Genetic History Research Articles

Existence of biogeographic barriers for the long-term Neogene–Quaternary divergence and differentiation ofKoenigia forrestiiin the Himalaya–Hengduan Mountains

AbstractThe prolonged interplay between orographic and climatic changes creates biogeographic barriers, resulting in the allopatric differentiation of plants in the Himalaya–Hengduan Mountains. Such consequences have led us to investigate the long-term Neogene–Quaternary geo-climatic history of the Eastern Himalaya–Hengduan Mountains. Narrowly distributed populations of Koenigia forrestii were sampled (ten populations, 97 individuals) and analysed for their genetic architecture, including phylogenetic reconstruction (based on plastome and plastid DNA/nuclear regions), molecular dating and demography, in combination with niche dynamics. We estimated that K. forrestii (stem age: 11.39 Mya) diverged into three non-overlapping distributed lineages during the Neogene–Quaternary periods (5.84–2.57 Mya), with Eastern Himalaya (EHa) being the first and most diverse lineage. ‘Isolation by environment’ revealed the existence of genetic structures that were significantly affected by the disparate environment. The presence of demographic events is well supported by the Bayesian skyline plot, indicating recent demographic expansion. Hence, lineage divergence and differentiation were mainly triggered by the heterogeneous environment associated with the biogeographic barriers due to the Tsangpo-Brahmaputra Grand Canyon, Mekong-Salween Divide and local mountain systems. Nevertheless, niche shift and local adaptation are the keys to determining the genetic architecture, demographic dynamics and diversification history of K. forrestii.

The Mitochondrial landscape of the Konjuh and Majevica mountains of northeastern Bosnia: The view in the context genetic and demographic history

This study is the first report on the mtDNA profile of human settlements of the Konjuh and Majevica mountains of northeastern Bosnia. The aims of this study were: a) determination of mitochondrial genetic structure of populations of the Konjuh and Majevica mountains of northeastern Bosnia; b) detection of trace of ancient of mtDNA variations; and c) assessment of genetic relations with other Bosnian and Herzegovina populations and neighboring populations from the Balkan region. The genetic structure of populations of Konjuh and Majevica is shaped by western Eurasian maternal signals, which may trace their ancestry to the Paleolithic, pre-Neolithic and Neolithic. Especially interesting is the feature of the Neolithic expansion in this area. This applies especially to the presence of the pre-Neolithic lineages HV*and N1a in northeastern Bosnia, which can indicate an early settlement of this region of Bosnia by pre-Neolithic populations from the Middle East. This region abounds with resources of salt sites, which might suggest in favor of the thesis that the early-Neolithic colonists needed a safe source of salts so as to settle in the Balkan area. The populations of mountains of northeastern Bosnia indicate elements of the local population history, but they do not show strict genetic closure in relation to the neighboring populations of the Balkans. This may be a consequence of the population size, degree of geographic isolation and events of migration.

Demographic model and biological adaptation inferred from the genome‐wide single nucleotide polymorphism data reveal tripartite origins of southernmost Chinese Huis

AbstractObjectivesThe culturally unique Sanya Hui (SYH) people are considered descendants of ancient Cham people in Central Vietnam and exhibit a scenario of complex migration and admixture history. We aimed to characterize the genetic structure, origin, and admixture history of SYH people and explore the effect of the cultural admixture from Central/South Asia and East Asia on their genetic admixture.Materials and MethodsWe sampled 94 Hui individuals from Hainan and genotyped these samples using the Infinium Global Screening Array version 2 with over 717K SNPs. We then investigated the demographic history of SYH people by combining currently available modern and ancient genome‐wide SNP data and leveraging shared allele‐ and haplotype‐based strategies.ResultsPatterns of genetic differentiation showed that SYH people were genetically different from the northern Hui but harbored a close genomic affinity with indigenous Vietnamese. SYH had a relatively distant relationship with the Cham, which confirmed the hypothesis of the documented recent historical migration from Central Vietnam and assimilation with the Hainan indigenous people. The fitted three‐way admixture models and the reconstructed demographic frameworks showed that SYH was the admixture result with primary ancestry from East Asia and mainland Southeast Asia and minor ancestry related to Central/South Asia. GLOBETTRTER and ALDER‐based admixture time estimation revealed that genetic contact with Central Asia occurred around 28 generations ago. Our model was consistent with the frequent cultural communication along the Southern Maritime Silk Road and extensive interaction with East Asia. Besides, analyses focused on natural‐selected signatures of SYH people revealed some candidate loci associated with metabolism and immune function.DiscussionThe SYH people are considered to be Cham refugees' descendants. A long‐standing hypothesis posits that SYH derives from different genetic and cultural origins, which hypothesizes that the genetically attested admixture history of SYH people is different from northern Hui people possessing prominent Han‐related ancestry and minor western Eurasian ancestry. We found that the genetic structure of SYH people was different from Vietnam Cham and geographically diverse Hui people. Generally, three genetically attested genealogies from Central Vietnam, East Asia, and Central/South Asia in modern SYH people supported their tripartite model of genomic origins.

Increased Nuchal Translucency Without Aneuploidy in a Fetus: Abnormal Postnatal Radiograph and a Novel Mutation.

Increased Nuchal Translucency Without Aneuploidy in a Fetus: Abnormal Postnatal Radiograph and a Novel Mutation.

Phylogenetic divergence and population genetics of the hydrothermal vent annelid genus Hesiolyra along the East Pacific Rise: Reappraisal using multi‐locus data

AbstractAimMaintaining genetic connectivity is crucial for species that inhabit the disjunct and unstable deep‐sea hydrothermal vents. We aimed to re‐assess the connectivity of the annelid genus Hesiolyra distributed at hydrothermal vents along the East Pacific Rise (EPR). A previous study detected a major clade among five Hesiolyra populations spanning from 13°N to 21°S and a minor sympatric southern clade with ~1% divergence from the major clade. However, this study was based on a short locus of 366‐bp COI gene, which might not contain sufficient informative sites.LocationEast Pacific Rise.MethodsWe sequenced 188 specimens of Hesiolyra from five hydrothermal vent fields along the East Pacific Rise for six mitochondrial and two nuclear loci to infer their genetic divergence, population diversity and gene flow.ResultsWe found a minor southern clade (Hesiolyra aff. bergi) which was genetically distinct from Hesiolyra bergi sensu stricto for all gene markers explored except 16S. We also found shared genotypes between H. bergi and H. aff. bergi likely resulted from incomplete lineage sorting. For H. bergi s.s., we found a low but fixed divergence between the north and south EPR populations. We estimated the northern and southern metapopulations of H. bergi s.s. split ~0.45 Mya (HPD: 0.27–0.74 Mya). The northern metapopulation had a higher haplotype diversity than the southern metapopulation, indicating historical gene flow and loss of genetic diversity in the southern clade.Main conclusionsWe confirmed that the equatorial dispersal filter observed previously on several other vent species also applies to H. bergi. Our results highlight the power of the multi‐locus approach in revealing the divergence and population genetic history of marine species with strong dispersal capabilities, indicating that the NEPR and the SEPR should be considered as separate biogeographic regions in environmental management and biological conservation.

Genetic Structure and Genetic History of the Sakha (Yakuts) Population

Genetic Structure and Genetic History of the Sakha (Yakuts) Population

Mitogenomic diversity and stable isotopes provide insights into the maternal genetic history, mobility patterns, and diet of early medieval individuals from the Eastern Italian Alps

The Eastern Italian Alps (South Tyrol) is a connection area between continental Italy and the northern Alps. Various local factors, such as the heterogeneous environment, complex historical events, and different mobility patterns, may have influenced the genetic makeup of early medieval alpine groups. However, no ancient genetic data from these groups are currently available. This study provides a first picture of the ancient mitochondrial DNA (mtDNA) diversity of alpine groups from four locations in South Tyrol (Adige, Isarco, Venosta, and Merano). In total, 94 ancient mitogenomes of individuals (dated from 400 to 1100AD) were reconstructed by shotgun sequencing and a mtDNA capture approach. Moreover, stable isotope ratios (δ13C, δ15N, δ34S) were analyzed in a subset of 32 individuals. The results indicate different mtDNA haplogroup distributions among the alpine locations and the presence of rare lineages besides a possible maternal relatedness between individuals buried in the same and in diverse archaeological contexts. The study also shows differences in the genetic and mobility patterns (δ34S) between individuals from the central and north-eastern parts (Adige, Merano, Isarco) and those from the north-western part of South Tyrol (Venosta). These results suggest genetic exchanges with allochthonous people in the first group probably linked to high mobility and to geomorphological, historical, and socio-cultural factors. Comparisons extended to present-day alpine populations also suggested maternal genetic continuity in this alpine area. Finally, stable isotope (δ13C, δ15N, δ34S) data provided further support for regional differences in the diet of past alpine groups possibly linked to altitude and/or social status.

Infantile epileptic spasms syndrome in children with cardiofaciocutanous syndrome: Clinical presentation and associations with genotype.

Gene variants that dysregulate signaling through the RAS-MAPK pathway cause cardiofaciocutaneous syndrome (CFCS), a rare multi-system disorder. Infantile epileptic spasms syndrome (IESS) and other forms of epilepsy are among the most serious complications. To investigate clinical presentation, treatment outcomes, and genotype-phenotype associations in CFCS patients with IESS, molecular genetics and clinical neurological history were reviewed across two large clinical research cohorts (n=180). IESS presented in 18/180 (10%) cases, including 16 patients with BRAF variants and 2 with MAP2K1 variants. Among IESS patients with BRAF variants, 16/16 (100%) had sequence changes affecting the protein kinase domain (exons 11-16), although only 57% of total BRAF variants occurred in this domain. Clinical onset of spasms occurred at a median age of 5.4months (range: 1-24 months). Among 13/18 patients whose IESS resolved with anti-seizure medications, 10 were treated with ACTH and/or vigabatrin. A substantial majority of CFCS patients with IESS subsequently developed other epilepsy types (16/18; 89%). In terms of neurodevelopmental outcomes, gross motor function and verbal communication were more limited in patients with a history of IESS compared to those without IESS. These findings can inform clinical neurological care guidelines for CFCS and development of relevant pre-clinical models for severe epilepsy phenotypes.

Detection and Prediction of Adverse Drug Reactions Using Data Driven Modelling with Machine Learning Models

Various pharmacological, genetic and immunity related reasons contribute to the recorded Adverse Drug Reactions (ADR) either directly or indirectly. The genetic factors are not limited to ethnicity, age and demographics, social and economical and gender factors. Such factors are considered to be the secondary reasons, whereas the primary reasons indicate the interactions between drug-drug, drug-protein and protein-protein entities. With advanced algorithms in Machine Learning and Data Science, the prediction of pharmacovigilance has reached greater heights in the recent past. The conventional methods are time-consuming and demands huge intervention from experts and manufacturers. The models built with machine learning models have simplified the analysis and regression models have identified serious adverse drug reactions better than conventional methods. Allergies, organ failures and haemorrhages are considered for this research work, focusing on the parameters such as age, number of medications consumed, number of illnesses affecting the specific patient, dosage, type of medical institution, previous or genetic history of adverse reactions to medicines, type of consumptions and method of medication intake. From the investigative results, elderly patients affected by multiple illness are bound to multiple medicine intake and thus are subjected to serious adverse drug reactions. Owing to the fact, the monitoring period should be shortened and supervised accordingly. Primary responsibility of medical institutions lies in monitoring the previous history of adverse reactions and the new symptoms upon consumption of new medicine. The proposed approach carefully studies the relationships between various factors and computes in a binary logistic model for effective detection and prediction. The outcomes of the proposed model justify the need for additional parameters for a promising accuracy in detection and prediction of ADRs.

Disparities in Breast Cancer Mortality Rates in Israel among Urban and Rural Women

Breast cancer is a leading cause of death. There are a number of risk factors for breast cancer mortality including parity, age, ethnicity, genetic history, and place of residence. This study examined the disparities in breast cancer-related mortality rates among women from urban areas compared to rural areas in Israel. This was a retrospective, follow-up study on mortality from breast cancer among 894,608 Israeli women born between the years of 1940 and 1960. Data was collected from the Israeli Central Bureau of Statistics, the Population Authority, the Education Ministry, and the Health Ministry. Over 80% of women lived in urban areas. A higher incidence of mortality from breast cancer in Israel was found among urban women compared to rural women (1047.8/100,000 compared to 837/100,000, respectively). Even after adjusting for sociodemographic variables, higher mortality rates were found among women from urban areas in Israel compared to women from rural areas in Israel. It is believed that environmental factors can partially explain the geographic variation of breast cancer incidence, and that breast cancer incidence is likely a complex interaction between genetic, environmental, and health factors.

Phenotypic and genetic factors associated with donation of DNA and consent to record linkage for prescription history in the Australian Genetics of Depression Study.

Samples can be prone to ascertainment and attrition biases. The Australian Genetics of Depression Study is a large publicly recruited cohort (n = 20,689) established to increase the understanding of depression and antidepressant treatment response. This study investigates differences between participants who donated a saliva sample or agreed to linkage of their records compared to those who did not. We observed that older, male participants with higher education were more likely to donate a saliva sample. Self-reported bipolar disorder, ADHD, panic disorder, PTSD, substance use disorder, and social anxiety disorder were associated with lower odds of donating a saliva sample, whereas anorexia was associated with higher odds of donation. Male and younger participants showed higher odds of agreeing to record linkage. Participants with higher neuroticism scores and those with a history of bipolar disorder were also more likely to agree to record linkage whereas participants with a diagnosis of anorexia were less likely to agree. Increased likelihood of consent was associated with increased genetic susceptibility to anorexia and reduced genetic risk for depression, and schizophrenia. Overall, our results show moderate differences among these subsamples. Most current epidemiological studies do not search for attrition biases at the genetic level. The possibility to do so is a strength of samples such as the AGDS. Our results suggest that analyses can be made more robust by identifying attrition biases both on the phenotypic and genetic level, and either contextualising them as a potential limitation or performing sensitivity analyses adjusting for them.

Phylogeographic history of mitochondrial haplogroup J in Scandinavia.

Mitochondrial DNA haplogroup J is the third most frequent haplogroup in modern-day Scandinavia, although it did not originate there. To infer the genetic history of haplogroup J in Scandinavia, we examined worldwide mitogenome sequences using a maximum-likelihood phylogenetic approach. Haplogroup J mitogenome sequences were gathered from GenBank (n= 2245) and aligned against the ancestral Reconstructed Sapiens Reference Sequence. We also analyzed haplogroup J Viking Age sequences from the European Nucleotide Archive (n= 54). Genetic distances were estimated from these data and projected onto a maximum likelihood rooted phylogenetic tree to analyze clustering and branching dates. Haplogroup J originated approximately 42.6 kya (95% CI: 30.0-64.7), with several of its earliest branches being found within the Arabian Peninsula and Northern Africa. J1b was found most frequently in the Near East and Arabian Peninsula, while J1c occurred most frequently in Europe. Based on phylogenetic dating, subhaplogroup J1c has its early roots in the Mediterranean and Western Balkans. Otherwise, the majority of the branches found in Scandinavia are younger than those seen elsewhere, indicating that haplogroup J dispersed relatively recently into Northern Europe, most plausibly with Neolithic farmers. Haplogroup J appeared when Scandinavia was transitioning to agriculture over 6 kya, with J1c being the most common lineage there today. Changes in the distribution of haplogroup J mtDNAs were likely driven by the expansion of farming from West Asia into Southern Europe, followed by a later expansion into Scandinavia, with other J subhaplogroups appearing among Scandinavian groups as early as the Viking Age.

RP2-Associated X-linked Retinopathy: Clinical Findings, Molecular Genetics, and Natural History

To review and describe in detail the clinical course, functional and anatomic characteristics of RP2-associated retinal degeneration. Retrospective case series. Male participants with disease-causing variants in the RP2 gene. Review of all case notes and results of molecular genetic testing, retinal imaging (fundus autofluorescence [FAF] imaging, OCT), and electrophysiology assessment. Molecular genetic testing, clinical findings including best-corrected visual acuity (BCVA), qualitative and quantitative retinal imaging analysis, and electrophysiology parameters. Fifty-four molecularly confirmed patients were identified from 38 pedigrees. Twenty-eight disease-causing variants were identified, with 20 not previously clinically characterized. Fifty-three patients (98.1%) presented with retinitis pigmentosa. The mean age of onset (range ± standard deviation [SD]) was 9.6 years (1-57 ± 9.2 years). Forty-four patients (91.7%) had childhood-onset disease, with mean age of onset of 7.6 years. The most common first symptom was night blindness (68.8%). Mean BCVA (range ± SD) was 0.91 logarithm of the minimum angle of resolution (logMAR) (0-2.7 ± 0.80) and 0.94 logMAR (0-2.7 ± 0.78) for right and left eyes, respectively. On the basis of the World Health Organization visual impairment criteria, 18 patients (34%) had low vision. The majority (17/22) showed electroretinogram (ERG) evidence of a rod-cone dystrophy. Pattern ERG P50 was undetectable in all but 2 patients. A range of FAF findings was observed, from normal to advanced atrophy. There were no statistically significant differences between right and left eyes for ellipsoid zone width (EZW) and outer nuclear layer (ONL) thickness. The mean annual rate of EZW loss was 219 μm/year, and the mean annual decrease in ONL thickness was 4.93 μm/year. No patient with childhood-onset disease had an identifiable ellipsoid zone (EZ) after the age of 26 years at baseline or follow-up. Four patients had adulthood-onset disease and a less severe phenotype. This study details the clinical phenotype of RP2 retinopathy in a large cohort. The majority presented with early-onset severe retinal degeneration, with early macular involvement and complete loss of the foveal photoreceptor layer by the third decade of life. Full-field ERGs revealed rod-cone dystrophy in the vast majority, but with generalized (peripheral) cone system involvement of widely varying severity in the first 2 decades of life. Proprietary or commercial disclosure may be found after the references.

A global analysis of matches and mismatches between human genetic and linguistic histories

Human history is written in both our genes and our languages. The extent to which our biological and linguistic histories are congruent has been the subject of considerable debate, with clear examples of both matches and mismatches. To disentangle the patterns of demographic and cultural transmission, we need a global systematic assessment of matches and mismatches. Here, we assemble a genomic database (GeLaTo, or Genes and Languages Together) specifically curated to investigate genetic and linguistic diversity worldwide. We find that most populations in GeLaTo that speak languages of the same language family (i.e., that descend from the same ancestor language) are also genetically highly similar. However, we also identify nearly 20% mismatches in populations genetically close to linguistically unrelated groups. These mismatches, which occur within the time depth of known linguistic relatedness up to about 10,000 y, are scattered around the world, suggesting that they are a regular outcome in human history. Most mismatches result from populations shifting to the language of a neighboring population that is genetically different because of independent demographic histories. In line with the regularity of such shifts, we find that only half of the language families in GeLaTo are genetically more cohesive than expected under spatial autocorrelations. Moreover, the genetic and linguistic divergence times of population pairs match only rarely, with Indo-European standing out as the family with most matches in our sample. Together, our database and findings pave the way for systematically disentangling demographic and cultural history and for quantifying processes of shifts in language and social identities on a global scale.

304 Sephardic Ancestry in Recessive Dystrophic Epidermolysis Bullosa Individuals Carrying the Prevalent c.6527insC Mutation

Epidermolysis Bullosa is a clinically and genetically heterogeneous rare blistering skin disorder. The most severe variant, Recessive Dystrophic Epidermolysis Bullosa (RDEB), is caused by loss-of-function mutations in the type VII collagen gene (COL7A1). The COL7A1 c.6527insC mutation in RDEB individuals is curiously prevalent and carries a unique genetic history. In this study, approximately 100 RDEB patients with the c.6527insC founder mutation from Spain, France, Argentina, Chile, Colombia, and the USA were investigated to identify common Sephardic ancestry.

Genetics, age, and crystallization history of group IC iron meteorites

The IC iron meteorite group is characterized utilizing nucleosynthetic mass-independent isotopic compositions and 182W age constraints, coupled with siderophile element concentration measurements and modeling of crystal-liquid fractionation processes. The six IC irons analyzed, Arispe, Bendego, Chihuahua City, Nocoleche, NWA 2743, and Winburg have indistinguishable Mo and W genetic isotopic compositions and are consistent with derivation from the same parent body, which formed in the non-carbonaceous (NC) nebular reservoir. A pre-exposure µ182W value (parts-per-million deviations in isotopic ratios from terrestrial standards) for the six IC irons of −337 ± 5 corresponds to a metal-silicate segregation age of 1.0 ± 0.4 Myr after calcium-aluminum-rich inclusion (CAI) formation. This age is similar to those determined for other NC iron groups. Siderophile element abundances of the IC irons are generally similar and characterized by minor depletions in the more volatile siderophile elements. Highly siderophile element (HSE) distributions among the IC group suggest that the initial parent body core was S-rich, with preferred model results indicating an initial melt composition with ∼ 18 wt% S, 2 wt% P and 0.03 wt% C. Processes in addition to fractional crystallization, such as late-stage parent body modification, possibly as a result of impacts, and subsequent metal-melt mixing, are required within the first 100 Myr of Solar System history to explain the range of HSE abundances.

Population Genetics of the European Roma-A Review.

The Roma are a group of populations with a common origin that share the Romani identity and cultural heritage. Their genetic history has been inferred through multiple studies based on uniparental and autosomal markers, and current genomic data have provided novel insights into their genetic background. This review was prompted by two factors: (i) new developments to estimate the genetic structure of the Roma at a fine-scale resolution have precisely identified the ancestral components and traced migrations that were previously documented only in historical sources, clarifying and solving debates on the origins and the diaspora of the Roma; (ii) while there has been an effort to review the health determinants of the Roma, the increasing literature on their population genetics has not been subjected to a dedicated review in the last two decades. We believe that a summary on the state of the art will benefit both the public and scholars that are approaching the subject.

Elucidation of the etiological mechanisms underlying rare hereditary cilia/centrosome disorders using genome editing technology

Deep sequencing technology in forward genetics is a powerful tool to identify causal mutations underlying hereditary human diseases. To elucidate the etiological mechanisms, reverse genetics in human cultured cells is useful for generating disease models in vitro. However, the development of reverse genetics has been slow because of the lower efficacy of homologous recombination in almost all mammalian cultured cells. The history of reverse genetics in cultured cells began with the advent of genome editing technology, which could effectively modify the genome via artificial nuclease-induced local DNA repair activity. Bidirectional genetics based on deep sequencing technology and genome editing technology is now an essential approach for clarifying the pathophysiology of hereditary diseases. Here, we provide an overview of the validity of genome editing in cultured cells and its technical problems, discussing the example of centrosome/cilia-related disease models in cultured cells.

Evaluating population histories in Patagonia and Tierra del Fuego, Chile, using ancient mitochondrial and Y-chromosomal DNA.

This study aims to characterize the genetic histories of ancient hunter-gatherer groups in Fuego-Patagonia (Chile) with distinct Marine, Terrestrial, and Mixed Economy subsistence strategies. Mitochondrial (mtDNA) and Y-chromosome data were generated to test three hypotheses. H0: All individuals were drawn from the same panmictic population; H1: Terrestrial groups first populated the region and gave rise to highly specialized Marine groups by ~7,500 cal BP; or H2: Marine and Terrestrial groups represent distinct ancestral lineages who migrated independently into the region. Ancient DNA was extracted from the teeth of 50 Fuegian-Patagonian individuals dating from 6,895 cal BP to after European arrival, and analyzed alongside other individuals from previous studies. Individuals were assigned to Marine, Terrestrial, and Mixed Economy groups based on archeological context and stable isotope diet inferences, and mtDNA (HVR1/2) and Y-chromosome variation was analyzed. Endogenous aDNA was obtained from 49/50 (98%) individuals. Haplotype diversities, FST comparisons, and exact tests of population differentiation showed that Marine groups were significantly different from Terrestrial groups based on mtDNA (p < 0.05). No statistically significant differences were found between Terrestrial and Mixed Economy groups. Demographic simulations support models in which Marine groups diverged from the others by ~14,000 cal BP. Y-chromosome results showed similar patterns but were not statistically significant due to small sample sizes and allelic dropout. These results support the hypothesis that Marine and Terrestrial economic groups represent distinct ancestral lineages who diverged during the time populations were expanding in the Americas, and may represent independent migrations into Fuego-Patagonia.

DIAGNOSTIC PATHWAYS IN LANADELUMAB-TREATED PATIENTS WITH NORMAL C1-INHIBITOR HEREDITARY ANGIOEDEMA (NC1-INH-HAE): A MULTICENTER CHART REVIEW

<h3>Introduction</h3> Hereditary angioedema (HAE) subtypes I/II are defined by abnormal plasma levels/activity of C1 esterase inhibitor (C1-INH). Diagnosis and management of the ultra-rare subtype with normal C1-INH (NC1-INH) is challenging without routine diagnostic assessments¹ and phase 3 trial data. This study describes diagnostic pathways used in real-world lanadelumab-treated patients with NC1-INH-HAE. <h3>Methods</h3> Four expert HAE clinicians were interviewed about NC1-INH-HAE diagnosis in their clinical practice, 3 then completed a case report form using data from patient records. Patients eligible for retrospective chart review had physician-diagnosed NC1-IHN-HAE, initiated lanadelumab treatment (index date) with prior medical and treatment history available and ≥ 1 follow-up assessment. <h3>Results</h3> Physician-experts discussed 6 diagnostic criteria, 4 were endorsed by all (Table). Charts from 24 patients (3 US centers) were reviewed: mean (SD) age at index 44.0 (18.0) years, 92% female, median (range) 5.0 (0-40.3) years between symptom onset and NC1-INH-HAE diagnosis. Top 3 previous misdiagnoses: ‘other GI disorder' (71%), ‘irritable bowel syndrome' (67%), and ‘anaphylaxis' (54%). Of 4 criteria endorsed by all experts at interview, 3 were well-represented in patient charts (100-92%), except family history (25%). Expert endorsement was lower for criteria 3 (50%) and 6 (75%) found in 8% and 100% of patient charts, respectively. For patients on prophylaxis prior to index date, monthly attack rates were 5.60 at baseline (n=10) and 2.41 7-12 months after lanadelumab treatment (n=7). <h3>Conclusion</h3> Real-world NC1-INH-HAE diagnosis aligned with US guidelines on diagnostic criteria, except genetic testing and family history. Broader study of diagnostic guideline implementation in clinical practice is warranted.