Current status and future of genomics in fetal and maternal medicine: A scientific review commissioned by European Board and College of Obstetrics and Gynaecology (EBCOG).

This EBCOG guidance reviews the current and future status of genomics within fetal and maternal medicine. This document addresses the clinical uses of genetic testing in both screening and diagnostic testing prenatally. The role of genomics within fetal and maternal medicine is described. The research and future implications of genetic testing as well as the educational, ethical and economic implications of genomics are discussed.

Bioinformatic Prediction and High Throughput In Vivo Screening to Identify Cis-Regulatory Elements for the Development of Algal Synthetic Promoters.

Algae biotechnology holds immense promise for revolutionizing the bioeconomy through the sustainable and scalable production of various bioproducts. However, their development has been hindered by the lack of advanced genetic tools. This study introduces a synthetic biology approach to develop such tools, focusing on the construction and testing of synthetic promoters. By analyzing conserved DNA motifs within the promoter regions of highly expressed genes across six different algal species, we identified cis-regulatory elements (CREs) associated with high transcriptional activity. Combining the algorithms POWRS, STREME, and PhyloGibbs, we predicted 1511 CREs and inserted them into a minimal synthetic promoter sequence in 1, 2, or 3 copies, resulting in 4533 distinct synthetic promoters. These promoters were evaluated in vivo for their capacity to drive the expression of a transgene in a high-throughput manner through next-generation sequencing post antibiotic selection and fluorescence-activated cell sorting. To validate our approach, we sequenced hundreds of transgenic lines showing high levels of GFP expression. Further, we individually tested 14 identified promoters, revealing substantial increases in GFP expression─up to nine times higher than the baseline synthetic promoter, with five matching or even surpassing the performance of the native AR1 promoter. As a result of this study, we identified a catalog of CREs that can now be used to build superior synthetic algal promoters. More importantly, here we present a validated pipeline to generate building blocks for innovative synthetic genetic tools applicable to any algal species with a sequenced genome and transcriptome data set.

Wild yeast isolation by middle school students reveals features of North American oak populations of Saccharomyces cerevisiae and Kluyveromyces lactis.

Features of the natural life cycle of the budding yeast Saccharomyces cerevisiae were crucial to its domestication as a laboratory experimental model, especially the ability to maintain stable haploid clones and cross them at will to combine alleles via meiosis. Stable haploidy results from mutations in HO, which encodes an endonuclease required for haploid-specific mating-type switching. Previous studies found an unexpected diversity of HO alleles among natural isolates within a small geographic area. We developed a hands-on field and laboratory activity for middle school students in Denver, Colorado, USA to isolate wild yeast from oak bark, identify species via DNA sequencing, and sequence HO from S. cerevisiae isolates. We find limited HO diversity in North American oak isolates, pointing to efficient, continuous dispersal across the continent. By contrast, we isolated the "dairy yeast", Kluyveromyces lactis, from a tree <10 m away and found that it represents a new population distinct from an oak population in an adjacent state, pointing to high genetic diversity. The outreach activity partnered middle school, high school, and university students in making scientific discoveries and can be adapted to other locations and natural yeast habitats. Indeed, a pilot sampling activity in southeast Texas yielded S. cerevisiae oak isolates with a new allele of HO and, from a nearby prickly pear cactus, a heat-tolerant isolate of Saccharomyces paradoxus.

Genetic Correlates of Treatment-Resistant Depression: Insights from Polygenic Scores Across Cognitive, Temperamental, and Sleep Traits in the All of US cohort.

Background: Treatment-resistant depression (TRD) is a major challenge in mental health, affecting a significant number of patients and leading to considerable economic and social burdens. The etiological factors contributing to TRD are complex and not fully understood. Objective: To investigate the genetic factors associated with TRD using polygenic scores (PGS) across various traits, and to explore their potential role in the etiology of TRD using large-scale genomic data from the All of Us Research Program (AoU). Methods: Data from 292,663 participants in the AoU were analyzed using a case-cohort design. Treatment resistant depression (TRD), treatment responsive Major Depressive Disorder (trMDD), and all others who have no formal diagnosis of Major Depressive Disorder (non-MDD) were identified through diagnostic codes and prescription patterns. Polygenic scores (PGS) for 61 unique traits from seven domains were used and logistic regressions were conducted to assess associations between PGS and TRD. Finally, Cox proportional hazard models were used to explore the predictive value of PGS for progression rate from the diagnostic event of Major Depressive Disorder (MDD) to TRD. Results: In the discovery set (104128 non-MDD, 16640 trMDD, and 4177 TRD), 44 of 61 selected PGS were found to be significantly associated with MDD, regardless of treatment responsiveness. Eleven of them were found to have stronger associations with TRD than with trMDD, encompassing PGS from domains in education, cognition, personality, sleep, and temperament. Genetic predisposition for insomnia and specific neuroticism traits were associated with increased TRD risk (OR range from 1.05 to 1.15), while higher education and intelligence scores were protective (ORs 0.88 and 0.91, respectively). These associations are consistent across two other independent sets within AoU (n = 104,388 and 63,330). Among 28,964 individuals tracked over time, 3,854 developed TRD within an average of 944 days (95% CI: 883 ~ 992 days) after MDD diagnosis. All eleven previously identified and replicated PGS were found to be modulating the conversion rate from MDD to TRD. Thus, those having higher education PGS would experiencing slower conversion rates than those who have lower education PGS with hazard ratios in 0.79 (80th versus 20th percentile, 95% CI: 0.74 ~ 0.85). Those who had higher insomnia PGS experience faster conversion rates than those who had lower insomnia PGS, with hazard ratios in 1.21 (80th versus 20th percentile, 95% CI: 1.13 ~ 1.30). Conclusions: Our results indicate that genetic predisposition related to neuroticism, cognitive function, and sleep patterns play a significant role in the development of TRD. These findings underscore the importance of considering genetic and psychosocial factors in managing and treating TRD. Future research should focus on integrating genetic data with clinical outcomes to enhance our understanding of pathways leading to treatment resistance.

The recent genetic modification techniques for improve soil conservation, nutrient uptake and utilization.

Advances in genetic modification (GM) techniques have generated huge interest in improving nutrient utilization, maximizing nutrient uptake, and conserving soil in the pursuit of sustainable agriculture. Unfortunately, little is still known about the recent advancements in the application of GM tactics to enhance each of these areas. This review explores the latest GM strategies intended to support soil conservation, maximize nutrient uptake, and improve nutrient utilization in farming, highlighting the critical roles that soil health and nutrient management play in sustainable farming. GM strategies such as improving the efficiency of nutrient uptake through enhanced root systems and increased nutrient transport mechanisms are well discussed. This study suggests that addressing potential obstacles, such as ethical and regulatory concerns, is a necessity for long-term sustainability applications of GM technologies to raise agricultural yields.

Joint modeling of human cortical structure: Genetic correlation network and composite-trait genetic correlation.

Heritability and genetic covariance/correlation quantify the marginal and shared genetic effects across traits. They offer insights on the genetic architecture of complex traits and diseases. To explore how genetic variations contribute to brain function variations, we estimated heritability and genetic correlation across cortical thickness, surface area, and volume of 33 anatomically predefined regions in left and right hemispheres, using summary statistics of genome-wide association analyses of 31,968 participants in the UK Biobank. To characterize the relationships between these regions of interest, we constructed a genetic network for these regions using recursive two-way cut-offs in similarity matrices defined by genetic correlations. The inferred genetic network matches the brain lobe mapping more closely than the network inferred from phenotypic similarities. We further studied the associations between the genetic network for brain regions and 30 complex traits through a novel composite-linkage disequilibrium score regression method. We identified seven significant pairs, which offer insights on the genetic basis for regions of interest mediated by cortical measures.

Inflammatory bowel disease and osteoporosis: Common genetic effects, pleiotropy, and causality.

INTRODUCTION: Previous studies have shown that inflammatory bowel disease (IBD) is associated with osteoporosis (OP) and bone mineral density (BMD), but the underlying genetic mechanisms are unclear. Our study wanted to explore the genetic and causal relationship between IBD and OP. MATERIALS AND METHODS: Based on large-scale genome-wide association summary statistics and individual-level datasets (i.e., the UK Biobank), this study performed linkage disequilibrium score regression (LDSC), pleiotropic analysis under the composite null hypothesis (PLACO), and Mendelian randomization (MR) analyses to explore the genetic association, the pleiotropic genes and the causal relationship between IBD and BMD. RESULTS: LDSC revealed significant genetic correlations between IBD and BMD (e.g., forearm BMD (rg = -0.3479, P = 0.019) and femoral neck BMD (rg = -0.1335, P = 0.0307). PLACO identified 14 overlapping pleiotropic loci, 1 shared risk gene (CDYL), and multiple shared pathways, revealing possible mechanisms for IBD and OP. MR analysis demonstrated a causal association between IBD and BMD. CONCLUSIONS: Our study indicates that IBD may increase the risk of OP and reveals a complex genetic mechanism linking IBD and the risk of osteoporosis, which has important implications for diagnosing and treating IBD and OP.

Variability of faecal microbiota and antibiotic resistance genes in flocks of migratory gulls and comparison with the surrounding environment.

Gulls commonly rely on human-generated waste as their primary food source, contributing to the spread of antibiotic-resistant bacteria and their resistance genes, both locally and globally. Our understanding of this process remains incomplete, particularly in relation to its potential interaction with surrounding soil and water. We studied the lesser black-backed gull, Larus fuscus, as a model to examine the spatial variation of faecal bacterial communities, antibiotic resistance genes (ARGs), and mobile genetic elements (MGEs) and its relationship with the surrounding water and soil. We conducted sampling campaigns within a connectivity network of different flocks of gulls moving across functional units (FUs), each of which represents a module of highly interconnected patches of habitats used for roosting and feeding. The FUs vary in habitat use, with some gulls using more polluted sites (notably landfills), while others preferring more natural environments (e.g., wetlands or beaches). Faecal bacterial communities in gulls from flocks that visit and spend more time in landfills exhibited higher richness and diversity. The faecal microbiota showed a high compositional overlap with bacterial communities in soil. The overlap was greater when compared to landfill (11%) than to wetland soils (6%), and much lower when compared to bacterial communities in surrounding water (2% and 1% for landfill and wetland water, respectively). The relative abundance of ARGs and MGEs were similar between FUs, with variations observed only for specific families of ARGs and MGEs. When exploring the faecal carriage of ARGs and MGEs in bird faeces relative to soil and water compartments, gull faeces were enriched in ARGs classified as High-Risk. Our results shed light on the complex dynamics of antibiotic resistance spread in wild bird populations, providing insights into the interactions among gull movement and feeding behavior, habitat characteristics, and the dissemination of antibiotic resistance determinants across environmental reservoirs.

A Wright-Fisher graph model and the impact of directional selection on genetic variation.

We introduce a multi-allele Wright-Fisher model with mutation and selection such that allele frequencies at a single locus are traced by the path of a hybrid jump-diffusion process. The state space of the process is given by the vertices and edges of a topological graph, i.e. edges are unit intervals. Vertices represent monomorphic population states and positions on the edges mark the biallelic proportions of ancestral and derived alleles during polymorphic segments. In this setting, mutations can only occur at monomorphic loci. We derive the stationary distribution in mutation-selection-drift equilibrium and obtain the expected allele frequency spectrum under large population size scaling. For the extended model with multiple independent loci we derive rigorous upper bounds for a wide class of associated measures of genetic variation. Within this framework we present mathematically precise arguments to conclude that the presence of directional selection reduces the magnitude of genetic variation, as constrained by the bounds for neutral evolution.

Development of a small shuttle plasmid for use in oral Veillonella and initial appraisal of potential for fluorescence-based applications.

Oral Veillonella species are among the early colonizers of the human oral cavity. We constructed a small, single-selectable-marker shuttle plasmid, examined its ability to be transformed into diverse oral Veillonella strains, and assessed its potential use for expressing a gene encoding an oxygen-independent fluorescent protein, thus generating a fluorescent Veillonella parvula strain. Because tetracycline resistance is common in Veillonella, we replaced genes encoding ampicillin- and tetracycline-resistance in a previously described shuttle plasmid (pBSJL2) with a chloramphenicol acetyltransferase gene. The resulting plasmid pCF1135 was successfully introduced into four strains representing V. parvula and V. atypica by either natural transformation or electroporation. We then modified this plasmid to express a gene encoding an oxygen-independent fluorescent protein in V. parvula SKV38. The resulting strain yielded a fluorescence signal intensity approximately 16 times higher than the wild-type in microplate-based fluorimetry experiments. While fluorescence microscopy demonstrated that planktonic cells, colonies, and biofilms of fluorescent V. parvula could also be imaged, photobleaching was a significant issue. In conclusion, we anticipate this genetic system and information provided here will facilitate expanded studies of oral Veillonella species' properties and behavior.

Targeting drug resistance in glioblastoma (Review).

Glioblastoma (GBM) is the most common malignancy of the central nervous system in adults. The current standard of care includes surgery, radiation therapy, temozolomide; and tumor­treating fields leads to dismal overall survival. There are far limited treatments upon recurrence. Therapies to date are ineffective as a result of several factors, including the presence of the blood­brain barrier, blood tumor barrier, glioma stem­like cells and genetic heterogeneity in GBM. In the present review, the potential mechanisms that lead to treatment resistance in GBM and the measures which have been taken so far to attempt to overcome the resistance were discussed. The complex biology of GBM and lack of comprehensive understanding of the development of therapeutic resistance in GBM demands discovery of novel antigens that are targetable and provide effective therapeutic strategies.

Paradoxical Psoriasis in Patients Receiving Therapy with Tumor Necrosis Factor Inhibitors: Potential Pathogenic Mechanisms and the Role of Genetic Factors.

TNF inhibitors (TNFi) have revolutionized the therapeutic management of various chronic immune-mediated inflammatory diseases. Despite their known benefits, these therapies are related to paradoxical adverse effects (PAEs), including paradoxical psoriasis (PP). Although the underlying mechanism remains somewhat unclear, some theories suggest that genetic factors, particularly certain single-nucleotide polymorphisms (SNPs), may play an important role. The present review aimed to research and analyze recent findings regarding the pathomechanisms involved in the appearance of PP and the association between various genetic factors and PP in individuals treated with TNFi. We performed a literature search and found that certain genes (IL23R, TNF, FBXL19, CTLA4, SLC12A8, TAP1) are strongly associated with the occurrence of PP in pediatric and adult patients during therapy with TNFi. The identification of the specific SNPs involved in the appearance of PP and other PAEs in patients treated with TNFi for various diseases and in different populations may later favor the recognition of those patients at a high risk of developing such adverse effects and could guide personalized therapeutic strategies in future years.

Genetic and Epigenetic Association of FOXP3 with Papillary Thyroid Cancer Predisposition.

Papillary thyroid cancer (PTC) is the most common type of thyroid malignancy with an increased female incidence ratio. The specific traits of X chromosome inheritance may be implicated in gender differences of PTC predisposition. The aim of this study was to investigate the association of two X-linked genes, Forkhead Box P3 (FOXP3) and Protein Phosphatase 1 Regulatory Subunit 3F (PPP1R3F), with PTC predisposition and gender disparity. One hundred thirty-six patients with PTC and an equal number of matched healthy volunteers were enrolled in the study. Genotyping for rs3761548 (FOXP3) and rs5953283 (PPP1R3F) was performed using polymerase chain reaction-restriction fragment length polymorphism assay (PCR-RFLP). The methylation status of FOXP3 was assessed using the combined bisulfite restriction analysis (COBRA) method. The SPSS software was used for statistical analyses. Gender stratification analysis revealed that the CA and AA genotypes and the A allele of FOXP3 rs3761548 variant are associated with PTC predisposition only in females. Moreover, different methylation status was observed up to the promoter locus of FOXP3 between PTC female patients, carrying the CA and CC genotype, and controls. Both revealed associations may explain the higher PTC incidence in females through reducing FOXP3 expression as reported in immune related blood cells.

Asparagine: A key metabolic junction in targeted tumor therapy.

Nutrient bioavailability in the tumor microenvironment plays a pivotal role in tumor proliferation and metastasis. Among these nutrients, glutamine is a key substance that promotes tumor growth and proliferation, and its downstream metabolite asparagine is also crucial in tumors. Studies have shown that when glutamine is exhausted, tumor cells can rely on asparagine to sustain their growth. Given the reliance of tumor cell proliferation on asparagine, restricting its bioavailability has emerged as promising strategy in cancer treatment. For instance, the use of asparaginase, an enzyme that depletes asparagine, has been one of the key chemotherapies for acute lymphoblastic leukemia (ALL). However, tumor cells can adapt to asparagine restriction, leading to reduced chemotherapy efficacy, and the mechanisms by which different genetically altered tumors are sensitized or adapted to asparagine restriction vary. We review the sources of asparagine and explore how limiting its bioavailability impacts the progression of specific genetically altered tumors. It is hoped that by targeting the signaling pathways involved in tumor adaptation to asparagine restriction and certain factors within these pathways, the issue of drug resistance can be addressed. Importantly, these strategies offer precise therapeutic approaches for genetically altered cancers.

Genetic susceptibility to neurodevelopmental conditions associates with neonatal DNA methylation patterns in the general population: an individual participant data meta-analysis.

Background: Autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and schizophrenia (SCZ) are highly heritable and linked to disruptions in foetal (neuro)development. While epigenetic processes are considered an important underlying pathway between genetic susceptibility and neurodevelopmental conditions, it is unclear (i) whether genetic susceptibility to these conditions is associated with epigenetic patterns, specifically DNA methylation (DNAm), already at birth; (ii) to what extent DNAm patterns are unique or shared across conditions, and (iii) whether these neonatal DNAm patterns can be leveraged to enhance genetic prediction of (neuro)developmental outcomes. Methods: We conducted epigenome-wide meta-analyses of genetic susceptibility to ASD, ADHD, and schizophrenia, quantified using polygenic scores (PGSs) on cord blood DNAm, using four population-based cohorts (n pooled=5,802), all North European. Heterogeneity statistics were used to estimate overlap in DNAm patterns between PGSs. Subsequently, DNAm-based measures of PGSs were built in a target sample, and used as predictors to test incremental variance explained over PGS in 130 (neuro)developmental outcomes spanning birth to 14 years. Outcomes: In probe-level analyses, SCZ-PGS associated with neonatal DNAm at 246 loci (p<9×10-8), predominantly in the major histocompatibility complex. Functional characterization of these DNAm loci confirmed strong genetic effects, significant blood-brain concordance and enrichment for immune-related pathways. 8 loci were identified for ASD-PGS (mapping to FDFT1 and MFHAS1), and none for ADHD-PGS. Regional analyses indicated a large number of differentially methylated regions for all PGSs (SCZ-PGS: 157, ASD-PGS: 130, ADHD-PGS: 166). DNAm signals showed little overlap between PGSs. We found suggestive evidence that incorporating DNAm-based measures of genetic susceptibility at birth increases explained variance for several child cognitive and motor outcomes over and above PGS. Interpretation: Genetic susceptibility for neurodevelopmental conditions, particularly schizophrenia, is detectable in cord blood DNAm at birth in a population-based sample, with largely distinct DNAm patterns between PGSs. These findings support an early-origins perspective on schizophrenia. Funding: HorizonEurope; European Research Council.

Results of comprehensive genetic testing in patients presenting to a multidisciplinary inherited heart disease clinic in India.

OBJECTIVES: This study aims to analyze the results of comprehensive genetic testing in patients presenting to a dedicated multidisciplinary inherited heart disease clinic in India. METHODS: All patients presenting to our clinic from August 2017 to October 2023 with a suspected inherited heart disease and consenting for genetic testing were included. The probands were grouped into familial cardiomyopathies namely hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), arrhythmogenic cardiomyopathy (ACM) and peripartum cardiomyopathy (PPCM), channelopathies namely congenital long QT syndrome (LQTS) and Brugada syndrome (BrS), and heritable connective tissue disorder namely Marfan Syndrome (MFS). Next generation sequencing (NGS) was used, and pre-test and post-test counseling were provided to probands and cascade screening offered to relatives. RESULTS: Mean age of the subjects (n = 77; 48 probands, 29 relatives) was 43 ± 18 years, 68 % male and 44 % symptomatic, with 36 HCM, 3 DCM, 3 ACM, 1 PPCM, 3 LQTS, 1 BrS and 1 MFS probands. The diagnostic yield of NGS-based genetic testing was 31 %; variants of uncertain significance (VUS) were identified in 54 %; and 15 % were genotype-negative. Twenty-nine relatives from 18 families with HCM (n = 12), DCM (n = 3), ACM (n = 2) and MFS (n = 1) underwent genetic testing. The genotype positive probands/relatives and VUS carriers with strong disease phenotype and/or high risk variant were advised periodic follow-up; the remaining probands/relatives were discharged from further clinical surveillance. CONCLUSIONS: Genetic testing guides treatment and follow-up of patients with inherited heart diseases and should be carried out in dedicated multidisciplinary clinics with expertise for counseling and cascade screening of family members.

Phylogenetic relationships and genetic diversity of the Korean endemic Phedimus latiovalifolius (Crassulaceae) and its close relatives.

Phedimus latiovalifolius (Y.N.Lee) D.C.Son & H.J.Kim is exclusively distributed in the high mountains in the Korean Peninsula, mainly along the Baekdudaegan mountain range. Despite its morphological and distributional distinction from other Phedimus Raf. species, its taxonomic identity and phylogenetic relationship with congeneric species remain unclear. This study employs genotyping-by-sequencing-derived genome-wide single nucleotide polymorphisms to establish the monophyly of P. latiovalifolius and its relationship with closely related species. Genetic diversity and population differentiation of P. latiovalifolius are also assessed to provide baseline genetic information for future conservation and management strategies. Our phylogenetic analyses robustly demonstrate the monophyletic nature of P. latiovalifolius, with P. aizoon (L.) 't Hart identified as its closest sister lineage. There is no genetic evidence supporting a hybrid origin of P. latiovalifolius from P. aizoon involving either P. ellacombeanus (Praeger) 't Hart or P. kamtschaticus (Fisch.) 't Hart. Population genetic analyses reveal two major groups within P. latiovalifolius. A higher genetic variation is observed in P. ellacombeanus than in the congeneric species. Notably, most of the genetic variation exists within P. latiovalifolius populations. Given its distribution and the potential role of Baekdudaegan as an East Asian Pleistocene refugia, P. latiovalifolius could be considered rare and endemic, persisting in the refugium across glacial/interglacial cycles.

Forest genomics in the Caucasus through the lens of its dominant tree species - Fagus orientalis.

The last glacial period is known to have greatly influenced the demographic history of temperate forest trees, with important range contractions and post-glacial expansions that led to the formation of multiple genetic lineages and secondary contact zones in the Northern Hemisphere. These dynamics have been extensively studied for European and North American species but are still poorly understood in other temperate regions of rich biodiversity such as the Caucasus. Our study helps filling that gap by deciphering the genomic landscapes of F. orientalis across the South Caucasus. The use of genome-wide data confirmed a past demographic history strongly influenced by the Last Glacial Maximum, revealing two disjunct glacial refugia in the Colchis and Hyrcanian regions. The resulting patterns of genetic diversity, load and differentiation are not always concordant across the region, with genetic load pinpointing the location of the glacial refugia more efficiently than genetic diversity alone. The Hyrcanian forests show depleted genetic diversity and substantial isolation, even if long-distance gene flow is still present with the main centre of diversity in the Greater Caucasus. Finally, we characterize a strong heterogeneity of genetic diversity and differentiation along the species chromosomes, with noticeably a first chromosome showing low diversity and weak differentiation.

Phenotype and prognostic factors in geriatric and non-geriatric patients with transthyretin cardiomyopathy.

AIMS: Transthyretin cardiac amyloidosis (ATTR-CM) may be an underestimated cause of heart failure among geriatric patients and represent a unique phenotype and prognostic profile. METHODS AND RESULTS: This retrospective, observational, cohort study characterizes cardiac and extracardiac disorders at diagnosis and assesses prognosis among ATTR-CM patients based on age (geriatric vs. non-geriatric) and amyloidosis subtype (wild type, ATTRwt and hereditary, ATTRv). In total, 943 patients with ATTR-CM were included, of which 306 had ATTRv and 637 had ATTRwt. Among these, 331 (35.1%) were non-geriatric (<75 years), and 612 (64.9%) were geriatric (≥75 years). The population exhibited conduction abnormalities, atrial fibrillation and ischaemic heart disease that progressively deteriorated with age. Among ATTRwt patients, peripheral neuropathy, neurovegetative symptoms, and hearing loss were present across all age groups, but reports of carpal tunnel symptoms or surgery decreased with age. Conversely, among ATTRv patients, reports of extracardiac symptoms increased with age and Val122ILe mutation was highly prevalent among geriatric patients. The 3-year survival was higher among non-geriatric ATTR-CM patients (76%) than geriatric patients (55%) and predictors of 3-year mortality differed. Notably, predictors identified among geriatric patients were alkaline phosphatase (ALP) (HR = 1.004, 95% CI: [0.001-1.100)], troponin T hs (HR = 1.005, 95% CI: [1.001-1.120)] and tricuspid insufficiency (HR = 1.194, 95% CI: [1.02-1.230)]. Whereas, among non-geriatric patients, NT-proBNP (HR = 1.002, 95% CI: [1.02-1.04], global longitudinal strain (HR = 0.95, 95% CI: [0.922-0.989], and glomerular filtration rate (HR = 0.984, 95% CI: [0.968-1.00) were identified. We propose a 3-stage prognostic staging system combining troponin T hs (≥44 ng/L) and ALP levels (≥119 UI/L). In the geriatric population, this model discriminated survival more precisely than the National Amyloidosis Centre staging, particularly for classifying between stage 1 (82%), stage 2 (50%) and stage 3 (32%) for ATTRv and ATTRwt. CONCLUSIONS: These diagnostic and prognostic indicators, along with ATTR subtype, highlight the distinct characteristics of this important, geriatric ATTR-CM patient group. Recognizing these mortality markers can be valuable for geriatricians to improve the prognostic quality management of geriatric patients with ATTR-CM.