Diagnosis Of Carriers Research Articles

Utility of left atrial strain in differentiating between cardiac amyloidosis and hypertrophic cardiomyopathy

Abstract Introduction and Objectives Cardiac amyloidosis (AL) is a disease characterized by the abnormal accumulation of anomalous proteins in cardiac tissue, while hypertrophic cardiomyopathy (HCM) is a hereditary cardiac disease characterized by abnormal thickening of the cardiac muscle, associated with tissue fibrosis and cardiac dysfunction in its natural progression. The echocardiogram has emerged as a fundamental tool in the diagnosis and follow-up of these patients, and strain analysis techniques can provide highly useful additional information on cardiac function in these patients, especially in the early stages of the disease. We questioned whether it might be useful in differentiating between these two diseases. Methods This retrospective analysis included adult patients who had undergone echocardiography at our center during the years 2023-2024. A total of 52 patients with a confirmed diagnosis of transthyretin AL confirmed by scintigraphy and/or biopsy, and another group of 51 patients with a confirmed diagnosis of HCM and ICD carriers for being high-risk patients were included. Various left atrial strain values (Reservoir, Conduit, and Pump) were analyzed. Descriptive statistics were calculated for each group and segment, and the Mann-Whitney U test was used to compare the groups. Results Patients with AL showed significantly lower absolute strain values compared to patients with HCM in all three analyzed varieties (Reservoir, Conduit, and Pump) with p<0.01 for all comparisons. The mean strain in the HCM group was 18.57 for reservoir strain, -11.85 for conduit strain, and -6.94 for pump strain; while the mean in the AL group was 9.28, -6.93, and -3.10, respectively. Conclusions Our study found significant differences in left atrial strain values between patients with HCM and patients with transthyretin AL. These findings suggest that left atrial strain analysis could be useful in evaluating cardiac function, follow-up, and differential diagnosis between patients with AL and HCM, especially in the earlier stages of the disease, where it is more challenging to establish a reliable diagnosis. HCM Vs amyloidosis

Advancing neurological disorders therapies: Organic nanoparticles as a key to blood-brain barrier penetration.

The blood-brain barrier (BBB) plays a vital role in protecting the central nervous system (CNS) by preventing the entry of harmful pathogens from the bloodstream. However, this barrier also presents a significant obstacle when it comes to delivering drugs for the treatment of neurodegenerative diseases and brain cancer. Recent breakthroughs in nanotechnology have paved the way for the creation of a wide range of nanoparticles (NPs) that can serve as carriers for diagnosis and therapy. Regarding their promising properties, organic NPs have the potential to be used as effective carriers for drug delivery across the BBB based on recent advancements. These remarkable NPs have the ability to penetrate the BBB using various mechanisms. This review offers a comprehensive examination of the intricate structure and distinct properties of the BBB, emphasizing its crucial function in preserving brain balance and regulating the transport of ions and molecules. The disruption of the BBB in conditions such as stroke, Alzheimer's disease, and Parkinson's disease highlights the importance of developing creative approaches for delivering drugs. Through the encapsulation of therapeutic molecules and the precise targeting of transport processes in the brain vasculature, organic NP formulations present a hopeful strategy to improve drug transport across the BBB. We explore the changes in properties of the BBB in various pathological conditions and investigate the factors that affect the successful delivery of organic NPs into the brain. In addition, we explore the most promising delivery systems associated with NPs that have shown positive results in treating neurodegenerative and ischemic disorders. This review opens up new possibilities for nanotechnology-based therapies in cerebral diseases.

Investigation of a hemophilia family with one female hemophilia A patient and 12 male hemophilia A patients.

Hemophilia A (HA) is an X-chromosome-linked recessive genetic disorder. Female carriers may have bleeding symptoms, but rarely have moderate or severe disease. We identified a female patient with moderate HA by pedigree tracking and genetic testing in a HA family involving consanguineous marriage. To investigate the clinical and laboratory data, as well as F8 genetic variant affecting members in her family. We constructed a detailed pedigree diagram and performed coagulation analyses, including factor VIII activity (FVIII:C), FVIII inhibitor, and von Willebrand factor antigen (VWF: Ag) on 20 family members. The genomic DNA of 11 members was screened for intron 1 and intron 22 inversions using long-distance real-time polymerase chain reaction (RT-PCR). Their F8 coding genes were sequenced with an automatic next-generation sequencing. Thirteen HA persons with hemophilia (12 males, one female) and 18 female carriers were identified in the family. VWF: Ag level was normal in all 13 persons with hemophilia and 7 carriers tested. The female HA patient had FVIII:C 1.9 IU/dL and was homozygous for F8:c.1918G > T:p.V640F. Genetic testing is conducive to the diagnosis of hemophilia carriers and persons with hemophilia. F8: c.1918G > T:p.V640F is the pathogenic HA variant in this family. In any hemophilia family, we need to pay more attention to female carriers and patients.

Light and shade of multigene panel testing for hereditary cancer: Examples from the real world.

MultiGene Panel Testing (MGPT) allows for simultaneous analysis of multiple cancer-related genes, enabling the identification of pathogenic variants in genes beyond those that would be analyzed based on a specific phenotype. However, a relevant fraction of variants so identified has little or no clinical utility, raising the need for guidance in selecting genes to include in panels and for interpretation of the results. Taking advantage of seven real paradigmatic cases, we analyze some of the scenarios where MGPT constitutes a meaningful advantage for diagnosis, as well as situations where panel use increases the risk of misinterpretation or complicates result communication and management. The use of MGPT facilitates prompt diagnosis in carriers of variants in rare genes (such as NTHL1), which would be diagnosed at a later stage if using a step-wise approach, as well as in carriers of bi-allelic variants (for instance in BRCA or MMR genes) leading to atypical phenotypes. Conversely, finding variants in moderate penetrance genes, such as ATM and CHEK2, may complicate interpretation and clinical management. Furthermore, for some of the genes included in MGPT, for instance NBN, the association with cancer risk has been questioned, leading to potentially misleading results. Taken together, the cases here described provide some examples of the benefits, as well as risks, involved by the use of MGPT, which may increase awareness among users and reinforce the need for establishing clear recommendations on genes to be included and management of the results.

Impact of high intensity and long duration exercise in genetic arrhythmogenic left ventricular cardiomyopathy

Abstract Background Arrhythmogenic left ventricular (LV) cardiomyopathy (ALVC) is a genetic disease associating extensive LV myocardial fibrosis with or without dysfunction and no or mild right ventricle (RV) involvement, at risk of life-threatening ventricular arrhythmias (VA). While high intensity (HI) and long duration (LD) exercise has been identified as a precipitating factor of RV dysfunction and VA in arrhythmogenic RV cardiomyopathy including in asymptomatic genetic variant carriers, the impact of exercise on disease phenotype and risk is not known in ALVC. Objective To study the relationship between practicing HI and LD exercise and the risk of developing an ALVC phenotype and its severity. Methods In a monocentric retrospective observational study, patients with a pathogenic variant in common ALVC genes (DSP, FLNC, DES, PLN, RBM20, TMEM43), including asymptomatic carriers without ALVC phenotype, were interviewed about their physical practice from age 7 to the time of genetic or disease diagnosis. Intensity and weekly duration of each activity were reported. HI and LD exercise were defined as having practiced at least 1 sport with an intensity ≥ 6 METs and ≥ 2.5 hours/week respectively. We studied the association of HI and LD exercise practice with the risk of ALVC phenotype occurrence and its severity, derived from clinical, ECG and imaging data. Results 114 out of 128 eligible patients answered the questionnaire and were included (85 (74.6%) with a DSP variant, 22 FLNC (19.3%), 6 DES (5.3%), 1 RBM20 (0.9%)). 35 were probands (31%) and 79 relatives (69%) among 46 families. 31 (27%) had no ALVC phenotype at the time of genetic diagnosis. Mean age at diagnosis was 41±18. 62 (54%) patients were women. 97 (85%) had practiced at least one sport, among which 81 (83.5%) at HI and 79 (81.4%) of LD. Median lifetime exercise dose was 18.5 MET.h/week. There were no differences in HI and LD exercise practice between probands and relatives (74.3% vs 69.6%, p=0.6 and 74.3% vs 67.1%, p=0.4 respectively), as well as between patients with and patients without ALVC phenotype at the time of diagnosis (74.7% vs 61.3%, p=0.2 and 72.3% vs 61.3%, p=0.3 respectively). Phenotypic features at diagnosis did not differ between patients with and without HI and LD practice (Table 1). Multivariate analysis adjusted on age and gender showed that HI and LD exercise were not significantly associated with an increased risk of developing an ALVC phenotype (Odds Ratio [95% confidence interval] for age, gender, HI and LD exercise were 1.03 [1.01-1.06] (p=0.013), 1.41 [0.58 ; 3.47] (p=0.45), 2.15 [0.63 ; 7.27] (p=0.22) and 1.17 [0.35 ; 3.87] (p=0.79) respectively). Phenotypic features at diagnosis did not differ across observed quartiles of lifetime exercise dose (Table 2). Conclusion Practicing HI and LD exercise was not associated with an increased risk of developing an ALVC phenotype and its severity at the time of diagnosis in genetic ALVC variant carriers.

Inverse Shifting-PCR Modified by Capillary Electrophoresis for Detecting F8 int22h and int1h Inversions in Severe Hemophilia A Patients and Probable Carriers.

Globally, intron 22 inversions (Inv22s) of the factor VIII gene (F8) are the most frequent pathogenic variants and account for 45-50% of severe hemophilia A (SHA) cases, while intron 1 inversion (Inv1) explains 1-5% of SHA cases. The detection of both inversions by an inverse shifting-polymerase chain reaction (IS-PCR) is the first choice worldwide for the diagnosis of patients and carriers of SHA. To improve its sensitivity and reproducibility in the visualization of PCR products, we approached the IS-PCR with fluorescent capillary electrophoresis instead of agarose electrophoresis. Based on the original protocol, we modified two primers by 5'-end labeling with FAM™ fluorescent dye for the detection of the PCR products by capillary electrophoresis. Additionally, the "fast enzymes" BclI and T4-Ligase were incorporated for work saving in the genomic digestion and ligation reactions, respectively. Once we accomplished the standardization and verified the reproducibility of the modified IS-PCR method, we applied it for the diagnosis of a cohort of SHA patients and carriers. The modified IS-PCR by fluorescent capillary electrophoresis for PCR product detection is more sensitive than agarose electrophoresis. The method was also improved by using the new rapid enzymes to save time in the whole process.

Apolipoproteine and KLOTHO Gene Variants Do Not Affect the Penetrance of Fragile X-Associated Tremor/Ataxia Syndrome.

In this study, the potential role and interaction of the APOε and KLOTHO genes on the penetrance of fragile X-associated tremor/ataxia syndrome (FXTAS) and on the IQ trajectory were investigated. FXTAS was diagnosed based on molecular, clinical and radiological criteria. Males with the premutation (PM) over 50 years, 165 with and 34 without an FXTAS diagnosis, were included in this study and were compared based on their APO (ε2-ε3-ε4) and KLOTHO variant (KL-VS) genotypes. The effect of APOε4 on FXTAS stage and on diagnosis did not differ significantly by KL-VS genotype with interaction effect p = 0.662 and p = 0.91, respectively. In the FXTAS individuals with an APOε2 allele, a marginal significance was observed towards a larger decline in verbal IQ (VIQ) in individuals with an APOε4 allele compared to those without an APOε4 allele (p = 0.071). In conclusion, our findings suggest that the APOε4 and KL-VS genotypes alone or through their interaction effect do not appear to predispose to either FXTAS diagnosis or stage in male carriers of the PM allele. A further study is needed to establish the trend of IQ decline in the FXTAS individuals who carry APOε4 with APOε2 compared to those without APOε4.

Germline Sequencing of DNA Damage Repair Genes in Two Hereditary Prostate Cancer Cohorts Reveals New Disease Risk-Associated Gene Variants.

Rare, inherited variants in DNA damage repair (DDR) genes have a recognised role in prostate cancer (PrCa) susceptibility. In addition, these genes are therapeutically targetable. While rare variants are informing clinical management in other common cancers, defining the rare disease-associated variants in PrCa has been challenging. Here, whole-genome and -exome sequencing data from two independent, high-risk Australian and North American familial PrCa datasets were interrogated for novel DDR risk variants. Rare DDR gene variants (predicted to be damaging and present in two or more family members) were identified and subsequently genotyped in 1963 individuals (700 familial and 459 sporadic PrCa cases, 482 unaffected relatives, and 322 screened controls), and association analyses accounting for relatedness (MQLS) undertaken. In the combined datasets, rare ERCC3 (rs145201970, p = 2.57 × 10-4) and BRIP1 (rs4988345, p = 0.025) variants were significantly associated with PrCa risk. A PARP2 (rs200603922, p = 0.028) variant in the Australian dataset and a MUTYH (rs36053993, p = 0.031) variant in the North American dataset were also associated with risk. Evaluation of clinicopathological characteristics provided no evidence for a younger age or higher-grade disease at diagnosis in variant carriers, which should be taken into consideration when determining genetic screening eligibility criteria for targeted, gene-based treatments in the future. This study adds valuable knowledge to our understanding of PrCa-associated DDR genes, which will underpin effective clinical screening and treatment strategies.

Contribution of mammography to breast cancer detection among pathogenic germline BRCA carriers by age and mutated gene.

10615 Background: Healthy carriers of pathogenic germline BRCA 1/2 (gBRCA) may choose between risk reducing mastectomy and intensive screening surveillance. Current international guidelines recommend both annual breast MRI and annual mammography. The aim of this study was to investigate the added contribution of annual mammography in gBRCA carriers to the annual breast MRI. Methods: A retrospective study from 2 large centers comprising gBRCA carriers who were diagnosed with breast cancer between 2000-2022 and were aware of their gBRCA status prior breast cancer diagnosis. Collected data included age at diagnosis, mutated gene and mode of breast cancer diagnosis (MRI, mammography, ultrasound [US], or other means [including clinical or incidental findings]). Data on pregnancy and breastfeeding at the time of breast cancer diagnosis were also collected. Differences in the mode of diagnosis were analyzed by age (≤40y vs. >40y) and mutated gene (BRCA1 vs. BRCA2). Results: The cohort included 200 gBRCA carries: 134 (67%) BRCA1, 62 (31%) BRCA2 and 4 (2%) with both BRCA1 and BRCA2 mutations. The median age at the time of breast cancer diagnosis was 41 (24-88). Most cancers (68%) were diagnosed by MRI, followed by mammography (14.5%), US (7%) and other means (10.5%). While MRI was the most common diagnosis modality in both age groups, the distribution of mode of diagnosis was significantly different in younger women (≤40y) where breast cancer detection was more commonly by US or following clinical findings, compared to older women, p< 0.001 (see Table). Five women were pregnant and 9 women were breastfeeding at the time of breast cancer diagnosis, all age 40 or younger. Four (80%) of pregnant carriers and 5 (55.6%) of breastfeeding carriers were diagnosed by US. There was no difference in mode of diagnosis between BRCA1 to BRCA2 carriers, p=0.974. There were only 16 women under age 30 that were diagnosed with breast cancer, 2 (12.5%) of whom were diagnosed with mammography. Conclusions: MRI is the most common modality for breast cancer diagnosis in gBRCA carriers who were aware if there gBRCA prior breast cancer diagnosis. Annual mammography also has a meaningful role in this population. We did not identify a subgroup in which it could be omitted. The increased utility of US among younger women is attributed to reduced utilization of MRI/mammography during pregnancy and breastfeeding. This finding strengthens the role of US screening in gBRCA carriers who are not eligible for other methods of imaging. [Table: see text]

Clinical breast exam contribution to breast cancer diagnosis in BRCA mutation carriers vs. average to intermediate risk women

PurposeThe contribution of clinical breast exam (CBE) to breast cancer diagnosis in average risk women undergoing regular screening mammography is minimal. To evaluate the role of CBE in high-risk women, we compared BC diagnosis by CBE in BRCA mutation carriers undergoing regular BC surveillance to average to intermediate risk women undergoing regular breast cancer screening.MethodsA retrospective chart review of all consecutive screening visits of BRCA mutation carriers (January 2012–October 2022) and average to intermediate risk women (November 2016–December 2022) was completed. Women with histologically confirmed BC diagnosis were included. Additional CBE yield for BC diagnosis, defined as the percentage of all BC cases detected by CBE alone, was assessed in both groups.ResultsOverall, 12,997 CBEs were performed in 1,328 BRCA mutation carriers in whom 134 BCs were diagnosed. In 7,949 average to intermediate risk women who underwent 15,518 CBEs, 87 BCs were diagnosed. CBE contributed to BC diagnosis in 3 (2%) BRCA mutation carriers and 3 (4%) non-carriers. In both groups, over 4,000 CBEs were needed in order to diagnose one cancer. In all 3 BRCA mutation carriers BC was palpated during the surveillance round that did not include MRI. In the average to intermediate risk group, 2 of 3 cancers diagnosed following CBE findings were in a different location from the palpable finding.ConclusionsThe contribution of CBE to BC diagnosis is marginal for all women including BRCA mutation carriers. In BRCA mutation carriers, CBE appears redundant during the MRI surveillance round.

Cardiovascular and renal physiological impacts seen in blood tests of flu diagnosed patients

Early detection of influenza virus infection can potentially reduce risk of morbidity, mortality, and virus transmission through earlier intervention strategies. Although seasonal influenza is a localized respiratory viral infection, changes in cardiovascular physiology and inflammatory biomarkers have been previously observed by our group in mice during influenza infection. Distinguishing patterns among common blood panels, including complete blood count, basic metabolic, comprehensive metabolic, coagulation panel, and c-reactive protein, could lead to earlier diagnosis and better prognosis of symptomatic carriers, but also be useful to diagnose asymptomatic carriers of the virus and provide better infectious disease surveillance. The objective of this study was to utilize the University of Mississippi Medical’s extensive clinical database (EPIC) to investigate the potential association between common blood tests with patients diagnosed with influenza from January 1, 2017 to December 31, 2022. Diagnosed patients were identified from over 1 million patients (of a total population of 3 million) and 36 million encounters of Mississippi residents from the electronic health record Data from patients with reported demographic dimensions (age, first race, and sex), offce visit dimensions (BMI, diastolic blood pressure (BP), pulse rate, respiration rate, systolic BP, and temperature), and common blood test values were obtained for 1896 influenza diagnosed patients, including day of diagnosis and additional encounter visits within 60 days before and after first unique influenza diagnosis. Overall, at day of influenza diagnosis, we see an increase in red blood cell (RBC) count, white blood cell (WBC) count, hemoglobin, hematocrit, estimated glomerular filtration rate (eGFR), aspartate aminotransferase (AST), prothrombin time (PT), and c-reactive protein (CRP) and a decrease in platelets, calcium, glucose, sodium, potassium, bicarbonate, chloride, blood urea nitrogen (BUN), creatinine, albumin, and alkaline phosphatase (AST). Yet, at the sex-specific level, there were differences; females have an increase in glucose, BUN, and creatinine, while males have an increase in albumin and ALP. Multivariate analyses of patients with complete data for 18 blood tests and binned by month relative to the day of diagnosis confirm distinct differences on the day of diagnosis. Future analysis will reveal which blood tests contribute to overall change on the day of diagnosis. Our findings show both changes in cardiovascular and renal physiology during influenza infection and the need to assess these blood measurements during influenza virus infection studies in mice. NIH/NIGMS — 1P20GM144041-01A1 5334 Host-pathogen molecular and cardiovascular interaction during influenza infection. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Long-read sequencing and optical mapping generates near T2T assemblies that resolves a centromeric translocation

Long-read genome sequencing (lrGS) is a promising method in genetic diagnostics. Here we investigate the potential of lrGS to detect a disease-associated chromosomal translocation between 17p13 and the 19 centromere. We constructed two sets of phased and non-phased de novo assemblies; (i) based on lrGS only and (ii) hybrid assemblies combining lrGS with optical mapping using lrGS reads with a median coverage of 34X. Variant calling detected both structural variants (SVs) and small variants and the accuracy of the small variant calling was compared with those called with short-read genome sequencing (srGS). The de novo and hybrid assemblies had high quality and contiguity with N50 of 62.85 Mb, enabling a near telomere to telomere assembly with less than a 100 contigs per haplotype. Notably, we successfully identified the centromeric breakpoint of the translocation. A concordance of 92% was observed when comparing small variant calling between srGS and lrGS. In summary, our findings underscore the remarkable potential of lrGS as a comprehensive and accurate solution for the analysis of SVs and small variants. Thus, lrGS could replace a large battery of genetic tests that were used for the diagnosis of a single symptomatic translocation carrier, highlighting the potential of lrGS in the realm of digital karyotyping.

Diagnosis of a sickle cell carrier while investigating the cause of neutropenia in a child with short stature receiving growth hormone

Short stature requiring growth hormone treatment is a well-known complication of sickle cell anemia (SCA). Sickle cell carriers can experience a variety of complications similar to SCA; however, short stature has not been documented in sickle cell carriers yet. Diagnosing using a complete blood count in sickle cell carriers is also difficult. Thus, hemoglobin (Hb) electrophoresis is useful in diagnosing these carriers. We present a case in which a sickle cell carrier is identified using Hb electrophoresis while investigating the etiology of neutropenia in a child using growth hormone for short stature.

Diagnostics of luminescent recording media based on the polarized scattering spectra of hologram sensors formed in the substance analyzed

The article is devoted to the diagnosis and identification of luminescent holographic information carriers in particular wine products using polarization holographic spectroscopy methods. For the first time, to our best knowledge, a technique has been developed for measuring and analyzing scattered polarized light (depolarization spectra) on polarization-holographic sensors formed in analyte. Polarized scattering spectra on a hologram sensor (measuring transducers) are of particular interest, since they provide information not only about the chemical composition of the media, for example, luminescence and absorption spectra, but also about particles that may be present in the analyte – the higher the anisotropy of the molecules and atoms, the greater the depolarization. Methods for measuring polarized scattering and excitation spectra carried out for various samples of holographic materials, as well as methods for processing and presenting the obtained spectral data are described. This may be of interest, since recording media, in particular wine, are complex colloidal systems. For the diagnosis, classification and identification of recording materials, it is proposed for the first time to use reflective holographic sensors (Yu.N. Denisyuk) of various physical natures (the concept of a spectral holographic portrait).

Distinct neural signatures of pulvinar in C9orf72 amyotrophic lateral sclerosis mutation carriers and noncarriers.

Thalamic alterations have been reported as a major feature in presymptomatic and symptomatic patients carrying the C9orf72 mutation across the frontotemporal dementia-amyotrophic lateral sclerosis (ALS) spectrum. Specifically, the pulvinar, a high-order thalamic nucleus and timekeeper for large-scale cortical networks, has been hypothesized to be involved in C9orf72-related neurodegenerative diseases. We investigated whether pulvinar volume can be useful for differential diagnosis in ALS C9orf72 mutation carriers and noncarriers and how underlying functional connectivity changes affect this region. We studied 19 ALS C9orf72 mutation carriers (ALSC9+) accurately matched with wild-type ALS (ALSC9-) and ALS mimic (ALSmimic) patients using structural and resting-state functional magnetic resonance imaging data. Pulvinar volume was computed using automatic segmentation. Seed-to-voxel functional connectivity analyses were performed using seeds from a pulvinar functional parcellation. Pulvinar structural integrity had high discriminative values for ALSC9+ patients compared to ALSmimic (area under the curve [AUC] = 0.86) and ALSC9- (AUC = 0.77) patients, yielding a volume cutpoint of approximately 0.23%. Compared to ALSmimic, ALSC9- showed increased anterior, inferior, and lateral pulvinar connections with bilateral occipital-temporal-parietal regions, whereas ALSC9+ showed no differences. ALSC9+ patients when compared to ALSC9- patients showed reduced pulvinar-occipital connectivity for anterior and inferior pulvinar seeds. Pulvinar volume could be a differential biomarker closely related to the C9orf72 mutation. A pulvinar-cortical circuit dysfunction might play a critical role in disease progression and development, in both the genetic phenotype and ALS wild-type patients.

The Early Care (0-3 Years) In Duchenne Muscular Dystrophy Meeting Report.

This report summarizes the key discussions from the "Early Care (0-3 years) in Duchenne Muscular Dystrophy" meeting, which aimed to address the challenges and opportunities in the diagnosis and care of Duchenne muscular dystrophy (DMD) and female carriers within the 0-3-year age group. The meeting brought together experts and healthcare providers who shared insights, discussed advancements in DMD care, and identified research needs. Presentations covered diagnostic challenges, approved therapies, clinical trials, identification of young female carriers, and the importance of clinical care and support for families. The meeting highlighted the importance of timely diagnosis and the lack of evidence-based guidelines for the care of children with DMD aged 0-3 years. Diagnostic challenges were discussed, including delays in receiving a DMD diagnosis and disparities based on ethnicity. The potential benefits and process of newborn screening were addressed.Approved therapeutic interventions, such as corticosteroids and exon-skipping drugs, were explored, with studies indicating the potential benefits of early initiation of corticosteroid therapy and the safety of exon-skipping drugs in DMD. Clinical trials involving infants and young boys were discussed, focusing on drugs like ataluren, vamorolone, and gene therapies.The meeting emphasized the importance of clinical care and support for families, including comprehensive information provision, early intervention services, and individualized support. The identification and care of young female carriers were also addressed. The meeting provided a platform for experts and healthcare providers to discuss and identify key aspects of early care for children with DMD aged 0-3 years. The meeting emphasized the need for early diagnosis, evidence-based guidelines, and comprehensive care and support for affected children and their families. Further research, collaboration, and the development of consensus guidelines are needed to improve early diagnosis, treatment, and outcomes in this population.

Genetic analysis of a pedigree with MECP2 duplication syndrome in China

BackgroundMECP2 duplication syndrome (MDS) is a rare X-linked genomic disorder that primarily affects males. It is characterized by delayed or absent speech development, severe motor and cognitive impairment, and recurrent respiratory infections. MDS is caused by the duplication of a chromosomal region located on chromosome Xq28, which contains the methyl CpG binding protein-2 (MECP2) gene. MECP2 functions as a transcriptional repressor or activator, regulating genes associated with nervous system development. The objective of this study is to provide a clinical description of MDS, including imaging changes observed from the fetal period to the neonatal period.MethodsConventional G-banding was employed to analyze the chromosome karyotypes of all pedigrees under investigation. Subsequently, whole exome sequencing (WES), advanced biological information analysis, and pedigree validation were conducted, which were further confirmed by copy number variation sequencing (CNV-seq).ResultsChromosome karyotype analysis revealed that a male patient had a chromosome karyotype of 46,Y,dup(X)(q27.2q28). Whole-exon duplication in the MECP2 gene was revealed through WES results. CNV-seq validation confirmed the presence of Xq27.1q28 duplicates spanning 14.45 Mb, which was inherited from a mild phenotype mother. Neither the father nor the mother's younger brother carried this duplication.ConclusionIn this study, we examined a male child in a family who exhibited developmental delay and recurrent respiratory tract infections as the main symptoms. We conducted thorough family investigations and genetic testing to determine the underlying causes of the disease. Our findings will aid in early diagnosis, genetic counseling for male patients in this family, as well as providing prenatal diagnosis and reproductive guidance for female carriers.

Cystic Fibrosis Carrier States Are Associated With More Severe Cases of Bronchiectasis.

People with cystic fibrosis (CF) are at increased risk for bronchiectasis, and several reports suggest that CF carriers may also be at higher risk for developing bronchiectasis. The purpose of this study was to determine if CF carriers are at risk for more severe courses or complications of bronchiectasis. Using MarketScan data (2001-2021), we built a cohort consisting of 105 CF carriers with bronchiectasis and 300 083 controls with bronchiectasis but without a CF carrier diagnosis. We evaluated if CF carriers were more likely to be hospitalized for bronchiectasis. In addition, we examined if CF carriers were more likely to be infected with Pseudomonas aeruginosa or nontuberculous mycobacteria (NTM) or to have filled more antibiotic prescriptions. We considered regression models for incident and rate outcomes that controlled for age, sex, smoking status, and comorbidities. The odds of hospitalization were almost 2.4 times higher (95% CI, 1.116-5.255) for CF carriers with bronchiectasis when compared with non-CF carriers with bronchiectasis. The estimated odds of being diagnosed with a Pseudomonas infection for CF carriers vs noncarriers was about 4.2 times higher (95% CI, 2.417-7.551) and 5.4 times higher (95% CI, 3.398-8.804) for being diagnosed with NTM. The rate of distinct antibiotic fill dates was estimated to be 2 times higher for carriers as compared with controls (95% CI, 1.735-2.333), and the rate ratio for the total number of days of antibiotics supplied was estimated as 2.8 (95% CI, 2.290-3.442). CF carriers with bronchiectasis required more hospitalizations and more frequent administration of antibiotics as compared with noncarriers. Given that CF carriers were also more likely to be diagnosed with Pseudomonas and NTM infections, CF carriers with bronchiectasis may have a phenotype more resembling CF-related bronchiectasis than non-CF bronchiectasis.

Development of low-cost in-house tetra-ARMS-PCR assay for the screening of five CBS mutations found in Pakistani homocystinuria patients

Background Classical homocystinuria is an inborn amino acid metabolism disorder resulting from mutations in the Cystathionine-β-Synthase (CBS) gene. These mutations lead to elevated homocysteine and methionine levels and reduced cysteine levels in the blood. Typically, diagnosis occurs after patients display symptoms, and various lab methods confirm it. DNA sequencing is the best option for early detection of genetic variants in asymptomatic suspected individuals. Unfortunately, its high cost can hinder its use, especially in low-income countries like Pakistan. Objective Aim of this study was to devise a robust low-cost diagnostic/screening assay based on Tetra-ARMS-PCR for five prevalent genetic variants found in Pakistani classical homocystinuria patients. Materials and methods In the current study, T-ARMS-PCR assays were developed for five mutations (c.975G > C, c.770C > T, c.752T > C, c.1039 + 1G > T, c.451 + 1GG > TA), which were characterized previously in classical homocystinuria patients. These low-cost T-ARMS-PCR assays were then used to screen the affected individuals and their family members to identify their genotypes for pathogenic variations in the asymptomatic patients and carriers in their respective families. Results The outcomes were entirely consistent with those obtained from Sanger DNA sequencing, confirming the sensitivity, specificity, and reliability of the T-ARMS-PCR assay for detecting CBS mutations. Conclusion T-ARMS-PCR has wide applications for low-income countries for the screening and early diagnosis of asymptomatic patients and carriers in the homocystinuria affected families as well as other inherited diseases.

Assessment of the frequency of BRCA1/2 mutations detection by means of PCR in State Budgetary Healthcare Institution «Saint-Petersburg clinical scientific and practical center for specialised types of medical care (oncological) named after N.P. Napalkov»

Background.BRCA1/2 germline testing allows us to optimize treatment strategy for patients with breast and ovarian cancer cases,to provide early diagnosis and also prophylactic measures for mutation carriers. Considering absence of large BRCA studies on Russian population, we do not have any clear understanding of approximate BRCA1/2 germline mutation frequency, a whole number of founder mutations and impact of non-founder BRCA1/2 mutations, which are not included in a standard PCR panel. Objective. Assessment of the frequency of BRCA1/2 mutations detection by means of PCR in breast and ovarian cancer patients in real clinical practice in St. Petersburg Clinical Scientific and Practical Center for Specialized Types of Medical Care (oncological) named after N.P. Napalkov. Analysis of a database for BRCA1/2-negative patients on a presence of risk factors associated with a probability of carrying a germline mutation in BRCA1/2 genes. Materials and methods. We retrospectively evaluated 335 ovarian and 1196 breast cancer patients, tested for germline BRCA1/2 by PCR in SPb CSPC(o) named after N.P. Napalkov from 01.01.2019 to 31.12.2021. For analysis was used patient’s blood plasma and a standard PCR panel detecting 8 mutation variants. A database for BRCA1/2-negative patients was retrospectively analyzed on a presence of risk factors associated with a high probability of hereditary cancer: an early onset and family history of cancer (BRCA associated). Statistical analysis was carried out using the SPSS software package (IBM® SPPS® Statistics v. 20), a number of graphs were carried out using Microsoft® Excel® 2016 programs. Results. BRCA1/2 germline mutations were detected in 6,4% (n= 98). Mean frequency of detection was 12,6% (n=45) for ovarian cancer patients, 4,3% (n=53) for breast cancer patients. Analysis of a database for BRCA1/2-negative patients demonstrated that 22,5% (n=346) BC and OC cases had an early onset. Family history of cancer was identified for 13,6% (n=195) patients with breast or ovarian cancer, including 3,8% (n=43) with 2 and more family cases of BRCA associated cancers. Conclusions. The frequency of detected BRCA1/2 germline mutations by PCR for breast and ovarian cancer patients in SPb CSPC(o) named after N.P. Napalkov is lower than the one described in international data. A large part of patients BRCA1/2 negative by PCR test has characteristics of hereditary breast cancer syndrome and requires further NGS.