Osteomesopyknosis associated with a novel ALOX5 variant that impacts the RANKL pathway.

BACKGROUND: Bone tissue homeostasis relies on the coordinated activity of the bone-forming osteoblasts and bone-resorbing osteoclasts. Osteomesopyknosis is considered a distinctive rare sclerosing skeletal disorder of unelucidated pathophysiology and presumably autosomal dominant transmission. However, the causal genes are unknown. METHODS: We present a case report encompassing clinical assessments, imaging studies, and whole-exome sequencing analysis, complemented by functional in vitro experiments. RESULTS: This new case of osteomesopyknosis was associated with a missense ALOX5 variant predicted to induce protein misfolding and proteasomal degradation. Transfection experiments demonstrated that the variant was associated with reduced protein levels restored by proteasomal inhibition with bortezomib. Likewise, gene expression analysis showed that the mutated gene was associated with a decreased RANKL/OPG ratio, which is a critical driver of osteoclast precursor differentiation. CONCLUSION: Our data indicate impaired bone resorption as the underlying mechanism of this rare osteosclerosis, implicating ALOX5 pathogenic variants as potential etiological factors.

Genetic causes of hypophosphatemia.

Phosphate is a key component of mineralized tissues and is also part of many organic compounds. Phosphorus homeostasis depends especially upon intestinal absorption, and renal excretion, which are regulated by various hormones, such as PTH, 1,25-dihydroxyvitamin D, and fibroblast growth factor 23. In this review we provide an update of several genetic disorders that affect phosphate transporters through cell membranes or the phosphate-regulating hormones, and, consequently, result in hypophosphatemia.

High Frequencies of Genetic Variants in Patients with Atypical Femoral Fractures.

This study explores the genetic factors associated with atypical femoral fractures (AFF), rare fractures associated with prolonged anti-resorptive therapy. AFF are fragility fractures that typically appear in the subtrochanteric or diaphyseal regions of the femur. While some cases resemble fractures in rare genetic bone disorders, the exact cause remains unclear. This study investigates 457 genes related to skeletal homeostasis in 13 AFF patients by exome sequencing, comparing the results with osteoporotic patients (n = 27) and Iberian samples from the 1000 Genomes Project (n = 107). Only one AFF case carried a pathogenic variant in the gene set, specifically in the ALPL gene. The study then examined variant accumulation in the gene set, revealing significantly more variants in AFF patients than in osteoporotic patients without AFF (p = 3.7 × 10-5), particularly in ACAN, AKAP13, ARHGEF3, P4HB, PITX2, and SUCO genes, all of them related to osteogenesis. This suggests that variant accumulation in bone-related genes may contribute to AFF risk. The polygenic nature of AFF implies that a complex interplay of genetic factors determines the susceptibility to AFF, with ACAN, SUCO, AKAP13, ARHGEF3, PITX2, and P4HB as potential genetic risk factors. Larger studies are needed to confirm the utility of gene set analysis in identifying patients at high risk of AFF during anti-resorptive therapy.

A Missense Variant in TP53 Could Be a Genetic Biomarker Associated with Bone Tissue Alterations.

Metabolic bone diseases cover a broad spectrum of disorders that share alterations in bone metabolism that lead to a defective skeleton, which is associated with increasing morbidity, disability, and mortality. There is a close connection between the etiology of metabolic bone diseases and genetic factors, with TP53 being one of the genes associated therewith. The single nucleotide polymorphism (SNP) Arg72Pro of TP53 is a genetic factor associated with several pathologies, including cancer, stroke, and osteoporosis. Here, we aim to analyze the influence of the TP53 Arg72Pro SNP on bone mass in humanized Tp53 Arg72Pro knock-in mice. This work reports on the influence of the TP53 Arg72Pro polymorphism in bone microarchitecture, OPG expression, and apoptosis bone status. The results show that the proline variant of the TP53 Arg72Pro polymorphism (Pro72-p53) is associated with deteriorated bone tissue, lower OPG/RANK ratio, and lower apoptosis in bone tissue. In conclusion, the TP53 Arg72Pro polymorphism modulates bone microarchitecture and may be a genetic biomarker that can be used to identify individuals with an increased risk of suffering metabolic bone alterations.

Puntuaciones de riesgo poligénico (PRS): una herramienta en la predicción de enfermedades y la medicina personalizada / Polygenic risk scores (PRS) - A tool for disease prediction and personalized medicine

En la última década, la genómica y la secuenciación de alto rendimiento han revolucionado la comprensión de las enfermedades complejas. las puntuaciones de riesgo poligénico (PRS) surgen como una prometedora herramienta para predecir enfermedades y personalizar tratamientos. Sin embargo, su implementación requiere confirmar la utilidad real y plantea importantes desafíos éticos y de privacidad. Las PRS se utilizan para identificar individuos de alto riesgo y guiar tratamientos personalizados. Su potencial es evidente en enfermedades como el cáncer o la osteoporosis, donde mejoran la estratificación de riesgo y permiten seleccionar tratamientos más efectivos. Sin embargo, las PRS tienen múltiples limitaciones, incluyendo la falta de precisión individual, la variabilidad en diferentes poblaciones y la incapacidad de considerar la influencia de los factores ambientales. La interpretación clínica y las implicaciones éticas, legales y sociales (ELSI) representan cuestiones muy relevantes en este campo. En el futuro, presumiblemente las PRS mejorarán su precisión predictiva, con la combinación de factores clínicos de riesgo y la adaptación a poblaciones de diversas etnias. Consecuentemente, se prevé que las PRS desempeñen un papel central en la medicina personalizada. (AU)

Over the past decade, genomics and high-throughput sequencing have revolutionized our understanding of complex diseases. Polygenic risk scores (PRS) have emerged as a promising tool for predicting diseases and personalizing treatments. However, their implementation requires confirmation of real utility, which raises significant ethical and privacy challenges. PRS are used to identify high-risk individuals and guide personalized treatments. Their potential is evident in diseases such as cancer or osteoporosis, where they improve risk stratification and enable the selection of more effective treatments. However, PRS have multiple limitations, including lack of individual accuracy, variability among different populations, and the inability to account for the impact of environmental factors. Clinical interpretation and ethical, legal, and social implications (ELSI) are highly relevant issues in this field. In the future, PRS are expected to improve their predictive accuracy by combining clinical risk factors and adapting to populations of various ethnicities. Consequently, PRS are expected to play a central role in personalized medicine. (AU)

Erdheim-Chester Disease Due to a Novel Internal Duplication of NRAS: Response to Targeted Therapy with Cobimetinib.

Histiocytoses encompass a group of exceptionally rare disorders characterized by the abnormal infiltration of tissues by histocytes. Among these, Erdheim-Chester disease (ECD) stands out as a multisystem histiocytosis that typically affects bones and various other tissues. Historically, the treatment of ECD has been challenging. However, recent breakthroughs in our understanding, particularly the discovery of somatic mutations in the RAS-MAPK pathway, have opened new opportunities for targeted therapy in a significant subset of patients with ECD and other histiocytoses. In this report, we present the case of a patient with ECD harboring a previously unidentified microduplication in the NRAS gene in a small fraction of skin cells. This discovery played a pivotal role in tailoring an effective therapeutic approach involving kinase inhibitors downstream of NRAS. This case underscores the crucial role of deep sequencing of tissue samples in ECD, enabling the delivery of personalized targeted therapy to patients.

HLA-A*11:01 and HLA-C*04:01 are associated with severe COVID-19.

We analyzed the association between HLA polymorphisms and susceptibility to SARS-CoV-2 infection and disease severity. Genotyping data from a total of 9373 COVID-19-positive cases from the Spanish Coalition to Unlock Research on Host Genetics on COVID-19 (SCOURGE) consortium and 5943 population controls were included in the study. We found an association of the alleles HLA-B*14:02 and HLA-C*08:02 with a lower risk to COVID-19 infection (p = 0.006, OR = 0.84, 95% CI = [0.75-0.95], p = 0.024, OR = 0.86, 95% CI = [0.78-0.95], respectively). We also found the alleles HLA-A*11:01 and HLA-C*04:01 associated with disease severity (p = 0.033, OR = 1.16, 95% CI = [1.04-1.31], p = 0.045, OR = 1.14, 95% CI = [1.05-1.25], respectively). These results suggest that an effective presentation of viral peptides by HLA class I alleles involve a faster infection clearance, decreasing the susceptibility and severity of COVID-19.

Engineering a Pro-Osteogenic Secretome through the Transient Silencing of the Gene Encoding Secreted Frizzled Related Protein 1.

The evidence sustaining the regenerative properties of mesenchymal stem cells' (MSCs) secretome has prompted a paradigm change, where MSCs have shifted from being considered direct contributors to tissue regeneration toward being seen as cell factories for producing biotech medicines. We have previously designed a method to prime MSCs towards osteogenic differentiation by silencing the Wnt/ß-Catenin inhibitor Sfpr1. This approach produces a significant increase in bone formation in osteoporotic mice. In this current work, we set to investigate the contribution of the secretome from the MSCs where Sfrp1 has been silenced, to the positive effect seen on bone regeneration in vivo. The conditioned media (CM) of the murine MSCs line C3H10T1/2, where Sfrp1 has been transiently silenced (CM-Sfrp1), was found to induce, in vitro, an increase in the osteogenic differentiation of this same cell line, as well as a decrease of the expression of the Wnt inhibitor Dkk1 in murine osteocytes ex vivo. A reduction in the RANKL/OPG ratio was also detected ex vivo, suggesting a negative effect of CM-Sfrp1 on osteoclastogenesis. Moreover, this CM significantly increases the mineralization of human primary MSCs isolated from osteoportotic patients in vitro. Proteomic analysis identified enrichment of proteins involved in osteogenesis within the soluble and vesicular fractions of this secretome. Altogether, we demonstrate the pro-osteogenic potential of the secretome of MSCs primmed in this fashion, suggesting that this is a valid approach to enhance the osteo-regenerative properties of MSCs' secretome.

GWAS and meta-analysis identifies 49 genetic variants underlying critical COVID-19.

Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown1 to be highly efficient for discovery of genetic associations2. Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group3. Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data. We find 49 genome-wide significant associations, of which 16 have not been reported previously. To investigate the therapeutic implications of these findings, we infer the structural consequences of protein-coding variants, and combine our GWAS results with gene expression data using a monocyte transcriptome-wide association study (TWAS) model, as well as gene and protein expression using Mendelian randomization. We identify potentially druggable targets in multiple systems, including inflammatory signalling (JAK1), monocyte-macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).

Influence of meteorological factors on the severity of COVID-19 in Spain: Observational ecological study.

Objectives: Evaluating whether meteorological and geographical variables could be associated with the severity of COVID-19 in Spain. Methods: An ecological study was performed to analyze the influence of meteorological and geographical factors in hospital admissions and deaths due to COVID-19 in the 52 provinces of Spain (24 coastal and 28 inland regions), during the first three pandemic waves. Medical and mortality data were collected from the Carlos III Health Institute (ISCIII) and meteorological variables were requested to the Spanish State Meteorological Agency (AEMET). Results: Regarding the diagnosed cases it is remarkable that the percentage of patients hospitalized for COVID-19 was lower in the coastal provinces than in the inland ones (8.7 ± 2.6% vs. 11.5 ± 2.6%; p = 9.9 × 10-5). Furthermore, coastal regions registered a lower percentage of mortality than inland regions (2.0 ± 0.6% vs. 3.1 ± 0.8%; p = 1.7 × 10-5). Mean air temperature was inversely correlated both with COVID-19 hospitalizations (Rho: -0.59; p = 3.0 × 10-6) and mortality (Rho: -0.70; p = 5.3 × 10-9). In those provinces with a mean air temperature <10 °C mortality by COVID-19 was twice that of those with >16 °C. Finally, we found an association between mortality and the location of the province (coastal/inland), altitude, patient age and the average air temperature; the latter was inversely and independently correlated with mortality (non standardised B coeff.: -0.24; IC 95%: -0.31 to -0.16; p = 2.38 × 10-8). Conclusions: The average air temperature was inversely associated with COVID-19 mortality in our country during the first three waves of the pandemic.

Objetivos: Evaluar si factores meteorológicos y geográficos pudieron relacionarse con la gravedad de la COVID-19 en España. Métodos: Estudio ecológico, a escala provincial, que analiza la influencia de factores meteorológicos y geográficos en la hospitalización y mortalidad por COVID-19 en las 52 provincias españolas (24 costeras y 28 del interior), durante las tres primeras olas. Los datos de hospitalizaciones y mortalidad se obtuvieron del Instituto de Salud Carlos III (ISCIII). Los datos epidemiológicos del Instituto Nacional Estadística (INE) y la Red Nacional de Vigilancia Epidemiológica (RENAVE). Las variables meteorológicas de la Agencia estatal de meteorología (AEMET). Resultados: El porcentaje de pacientes hospitalizados por COVID-19, del total de personas infectadas, fue inferior en las provincias costeras que en las del interior peninsular (8,7 ± 2,6% vs. 11,5 ± 2,6%; p = 9,9 × 10−5). De igual manera la costa registró menor porcentaje de mortalidad que el interior peninsular (2,0 ± 0,6% vs. 3,1 ± 0,8%; p = 1,7 × 10−5). La temperatura media correlacionó negativamente con la hospitalización (Rho: −0,59; p = 3,0 × 10−6) y la mortalidad por COVID-19 (Rho: −0,70; p = 5,3 × 10−9). Las provincias con una temperatura media <10 °C duplicaron la mortalidad por COVID respecto a las de >16 °C. La mortalidad se relacionó con la localización provincial (costa/interior), la altitud, la edad de la población y la temperatura media, siendo esta última la variable asociada de manera independiente (Coef. B no estandarizado: −0,24; IC 95%: −0,31 a −0,16; p = 2,38 × 10−8). Conclusiones: La mortalidad por COVID-19 durante las tres primeras olas de la pandemia en nuestro país se asoció inversamente con la temperatura media.

Influencia de los factores meteorológicos en la gravedad de la COVID-19 en España: estudio observacional ecológico / Influence of meteorological factors on the severity of COVID-19 in Spain: Observational ecological study

Objetivos: Evaluar si factores meteorológicos y geográficos pudieron relacionarse con la gravedad de la COVID-19 en España.MétodosEstudio ecológico, a escala provincial, que analiza la influencia de factores meteorológicos y geográficos en la hospitalización y en la mortalidad por COVID-19 en las 52 provincias españolas (24 costeras y 28 del interior) durante las tres primeras olas. Los datos de hospitalizaciones y de mortalidad se obtuvieron del Instituto de Salud CarlosIII (ISCIII); los datos epidemiológicos, del Instituto Nacional de Estadística (INE) y de la Red Nacional de Vigilancia Epidemiológica (RENAVE), y las variables meteorológicas, de la Agencia Estatal de Meteorología (AEMET).ResultadosEl porcentaje de pacientes hospitalizados por COVID-19, del total de personas infectadas, fue inferior en las provincias costeras que en las del interior peninsular (8,7±2,6% vs. 11,5±2,6%; p=9,9×10−5). De igual manera, la costa registró menor porcentaje de mortalidad que el interior peninsular (2,0±0,6% vs. 3,1±0,8%; p=1,7×10−5). La temperatura media correlacionó negativamente con la hospitalización (Rho: −0,59; p=3,0×10−6) y la mortalidad por COVID-19 (Rho: −0,70; p=5,3×10−9). Las provincias con una temperatura media <10°C duplicaron la mortalidad por COVID respecto a las de >16°C. La mortalidad se relacionó con la localización provincial (costa/interior), la altitud, la edad de la población y la temperatura media, siendo esta última la variable asociada de manera independiente (Coef.B no estandarizado: −0,24; IC95%: −0,31 a −0,16; p=2,38×10−8). (AU)

Objectives: Evaluating whether meteorological and geographical variables could be associated with the severity of COVID-19 in Spain.MethodsAn ecological study was performed to analyze the influence of meteorological and geographical factors in hospital admissions and deaths due to COVID-19 in the 52 provinces of Spain (24 coastal and 28 inland regions), during the first three pandemic waves. Medical and mortality data were collected from the CarlosIII Health Institute (ISCIII) and meteorological variables were requested to the Spanish State Meteorological Agency (AEMET).ResultsRegarding the diagnosed cases it is remarkable that the percentage of patients hospitalized for COVID-19 was lower in the coastal provinces than in the inland ones (8.7±2.6% vs. 11.5±2.6%; P=9.9×10−5). Furthermore, coastal regions registered a lower percentage of mortality than inland regions (2.0±0.6% vs. 3.1±0.8%; P=1.7×10−5). Mean air temperature was inversely correlated both with COVID-19 hospitalizations (Rho: −0.59; P=3.0×10−6) and mortality (Rho: −0.70; P=5.3×10−9). In those provinces with a mean air temperature <10°C mortality by COVID-19 was twice that of those with >16°C. Finally, we found an association between mortality and the location of the province (coastal/inland), altitude, patient age and the average air temperature; the latter was inversely and independently correlated with mortality (non-standardized β coeff.: −0.24; 95%CI: −0.31 to −0.16; P=2.38×10−8).ConclusionsThe average air temperature was inversely associated with COVID-19 mortality in our country during the first three waves of the pandemic. (AU)

Overcoming Barriers to Tumor Genomic Profiling through Direct-to-Patient Outreach.

PURPOSE: To overcome barriers to genomic testing for patients with rare cancers, we initiated a program to offer free clinical tumor genomic testing worldwide to patients with select rare cancer subtypes. EXPERIMENTAL DESIGN: Patients were recruited through social media outreach and engagement with disease-specific advocacy groups, with a focus on patients with histiocytosis, germ cell tumors (GCT), and pediatric cancers. Tumors were analyzed using the MSK-IMPACT next-generation sequencing assay with the return of results to patients and their local physicians. Whole-exome recapture was performed for female patients with GCTs to define the genomic landscape of this rare cancer subtype. RESULTS: A total of 333 patients were enrolled, and tumor tissue was received for 288 (86.4%), with 250 (86.8%) having tumor DNA of sufficient quality for MSK-IMPACT testing. Eighteen patients with histiocytosis have received genomically guided therapy to date, of whom 17 (94%) have had clinical benefit with a mean treatment duration of 21.7 months (range, 6-40+). Whole-exome sequencing of ovarian GCTs identified a subset with haploid genotypes, a phenotype rarely observed in other cancer types. Actionable genomic alterations were rare in ovarian GCT (28%); however, 2 patients with ovarian GCTs with squamous transformation had high tumor mutational burden, one of whom had a complete response to pembrolizumab. CONCLUSIONS: Direct-to-patient outreach can facilitate the assembly of cohorts of rare cancers of sufficient size to define their genomic landscape. By profiling tumors in a clinical laboratory, results could be reported to patients and their local physicians to guide treatment. See related commentary by Desai and Subbiah, p. 2339.

Uncovering genetic causes of hypophosphatemia.

BACKGROUND: Chronic hypophosphatemia can result from a variety of acquired disorders, such as malnutrition, intestinal malabsorption, hyperparathyroidism, vitamin D deficiency, excess alcohol intake, some drugs, or organ transplantation. Genetic disorders can be a cause of persistent hypophosphatemia, although they are less recognized. We aimed to better understand the prevalence of genetic hypophosphatemia in the population. METHODS: By combining retrospective and prospective strategies, we searched the laboratory database of 815,828 phosphorus analyses and included patients 17-55 years old with low serum phosphorus. We reviewed the charts of 1287 outpatients with at least 1 phosphorus result ≤2.2 mg/dL. After ruling out clear secondary causes, 109 patients underwent further clinical and analytical studies. Among them, we confirmed hypophosphatemia in 39 patients. After excluding other evident secondary causes, such as primary hyperparathyroidism and vitamin D deficiency, we performed a molecular analysis in 42 patients by sequencing the exonic and flanking intronic regions of a panel of genes related to rickets or hypophosphatemia (CLCN5, CYP27B1, dentin matrix acidic phosphoprotein 1, ENPP1, FAM20C, FGFR1, FGF23, GNAS, PHEX, SLC34A3, and VDR). RESULTS: We identified 14 index patients with hypophosphatemia and variants in genes related to phosphate metabolism. The phenotype of most patients was mild, but two patients with X-linked hypophosphatemia (XLH) due to novel PHEX mutations had marked skeletal abnormalities. CONCLUSION: Genetic causes should be considered in children, but also in adult patients with hypophosphatemia of unknown origin. Our data are consistent with the conception that XLH is the most common cause of genetic hypophosphatemia with an overt musculoskeletal phenotype.

Diagnostic Approach to Patients with Low Serum Alkaline Phosphatase.

Increased serum levels of alkaline phosphatase (ALP) are widely recognized as a biochemical marker of many disorders affecting the liver or bone. However, the approach for patients with low ALP phosphatase is not well-established. Low serum ALP is an epiphenomenon of many severe acute injuries and diseases. Persistently low serum ALP may be secondary to drug therapy (including antiresorptives) or a variety of acquired disorders, such as malnutrition, vitamin and mineral deficiencies, endocrine disorders, etc. Hypophosphatasia, due to pathogenic variants of the ALPL gene, which encodes tissue non-specific ALP, is the most common genetic cause of low serum ALP. Marked bone hypomineralization is frequent in severe pediatric-onset cases. However, adult forms of hypophosphatasia usually present with milder manifestations, such as skeletal pain, chondrocalcinosis, calcific periarthritis, dental problems, and stress fractures. The diagnostic approach to these patients is discussed. Measuring several ALP substrates, such as pyrophosphate, pyridoxal phosphate, or phosphoethanolamine, may help to establish enzyme deficiency. Gene analysis showing a pathogenic variant in ALPL may confirm the diagnosis. However, a substantial proportion of patients show normal results after sequencing ALPL exons. It is still unknown if those patients carry unidentified mutations in regulatory regions of ALPL, epigenetic changes, or abnormalities in other genes.

[Influence of meteorological factors on the severity of COVID-19 in Spain: Observational ecological study]. / Influencia de los factores meteorológicos en la gravedad de la COVID-19 en España: estudio observacional ecológico.

OBJECTIVES: Evaluating whether meteorological and geographical variables could be associated with the severity of COVID-19 in Spain. METHODS: An ecological study was performed to analyze the influence of meteorological and geographical factors in hospital admissions and deaths due to COVID-19 in the 52 provinces of Spain (24 coastal and 28 inland regions), during the first three pandemic waves. Medical and mortality data were collected from the CarlosIII Health Institute (ISCIII) and meteorological variables were requested to the Spanish State Meteorological Agency (AEMET). RESULTS: Regarding the diagnosed cases it is remarkable that the percentage of patients hospitalized for COVID-19 was lower in the coastal provinces than in the inland ones (8.7±2.6% vs. 11.5±2.6%; P=9.9×10-5). Furthermore, coastal regions registered a lower percentage of mortality than inland regions (2.0±0.6% vs. 3.1±0.8%; P=1.7×10-5). Mean air temperature was inversely correlated both with COVID-19 hospitalizations (Rho: -0.59; P=3.0×10-6) and mortality (Rho: -0.70; P=5.3×10-9). In those provinces with a mean air temperature <10°C mortality by COVID-19 was twice that of those with >16°C. Finally, we found an association between mortality and the location of the province (coastal/inland), altitude, patient age and the average air temperature; the latter was inversely and independently correlated with mortality (non-standardized ß coeff.: -0.24; 95%CI: -0.31 to -0.16; P=2.38×10-8). CONCLUSIONS: The average air temperature was inversely associated with COVID-19 mortality in our country during the first three waves of the pandemic.

High Bone Mass Disorders: New Insights From Connecting the Clinic and the Bench.

Monogenic high bone mass (HBM) disorders are characterized by an increased amount of bone in general, or at specific sites in the skeleton. Here, we describe 59 HBM disorders with 50 known disease-causing genes from the literature, and we provide an overview of the signaling pathways and mechanisms involved in the pathogenesis of these disorders. Based on this, we classify the known HBM genes into HBM (sub)groups according to uniform Gene Ontology (GO) terminology. This classification system may aid in hypothesis generation, for both wet lab experimental design and clinical genetic screening strategies. We discuss how functional genomics can shape discovery of novel HBM genes and/or mechanisms in the future, through implementation of omics assessments in existing and future model systems. Finally, we address strategies to improve gene identification in unsolved HBM cases and highlight the importance for cross-laboratory collaborations encompassing multidisciplinary efforts to transfer knowledge generated at the bench to the clinic. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

A genome-wide association study with tissue transcriptomics identifies genetic drivers for classic bladder exstrophy.

Classic bladder exstrophy represents the most severe end of all human congenital anomalies of the kidney and urinary tract and is associated with bladder cancer susceptibility. Previous genetic studies identified one locus to be involved in classic bladder exstrophy, but were limited to a restrict number of cohort. Here we show the largest classic bladder exstrophy genome-wide association analysis to date where we identify eight genome-wide significant loci, seven of which are novel. In these regions reside ten coding and four non-coding genes. Among the coding genes is EFNA1, strongly expressed in mouse embryonic genital tubercle, urethra, and primitive bladder. Re-sequence of EFNA1 in the investigated classic bladder exstrophy cohort of our study displays an enrichment of rare protein altering variants. We show that all coding genes are expressed and/or significantly regulated in both mouse and human embryonic developmental bladder stages. Furthermore, nine of the coding genes residing in the regions of genome-wide significance are differentially expressed in bladder cancers. Our data suggest genetic drivers for classic bladder exstrophy, as well as a possible role for these drivers to relevant bladder cancer susceptibility.