enhance understanding of the associations between sex and APOE ε4 on cognitive aging. Thus, the current study aimed to investigate whether associations between APOE ε4 status and memory vary according to rates of biological aging, using a DNA methylation age biomarker, in older men and women without dementia.Participants and Methods:Cross-sectional data were obtained from 1771 older adults enrolled in the 2016 wave of the Health and Retirement Study (Mean age = 75, SD = 7; 57% female; 76% non-Hispanic white). The standardized residual from regressing chronological age on the epigenetic clock “DNAGrimAge” was used as a measure of the aging rate. A series of ANCOVAs with Bonferroni corrected post hoc pairwise tests, adjusting for education, white blood cell count, chronological age, and depressive symptoms were used to test the main and interaction effects of APOE ε4 status (non-carriers = 0; carriers = 1) and aging rates, defined as 1 standard deviation below (i.e., slow rate), or above (i.e., fast rate) sex-specific mean rate (i.e., average) of aging, on a standardized composite measure of verbal memory. Alpha was set at .05 and all raw scores were converted to z-score metric prior to analyses.Results:APOE ε4 female carriers with slow rates of aging (n = 34) had significantly better memory performances compared to APOE ε4 female carriers with fast rates of aging (n = 41), mean difference = .61, p = .006, and average rates of aging (n = 170), mean difference = .44, p = .017. There was no effect of aging rate on memory in the female non-carriers and there were no significant differences in memory performances based on rates of aging in either male APOE ε4 carriers or non-carriers.Conclusions:Although the presence of the APOE ε4 has previously been shown to represent a stronger risk of AD for women compared to men, results from the current study suggest that slower rates of aging in this high-risk group may confer protection against clinical symptoms (i.e., memory impairment). Conversely, faster than average aging in female APOE ε4 carriers may represent a group at greater risk of memory impairment due to AD. However, longitudinal studies with larger sample sizes are needed to evaluate the risk of dementia/memory impairment based on rates of aging in female APOE ε4 carriers.

Effects of chromosomal translocation characteristics on fertilization and blastocyst development - a retrospective cohort study.

To determine the effect of different translocation characteristics on fertilization rate and blastocyst development in chromosomal translocation patients. This retrospective cohort study was conducted at the Third Affiliated Hospital of Zhengzhou University From January 2017 to December 2022.All couples were diagnosed as reciprocal translocation or Robertsonian translocation by karyotype of peripheral blood lymphocytes test. After adjusting for confounding factors, the effect of chromosomal rearrangement characteristics, such as carrier sex, translocation type, chromosome length and break sites, on fertilization rate and embryo development were analysed separately using multiple linear regression. In cases of Robertsonian translocation (RobT), the carrier sex plays an independent role in fertilization rate, and the male carriers was lower than that of female carriers (76.16% vs.86.26%, P = 0.009). In reciprocal translocation (RecT), the carrier sex, chromosome types and break sites had no influence on fertilization rate, blastocyst formation rate (P > 0.05). However, patients with human longer chromosomal (chromosomes 1-5) translocation have a lower available blastocyst formation rate (Group AB vs. Group CD: 41.49%vs.46.01%, P = 0.027). For male carriers, the translocation types was an independent factor affecting the fertilization rate, and the RobT was the negative one (B = - 0.075, P = 0 0.009). In female carriers, we did not observe this difference (P = 0.227). In patients with chromosomal translocation, the fertilization rate may be influenced by carrier sex and translocation type, chromosomes 1-5 translocation may adversely affect the formation of available blastocysts. Break sites have no role in fertilization and blastocyst development.

Taking it to the extreme: The search for determinants of cognitive vulnerability and resilience in children with autosomal dominant Alzheimer’s disease

Abstract:Presenilin-1 (PSEN1) mutations predispose individuals to develop autosomal-dominant Alzheimer's disease (ADAD) in middle adulthood. While the pathogenesis of ADAD may be different from late-onset sporadic AD (e.g., differences in disease etiology, age of disease onset, etc), these conditions share many characteristics, including similar abnormalities in amyloid and tau biomarkers, brain structure and brain activity, and clinical features (Quiroz et al., 2010, Quiroz et al., 2011, Quiroz et al. 2018). Biomarker investigations of families with ADAD have already shed light on the trajectory of some AD-related brain changes, especially prior to the onset of clinical symptoms.We have been studying a Colombian kindred with a genetic form of AD caused by a single genetic mutation in the PSEN1 (E280A), which serves as a unique model for preclinical AD. Because of a well-defined age at clinical onset, and near 100% penetrance, this kindred provides important information about the time course and relationships between physiological mechanisms and cognitive changes, and in so doing, it has yielded new insights about presymptomatic AD that will enhance future prevention trials for AD, including primary prevention trials.The well-characterized clinical trajectory of these PSEN1 E280A mutation carriers allow us to examine brain function in children, more than three decades before the average age of onset of mild cognitive impairment (MCI) and dementia in this cohort (45 years for MCI, 50 years for dementia). This is giving us the unique opportunity to characterize the cognitive and behavioral profiles of children genetically determined to develop dementia in their forties, and is helping us improve our understanding of the impact of ADAD mutations in early life cognitive and brain functioning, as well as its potential impact on learning, academic performance and educational attainment. We previously studied 20 PSEN1 E280A carriers and 20 non-carriers aged 9 to 17 years from the Colombian ADAD cohort and showed that mutation-carrying children were distinguished from non-carriers by plasma biomarker findings consistent with Aß1-42 overproduction, as well as by increased functional connectivity of the posterior cingulate cortex with medial temporal lobe regions (Quiroz et al 2015). More recently, we used the WISC-IV, a measure of general intellectual abilities to examine cognitive abilities in these children. We reported in 265 children with the E280A mutation and 1089 non-carriers that they did not differ on any of the WISC-IV indices. Surprisingly, male carriers performed slightly worse than female carriers on working memory (mean difference = -4.97; P = .001) (Fox-Fuller et al., 2021). Some of our ongoing work includes comprehensive examinations of social, educational and developmental histories along with functional brain networks, as markers of synaptic dysfunction in individuals with ADAD, as this is particularly relevant to understanding the impact of PSEN1 mutations on the developing brain and subsequent neurodegenerative changes seen later in life, without the confounds of aging and age-related comorbidities that often exist in late-onset sporadic AD.Disclosures: Financial: Dr. Quiroz receives a consulting fee from Biogen. Non-Financial: Dr. Quiroz is a Hispanic Neuropsychological Society Member-At-Large and serves as the INS Teleneuropsychology Special Interest Group Chair

Variable clinical consequences of mosaicism for c.1167dupC in IKBKG in male and female patients with incontinentia pigmenti and related phenotypes.

In the present study, we report a duplication variant found in two families with incontinentia pigmenti, which exhibited a variety of phenotypes in both male and female carriers. Although natural mosaicism through Lyonization, with variably skewed X-inactivation, accounts for the phenotype in females, our study also demonstrates that mosaicism, albeit through a different mechanism, should also be remembered in understanding the phenotypic expression of IKBKG-related disorders in some males.

A - 21 Sex Differences in Cortical Thickness and Cognition in Individuals with Autosomal Dominant Alzheimer's Disease.

Cortical thinning is a marker of neurodegeneration. Individuals with autosomal dominant Alzheimer's disease (ADAD) develop early-onset dementia with virtually 100% certainty. Cortical thickness fluctuates across the ADAD lifespan, from early-life increased thickness to atrophy proximal to clinical onset. Females have higher cortical thickness and better cognition than males as they age. We examined sex differences in cortical thickness and cognitive performance in adults with ADAD. We assessed 85 Presenilin-1 E280A mutation carriers (74 cognitively-unimpaired, 11 mildly-impaired) from the Colombia-Boston Biomarker Study of ADAD. Mean age was 35.7 (SD = 10), education 10.2 (SD = 9), and 55 were female. Global cognition was measured using Mini-Mental State Examination (MMSE), and memory using CERAD Word List Delayed Recall. Participants underwent structural brain MRI. T-tests assessed between-group differences. Pearson correlations examined associations between cortical thickness and cognition. There were no sex differences in cortical thickness or cognitive performance (all ps > =0.05). For carriers, greater cortical thickness was associated with higher MMSE (r = 0.40, p < 0.001) and memory recall scores (r = 0.43, p < 0.01). Female carriers drove this effect, where greater cortical thickness was associated with higher MMSE (r = 0.46, p < 0.001) and memory recall scores (r = 0.47, p < 0.001); these associations were non-significant in male carriers alone. In cognitively-unimpaired female carriers, increased cortical thickness was associated with worse MMSE (r = -0.44, p < 0.001). We found sex differences in the relation between cortical thickness and cognition in ADAD carriers, which may be relevant to the differential vulnerability and progression of ad in females and males. Future work should investigate potential underlying mechanisms contributing to this sex difference.

Lifetime risk of liver-related outcomes and determinants in male inactive carriers of chronic hepatitis B.

The full spectrum of risks for the life course of inactive hepatitis B virus (HBV) carriers remains unclear. In this study, 995 untreated HBV carriers (median age: 42.8 years; median follow-up: 30.2 years) were included. Their data were sourced from a population-based cohort study of male civil servants recruited in 1989-1992. Outcomes were identified by active follow-up examinations and linkage with national health insurance research database. At baseline, 483 subjects were inactive carriers, 385 with indeterminate phase, and 127 with other phases. The joint lifetime risk for incident cirrhosis, decompensation, hepatocellular carcinoma, and liver-related deaths was lower for inactive carriers compared to subjects in other phases (p < 0.0001). There was a trend of increase in incidence among inactive carriers; the 5-, 10-, and 20-year cumulative incidences were 1.86%, 6.03%, and 10.07%, respectively. Of the inactive carriers, 37.7% cleared HBsAg and 36.6% had biochemical relapse during the study. Biochemical relapse, obesity, and advanced age were predictors for disease progression in inactive carriers. Virological relapse was the predominant cause of biochemical relapse. Higher HBV-DNA levels (≥1000 copies/mL or 200 IU/mL) and HBV genotype B (vs. C) were associated with higher virological relapse rate. After 30 years, we found that one-time measure of inactive carrier state continued to have the lowest risk compared with other infection phases. Despite a more favorable prognosis, inactive carriers had a non-negligible risk. Our findings of lifetime risk may provide important clues for the management of such patients and consideration of therapeutic strategies aiming to achieve functional cure.

B-262 Evaluation of the Genotypic Profile of the c.202 G&amp;gt;A Mutation in the G6PD Gene in Brazil

Abstract Introduction Glucose 6 phosphate dehydrogenase (G6PD) is an enzyme found in the cytoplasm of all human cells and plays an important role in preventing cellular damage to reactive oxygen species (ROS). G6PD deficiency is inherited in an X-linked recessive genetic disorder that can destroy red blood cells (hemolysis) leading to acute hemolytic anemia during periods of increased ROS production. The disease prevalence is more frequent in male individuals. To date, more than 400 G6PD variants have been identified, and molecular studies have shown that G6PD deficiency can be associated with different mutations. The c.202 G &amp;gt; A mutation (rs1050828; NM_000402.4) was described as the most frequent. The rapid and accurate diagnosis of this condition is extremely important in neonatal screening and cases of diagnostic suspicion. Therefore, this study aims to describe the genotypic profile of the c.202 G &amp;gt; A mutation in the G6PD gene in Brazilian samples by two molecular assays. Methods Genomic DNA samples from 130 individuals previously genotyped by Restriction Fragment Length Polymorphism PCR were used for validation. DNA isolation was performed in MagNA Pure 24 Total NA Isolation Kit at the automated platform MagNA Pure 24 System (Roche Diagnostics, Basel, Switzerland), according to manufacturer instructions. Genotyping for rs1050828 was performed using TaqMan SNP Genotyping Assays (Thermo Fisher, Foster City, CA) at 7500 Fast Real-Time PCR System (Thermo Fisher, Foster City, CA), according to manufacturer instructions. The results were analyzed using TaqMan Genotyper Software version 1.0.1. Results This study evaluated 130 blood samples, of which 81 were men (62.3%) and 49 were women (37.7%). Male carriers of rs1050828 A genotype (hemizygotes) predominated (56/81, 69.1%) and the remaining carriers for allele G (wild type) were 25/81 (30.9%). While female carriers of rs1050828 GG (wild type) predominated (39/49, 79.6%), heterozygotes were 5/49 (10.2%), and homozygotes also were 5/49 (10.2%). The number of male individuals with the presence of the mutation in hemi/homozygotes was considerably higher when compared to female individuals. This is explained by the fact that the mutation is inherited in an X-linked recessive manner. The results showed agreement and reproducibility of 100% for both methodologies. However, the qPCR assay sensibility and efficiency (&amp;gt;99%) were higher than the RFLP PCR assay. Conclusions Here, we described an efficient molecular method to detect the mutation c.202 G&amp;gt;A in the G6PD gene. The frequency of c.202 G&amp;gt;A described in this study was similar to that observed in others population studies in Brazil. Detection of the mutation target requests an additional evaluation of the G6PD activity level. Obtained results should be evaluated in association with the clinical aspects. The absence of the c.202 G&amp;gt;A in the G6PD gene does not exclude the existence of other mutations in the same region.

EFMR Syndrome: Epilepsy and Mental Retardation Restricted to Females in Childhood

Epilepsy with intelligence impairment, restricted to the female sex, is a rare X-linked epilepsy syndrome. It is characterized by febrile or afebrile seizures, mainly tonic-clonic, but also absence, myoclonic, and atonic beginning in the first years of life. In most cases, developmental delay and intelligence impairment of varying severity is present. Behavioral disorders, autistic traits, hyperactivity, and aggressiveness are commonly associated. This disease exclusively affects females. Male carriers are not affected despite an X-linked inheritance.

Risks of Ventricular Arrhythmia and Heart Failure in Carriers of RBM20 Variants.

Variants in RBM20 are reported in 2% to 6% of familial cases of dilated cardiomyopathy and may be associated with fatal ventricular arrhythmia and rapid heart failure progression. We sought to determine the risk of adverse events in RBM20 variant carriers and the impact of sex on outcomes. Consecutive probands and relatives carrying RBM20 variants were retrospectively recruited from 12 cardiomyopathy units. The primary end point was a composite of malignant ventricular arrhythmia (MVA) and end-stage heart failure (ESHF). MVA and ESHF end points were also analyzed separately and men and women compared. Left ventricular ejection fraction (LVEF) contemporary to MVA was examined. RBM20 variant carriers with left ventricular systolic dysfunction (RBM20LVSD) were compared with variant-elusive patients with idiopathic left ventricular systolic dysfunction. Longitudinal follow-up data were available for 143 RBM20 variant carriers (71 men; median age, 35.5 years); 7 of 143 had an MVA event at baseline. Thirty of 136 without baseline MVA (22.0%) reached the primary end point, and 16 of 136 (11.8%) had new MVA with no significant difference between men and women (log-rank P=0.07 and P=0.98, respectively). Twenty of 143 (14.0%) developed ESHF (17 men and 3 women; log-rank P<0.001). Four of 10 variant carriers with available LVEF contemporary to MVA had an LVEF >35%. At 5 years, 15 of 67 (22.4%) RBM20LVSD versus 7 of 197 (3.6%) patients with idiopathic left ventricular systolic dysfunction had reached the primary end point (log-rank P<0.001). RBM20 variant carriage conferred a 6.0-fold increase in risk of the primary end point. RBM20 variants are associated with a high risk of MVA and ESHF compared with idiopathic left ventricular systolic dysfunction. The risk of MVA in male and female RBM20 variant carriers is similar, but male sex is strongly associated with ESHF.

Abstract P3123: Sex-related Differences In Cardiac Biomarkers And Ventricular Fibrosis In A Minipig Model Of Hypertrophic Cardiomyopathy

Hypertrophic Cardiomyopathy (HCM) is characterized by ventricular hypertrophy and stiffness resulting in part from interstitial fibrosis. While associated with autosomal dominant mutations in sarcomere proteins, it has been reported that males and females may have different clinical presentations and disease courses. We have previously shown that minipigs carrying the R403Q mutation in MYH7 demonstrate a phenotype that recapitulates human non-obstructive HCM with increased hypertrophy, markers of cardiac stress, and diastolic dysfunction. Under the hypothesis that sex-dependent differences in cardiac physiology can independently modulate disease phenotype, we evaluated ventricular fibrosis and cardiac biomarkers in both male and female mutant pigs. Purpose-bred Yucatan R403Q MYH7 heterozygous mutant minipigs of either sex (M: n=8, F: n=6) and wild-type littermates (M: n=4, F: n=14) were used; for the purposes of these comparisons, cloned male pigs were also included (R403Q: 8). Males were castrated, and all pigs received soybean-based feed. Circulating levels of both cardiac troponin T (cTnT) and brain natriuretic peptide (BNP), markers of cardiac injury and stress, were assessed. Interstitial fibrosis was assessed in left ventricular free wall (LV-FW) and apical tissue samples utilizing picrosirius red staining and semi-automated quantification (HALO). Male HCM pigs died earlier (&lt;9M of age, P&lt;0.05) and had higher serum biomarkers than females (cTnT levels (M: 143±17 vs F: 44±7 ng/L, P&lt;0.05; BNP 1536±335 vs 4881±414 ng/L, P&lt;0.05) Consistent with the higher cTnT levels, male HCM pigs had greater fibrosis areas than females in both LV-FW (11±3% vs 7±2%, P&lt;0.05) and apical regions (13±1% vs. 8±2%, respectively, P&lt;0.05). All HCM pigs had significantly increased fibrotic area vs WT controls (R403Q: 10±3% vs WT: 3±2%, P&lt;0.05). Our findings demonstrate that despite a common genotype, female and male carriers of the HCM pathogenic R403Q mutation present different disease phenotypes, with castrated males showing greater fibrotic burden. Future studies to understand the mechanistic drivers of these differences should not only help elucidate the role of sex in HCM disease progression, but also the development of sex-informed therapies.

The arrhythmogenic cardiomyopathy phenotype associated with PKP2 c.1211dup variant.

The arrhythmogenic cardiomyopathy (ACM) phenotype, with life-threatening ventricular arrhythmias and heart failure, varies according to genetic aetiology. We aimed to characterise the phenotype associated with the variant c.1211dup (p.Val406Serfs*4) in the plakophilin‑2 gene (PKP2) and compare it with previously reported Dutch PKP2 founder variants. Clinical data were collected retrospectively from medical records of 106 PKP2 c.1211dup heterozygous carriers. Using data from the Netherlands ACM Registry, c.1211dup was compared with 3 other truncating PKP2 variants (c.235C > T (p.Arg79*), c.397C > T (p.Gln133*) and c.2489+1G > A (p.?)). Of the 106 carriers, 47 (44%) were diagnosed with ACM, at amean age of 41years. By the end of follow-up, 29 (27%) had experienced sustained ventricular arrhythmias and 12 (11%) had developed heart failure, with male carriers showing significantly higher risks than females on these endpoints (p < 0.05). Based on available cardiac magnetic resonance imaging and echocardiographic data, 46% of the carriers showed either right ventricular dilatation and/or dysfunction, whereas asubstantial minority (37%) had some form of left ventricular involvement. Both geographical distribution of carriers and haplotype analysis suggested PKP2 c.1211dup to be afounder variant originating from the South-Western coast of the Netherlands. Finally, aCox proportional hazards model suggested significant differences in ventricular arrhythmia-free survival between 4 PKP2 founder variants, including c.1211dup. The PKP2 c.1211dup variant is aDutch founder variant associated with atypical right-dominant ACM phenotype, but also left ventricular involvement, and apossibly more severe phenotype than other Dutch PKP2 founder variants.

Optical genome mapping in an atypical Pelizaeus-Merzbacher prenatal challenge.

Pathogenic genetic variants represent a challenge in prenatal counseling, especially when clinical presentation in familial carriers is atypical. We describe a prenatal case involving a microarray-detected duplication of PLP1 which causes X-linked Pelizaeus-Merzbacher disease, a progressive hypomyelinating leukodystrophy. Because of atypical clinical presentation in an older male child, the duplication was examined using a novel technology, optical genome mapping, and was found to be an inverted duplication, which has not been previously described. Simultaneously, segregation analysis identified another healthy adult male carrier of this unique structural rearrangement. The novel PLP1 structural variant was reclassified, and a healthy boy was delivered. In conclusion, we suggest that examining structural variants with novel methods is warranted especially in cases with atypical clinical presentation and may in these cases lead to improved prenatal and postnatal genetic counseling.