AI-guided identification of risk variants for adrenocortical tumours in TP53 p.R337H carrier children: a genetic association study.

Background: Adrenocortical tumours (ACT) in children are part of the Li-Fraumeni cancer spectrum and are frequently associated with a germline TP53 pathogenic variant. TP53 p.R337H is highly prevalent in the south and southeast of Brazil and predisposes to ACT with low penetrance. Thus, we aimed to investigate whether genetic variants exist which are associated with an increased risk of developing ACT in TP53 p.R337H carrier children. Methods: A genetic association study was conducted in trios of children (14 girls, 7 boys) from southern Brazil carriers of TP53 p.R337H with (n = 18) or without (n = 3) ACT and their parents, one of whom also carries this pathogenic variant (discovery cohort). Results were confirmed in a validation cohort of TP53 p.R337H carriers with (n = 90; 68 girls, 22 boys) or without ACT (n = 302; 165 women, 137 men). Findings: We analysed genomic data from whole exome sequencing of blood DNA from the trios. Using deep learning algorithms, according to a model where the affected child inherits from the non-carrier parent variant(s) increasing the risk of developing ACT, we found a significantly enriched representation of non-coding variants in genes involved in the cyclic AMP (cAMP) pathway known to be involved in adrenocortical tumorigenesis. One among those variants (rs2278986 in the SCARB1 gene) was confirmed to be significantly enriched in the validation cohort of TP53 p.R337H carriers with ACT compared to carriers without ACT (OR 1.858; 95% CI 1.146, 3.042, p = 0.01). Interpretation: Profiling of the variant rs2278986 is a candidate for future confirmation and possible use as a tool for ACT risk stratification in TP53 p.R337H carriers. Funding: Centre National de la Recherche Scientifique (CNRS), Behring Foundation, Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq).

Structure-Elasticity Relationships in Hybrid-Carrageenan Hydrogels Studied by Image Dynamic Light Scattering, Ultra-Small-Angle Light Scattering and Dynamic Rheometry.

Hybrid-carrageenan hydrogels are characterized using novel techniques based on high-resolution speckle imaging, namely image dynamic light scattering (IDLS) and ultra-small-angle light scattering (USALS). These techniques, used to probe the microscopic structure of the system in sol-gel phase separation and at different concentrations in the gel phase, give access to a better understanding of the network's topology on the basis of fractals in the dense phase. Observations of the architecture and the spatial and the size distributions of gel phase and fractal dimension were performed by USALS. The pair-distance distribution function, P(r), extracted from USALS patterns, is a new methodology of calculus for determining the network's internal size with precision. All structural features are systematically compared with a linear and non-linear rheological characterization of the gels and structure-elasticity relationships are identified in the framework of fractal colloid gels in the diffusion limit.

Germline p.R181H variant in TP53 in a family exemplifying the genotype-phenotype correlations in Li-Fraumeni syndrome.

Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome associated with germline pathogenic/likely pathogenic variants in TP53. Genotype-phenotype correlations are progressively being characterized in LFS with certain TP53 variants associated with attenuated penetrance and phenotypes. We report on a family harboring a TP53 p.R181H variant presenting with a restricted cancer phenotype in adulthood. The proband was a female with breast cancer at the age of 71 years who had three first degree relatives also diagnosed with breast cancer after the age of 40 years (mother, two sisters). Of the nine individuals harboring the variant (6 genetically confirmed, 3 obligate heterozygous), six have not developed malignancies at this time (age range: 36-42). No childhood-onset cancers were reported in this family. A concomitant literature review identified 51 additional individuals harboring the p.R181H variant in TP53, presenting a tumor phenotype dominated by breast cancer. Rare occurrences of other adult-onset cancers (prostate, colorectal and thyroid) and only few childhood onset cancer were documented. These observations are consistent with functional analysis showing that p.R181H retains partial p53 function and suggesting possible reduced cancer penetrance, particularly in the pediatric setting.

Diabetes with GLP-1R polymorphism (rs3765467) accompanied by myotonic dystrophy: A case of myotonic dystrophy with p.R131Q polymorphism at the glucagon-like peptide-1 receptor (rs3765467) resulting in marked effects of its agonist, dulaglutide.

A 47-year-old woman was diagnosed with myotonic dystrophy when admitted for traumatic subarachnoid hemorrhage. Her glycemic control was poor despite administration of pioglitazone, a PPARɤ agonist, and subcutaneous insulin infusion. However, adding a GLP-1 receptor (GLP-1R) agonist markedly improved blood glucose levels, resulting in eventual insulin withdrawal. Genetic testing revealed a heterozygous variant, p.R131Q, in the GLP1R (rs3765467), a common variant in Asia. This variant is known to be associated with increased endogenous insulin from beta cells in response to exogenous GLP-1 infusion. This is the first report and short review of a Japanese case of myotonic dystrophy accompanied by GLP-1R gene polymorphism.

TP53 p.R337H Germline Variant among Women at Risk of Hereditary Breast Cancer in a Public Health System of Midwest Brazil.

Despite the high prevalence of TP53 pathogenic variants (PV) carriers in the South and Southeast regions of Brazil, germline genetic testing for hereditary breast cancer (HBC) is not available in the Brazilian public health system, and the prevalence of Li-Fraumeni syndrome (LFS) is not well established in other regions of Brazil. We assessed the occurrence of TP53 p.R337H carriers among women treated for breast cancer (BC) between January 2021 and January 2022 at public hospitals of Brasilia, DF, Brazil. A total of 180 patients who met at least one of the NCCN criteria for HBC underwent germline testing; 44.4% performed out-of-pocket germline multigene panel testing, and 55.6% were tested for the p.R337H variant by allelic discrimination PCR. The median age at BC diagnosis was 43.5 years, 93% had invasive ductal carcinoma, 50% had estrogen receptor-positive/HER2 negative tumors, and 41% and 11% were diagnosed respectively at stage III and IV. Two patients (1.11%) harbored the p.R337H variant, and cascade family testing identified 20 additional carriers. The TP53 p.R337H detection rate was lower than that reported in other studies from south/southeast Brazil. Nonetheless, identifying TP53 PV carriers through genetic testing in the Brazilian public health system could guide cancer treatment and prevention.

Return on investment in science: twenty years of European Commission funded research in Alzheimer's dementia, breast cancer and prostate cancer.

Alzheimer's disease (AD), breast cancer (BC) and prostate cancer (PC) continue to be high in the research and innovation agenda of the European Commission (EC). This is due to their exceptionally large burden to the national health systems, the profound economic effects of opportunity costs attributable to decreased working ability, premature mortality and the ever-increasing demand for both hospital and home-based medical care. Over the last two decades, the EC has been steadily increasing both the number of proposals being funded and the amounts of financial resources being allocated to these fields of research. This trend has continued throughout four consecutive science funding cycles, namely framework programme (FP)5, FP6, FP7 and Horizon 2020 (H2020). We performed a retrospective assessment of the outputs and outcomes of EC funding in AD, BC and PC research over the 1999-2019 period by means of selected indicators. These indicators were assessed for their ability to screen the past, present and future for an array of causal relationships and long-term trends in clinical, epidemiological and public health sphere, while considering also the broader socioeconomic impact of funded research on the society at large. This analysis shows that public-private partnerships with large industry and university-based consortia have led to some of the most impactful proposals being funded over the analysed time period. New pharmaceuticals, small molecules and monoclonal antibodies alike, along with screening and prevention, have been the most prominent sources of innovation in BC and PC, extending patients' survival and enhancing their quality of life. Unlike oncology, dementia drug development has been way less successful, with only minor improvements related to the quality of supportive medical care for symptoms and more sensitive diagnostics, without any ground-breaking disease-modifying treatment(s). Significant progresses in imaging diagnostics and nanotechnology have been largely driven by the participation of medical device industry multinational companies. Clinical trials funded by the EC were conducted, leading to the development of brand-new drug molecules featuring novel mechanisms of action. Some prominent cases of breakthrough discoveries serve as evidence for the European capability to generate cutting-edge technological innovation in biomedicine. Less productive areas of research may be reconsidered as priorities when shaping the new agenda for forthcoming science funding programmes.

Combined effect of Poynting-Robertson (P-R) drag, oblateness and radiation on the triangular points in the elliptic restricted three-body problem.

This study investigates the motion of a test particle around triangular equilibrium points in the elliptic restricted three-body problem (ER3BP) under the influence of the two oblate and radiating primaries having Poynting-Robertson (P-R) drag. It is observed that the position of triangular points of the problem is affected by oblateness, radiation pressure, eccentricity, semi-major axis and Poynting-Robertson (P-R) drag. The stability of these points is demonstrated analytically by the Routh-Hurwitz criterion. It is seen that they are unstable under the combined effect of involved parameters. The effect of these parameters on the position of triangular points is examined numerically using the binary systems, 61 Cygni and Archird. The results obtained by these binary systems can be used to broaden the scope of interest in astronomy, astrophysics, space science and celestial mechanics in general.

Unraveling the impact of the p.R107L mutation on the structure and function of human αB-Crystallin: Implications for cataract formation.

To date, several pathogenic mutations have been identified in the primary structure of human α-Crystallin, frequently involving the substitution of arginine with a different amino acid. These mutations can lead to the incidence of cataracts and myopathy. Recently, an important cataract-associated mutation has been reported in the functional α-Crystallin domain (ACD) of human αB-Crystallin protein, where arginine 107 (R107) is replaced by a leucine. In this study, we investigated the structure, chaperone function, stability, oligomerization, and amyloidogenic properties of the p.R107L human αB-Crystallin using a number of different techniques. Our results suggest that the p.R107L mutation can cause significant changes in the secondary, tertiary, and quaternary structures of αB-Crystallin. This cataractogenic mutation led to the formation of protein oligomers with larger sizes than the wild-type protein and reduced the chemical and thermal stability of the mutant chaperone. Both fluorescence and microscopic assessments indicated that this mutation significantly altered the amyloidogenic properties of human αB-Crystallin. Furthermore, the mutant protein indicated an attenuated in vitro chaperone activity. The molecular dynamics (MD) simulation confirmed the experimental results and indicated that p.R107L mutation could alter the proper conformation of human αB-Crystallin dimers. In summary, our results indicated that the p.R107L mutation could promote the formation of larger oligomers, diminish the stability and chaperone activity of human αB-Crystallin, and these changes, in turn, can play a crucial role in the development of cataract disorder.

Moyamoya disease in Southeast Asians: genetic and autopsy data, new cases, systematic review, and meta-analysis of all patients from the literature.

BACKGROUND: Moyamoya disease (MMD) is a rare disorder causing ischemic and hemorrhagic juvenile stroke. It is associated with the founder susceptibility variant p.R4810K in the RNF213 gene in East Asia. Our aim was to enhance understanding of MMD in so far poorly characterized Southeast Asians and exploring differences with Caucasian Europeans. METHODS: By retrospective analysis of medical records and systematic database search on PubMed for all published cases, we identified Southeast Asian patients with MMD. We extracted and pooled proportions using fixed-effects models. Our own cohort was tested for the East Asian RNF213 founder variant p.R4810K. One of our Southeast Asian patients underwent post-mortem histopathological examination. RESULTS: The study cohort comprised 32 Southeast Asians. Mean age at onset in the entire cohort was 32.5 ± 20.3 years (n = 24), 43.4 ± 8.7 years in patients admitted to our center (n = 11), and 23.4 ± 22.4 years in patients from the international literature (n = 13). Female-to-male ratio was 1.6:1. MMD predominantly affected bilateral anterior intracranial vessels. Cerebral ischemia outnumbered transient ischemic attacks (TIAs) and intracranial hemorrhage. TIAs, arterial hypertension and obesity were significantly less frequent in Southeast Asian patients compared to Caucasian Europeans. p.R4810K was absent in all examined Southeast Asians despite of typical histopathological signs of MMD in one autopsy case. CONCLUSION: Clinical and histopathological manifestations of MMD in Southeast Asians are similar to those in Caucasian Europeans. The genotype of MMD in Southeast Asians differs from that of most East Asian patients.

Can prolonged P-R interval predict clinical outcomes in non-ST elevation acute coronary syndrome patients?

BACKGROUND: The present study aimed to respond to clinical question, can prolonged P-R interval predict clinical outcomes in non-ST elevation acute coronary syndrome patients? METHODS: This descriptive-analytical study was conducted on cardiac patients. All of the non-ST elevation acute coronary syndrome (NSTEACS) including non-ST elevation myocardial infarction (NSTEMI) and unstable angina patients included in the study. Then they divided into two groups: prolonged P-R interval and normal P-R interval. The patients who had a history of digoxin and calcium channel blocker use, using antiarrhythmic drugs, known valvular or congenital heart disease and connective tissue, unreadable P-R interval and cardiac block were excluded. Data were collected using the questionnaire consisted demographic data and clinical outcomes and a follow-up part was completed by one of the researchers. RESULTS: Finally, 248 patients completed the study. The results showed both of the two groups had significant differences in terms of the history of myocardial infarction (MI) (p = 0.018), the level of high-density lipoprotein (HDL) (p = 0.004), heart rate (p = 0.042), inverted T wave (p = 0.017), anterior ST- segment depression (p = 0.008), normal report of coronary angiography (CAG) (p = 0.003), three vessels disease (p = 0.043), left main lesion (p = 0.045) and SYNTAX score (p = 0.032) based on the CAG report. The results of six-month follow-up showed although, the frequency of ischemic stroke, coronary artery disease (CAD) and cardiovascular death were higher in prolonged P-R interval groups. The chi-square test showed this difference was statistically non-significant (p > 0.05). The multivariate logistic regression model revealed non-significant relationships between prolonged P-R interval and SYNTAX score, significant CAD, three-vessel disease, inverted T wave, anterior ST depression, heart rate and HDL. CONCLUSIONS: Based on the results of our study the six-month follow-up showed non-significant outcomes. Further studies are recommended to assess the long-term outcomes.

Pricing and reimbursement mechanisms for advanced therapy medicinal products in 20 countries.

Introduction: Advanced Therapy Medicinal Products are a type of therapies that, in some cases, hold great potential for patients without an effective current therapeutic approach but they also present multiple challenges to payers. While there are many theoretical papers on pricing and reimbursement (P&R) options, original empirical research is very scarce. This paper aims to provide a comprehensive international review of regulatory and P&R decisions taken for all ATMPs with centralized European marketing authorization in March 2022. Methods: A survey was distributed in July 2022 to representatives of 46 countries. Results: Responses were received from 20 countries out of 46 (43.5%). 14 countries reimbursed at least one ATMP. Six countries in this survey reimbursed no ATMPs. Conclusion: Access to ATMPs is uneven across the countries included in this study. This arises from regulatory differences, commercial decisions by marketing authorization holders, and the divergent assessment processes and criteria applied by payers. Moving towards greater equality of access will require cooperation between countries and stakeholders, for example, through the WHO Regional Office for Europe's Access to Novel Medicines Platform.

Amplified Risk of Intracranial Artery Stenosis/Occlusion Associated With RNF213 p.R4810K in Familial Hypercholesterolemia.

Background: The RNF213 p.R4810K variant is associated with moyamoya disease in East Asian individuals and increases the risk of developing intracranial major artery stenosis/occlusion (ICASO) that affects anterior circulation. Meanwhile, 0.5% to 2.5% of asymptomatic East Asian individuals also carry this variant. As such, additional factors are likely required to develop ICASO in variant carriers. Familial hypercholesterolemia (FH) is a common genetic disorder in Japan that has a significant associated risk of developing premature coronary atherosclerosis; however, the relationship between ICASO and FH remains unknown. Objectives: This study aimed to determine if FH facilitates RNF213 p.R4810K carriers to develop ICASO. Methods: We enrolled patients with FH who had undergone brain magnetic resonance angiography at our hospital from May 2005 to March 2020. The RNF213 p.R4810K variant, and LDLR and PCSK9 mutations were genotyped. ICASO lesions in the brain magnetic resonance angiogram were analyzed. Results: Six RNF213 p.R4810K variant carriers were identified among 167 patients with FH (LDLR, n = 104; PCSK9, n = 22). Five of the carriers (83.3%) exhibited ICASO in the anterior circulation; a significant difference in ICASO frequency was observed between the variant carriers and noncarriers (P = 0.025). The median number of stenotic or occluded arteries in the anterior circulation was also significantly larger in the variant carriers (3 vs 1, P = 0.01); however, did not differ between patients with FH with LDLR and PCSK9 mutations. Conclusions: Patients with FH exhibit increased prevalence and severity of ICASO associated with RNF213 p.R4810K. Gene mutations for FH may confer an increased risk of ICASO in RNF213 p.R4810K carriers.

A TRPV4 mutation caused Charcot-Marie-Tooth disease type 2C with scapuloperoneal muscular atrophy overlap syndrome and scapuloperoneal spinal muscular atrophy in one family: a case report and literature review.

BACKGROUND: Charcot-Marie-Tooth disease 2C (CMT2C) and scapuloperoneal spinal muscular atrophy (SPSMA) are different clinical phenotypes of TRPV4 mutation. The mutation of p.R316C has been reported to cause CMT2C and SPSMA separately. CASE PRESENTATION: Here, we reported a Chinese family harboring the same p.R316C variant, but with an overlap syndrome and different clinical manifestations. A 58-year-old man presented with severe scapula muscle atrophy, resulting in sloping shoulders. He also exhibited distinct muscle atrophy in his four limbs, particularly in the lower limbs. The sural nerve biopsy revealed severe loss of myelinated nerve fibers with scattered regenerating clusters and pseudo-onion bulbs. Nerve conduction study showed axon damage in both motor and sensory nerves. Sensory nerve action potentials could not be evoked in bilateral sural or superficial peroneal nerves. He was diagnosed with Charcot-Marie-Tooth disease type 2C and scapuloperoneal muscular atrophy overlap syndrome, whereas his 27-year-old son was born with clubfoot and clinodactyly. Electromyogram examination indicated chronic neurogenic changes and anterior horn cells involvement. Although there was no obvious weakness or sensory symptoms, early SPSMA could be considered for him. CONCLUSIONS: A literature review of the clinical characteristics in CMT2C and SPSMA patients with TRPV4 mutation suggested that our case was distinct due to the overlap syndrome and phenotype variation. Altogether, this case broadened the phenotype spectrum and provided the nerve biopsy pathological details of TRPV4-related neuropathies.

A long-term study of posterior circulation changes after revascularization in patients with moyamoya disease.

OBJECTIVE: This study aimed to explore the long-term course of posterior circulation changes and predictors in patients with moyamoya disease (MMD). METHODS: The authors retrospectively enrolled patients who were diagnosed with MMD and underwent encephaloduroarteriosynangiosis (EDAS) surgery at the authors' department from December 2002 to September 2011. A comparative study between short-term (6-12 months) and long-term (≥ 9 years) follow-up angiography was conducted. The progression of lesions was defined from lower to higher stages of the posterior cerebral artery (PCA). RESULTS: Eighty-eight patients who received indirect EDAS were enrolled in the study. The mean age at first surgery was 28.1 ± 15.0 years. Among these 88 patients with MMD, 39 (44.3%) exhibited transient ischemic attack and 27 (30.7%) exhibited infarction, comprising 5 with occipital lobe infarction, 14 (15.9%) with hemorrhagic symptoms, and 8 (9.1%) with atypical symptoms as the initial symptoms. Heterozygous mutations occurred significantly more frequently in the cases that presented with PCA involvement. During follow-up, stage progression of PCA was observed in 21 patients (28 hemispheres). At short-term follow-up, 21/176 (11.9%) hemispheres had progression of steno-occlusive lesions in the PCA. At long-term follow-up, 7 (4.0%) hemispheres had progression of steno-occlusive lesions in the PCA. At short-term follow-up, the progression of steno-occlusive lesions in the PCA was associated with progression of the internal carotid artery. Stage progression of PCA occurred significantly more frequently in the cases with PCA involvement on preoperative angiography. Nine strokes (10.2%) occurred in 88 patients during long-term follow-up. Four patients (4.5%) presented with ischemic stroke, including 2 with occipital lobe infarctions. CONCLUSIONS: Progression of PCA stenosis is common in patients with MMD, even if the PCA is normal initially. Mutations of RNF213 p.R4810K may predict PCA involvement or progression. Follow-up of the PCA in MMD patients should be conducted, and timely surgical revascularization is needed.

The pathway to the natural gas industry: Financial development, coal consumption, and carbon dioxide emissions in P.R. China.

This paper revisits the causal links between financial development, coal consumption, and CO2 emissions in P.R. China over the 1977-2017 period to validate the development of its natural gas industry. It uses a Bootstrap ARDL bound test with structural breaks to establish stationarity, short- and long-run dynamics, and causality of the series. The results show there are no long-run relationships among these three variables, but a Granger causality test does indicate the presence of both a two-way Granger causality between coal consumption and CO2 emissions, and a one-way Granger causality running from financial development to both coal consumption and CO2 emissions. These results have important policy implications for the Chinese government's efforts to meet its commitment at the 75th UN General Assembly to achieve carbon neutrality. In that context, the promotion of its natural gas industry, including carbon pricing mechanisms and taxation schemes while enacting environmentally friendly energy abatement policies become a must.

Structure of Helicobacter pylori dihydroneopterin aldolase suggests a fragment-based strategy for isozyme-specific inhibitor design.

Dihydroneopterin aldolase (DHNA) is essential for folate biosynthesis in microorganisms. Without a counterpart in mammals, DHNA is an attractive target for antimicrobial agents. Helicobacter pylori infection occurs in human stomach of over 50% of the world population, but first-line therapies for the infection are facing rapidly increasing resistance. Novel antibiotics are urgently needed, toward which structural information on potential targets is critical. We have determined the crystal structure of H. pylori DHNA (HpDHNA) in complex with a pterin molecule (HpDHNA:Pterin) at 1.49-Å resolution. The HpDHNA:Pterin complex forms a tetramer in crystal. The tetramer is also observed in solution by dynamic light scattering and confirmed by small-angle X-ray scattering. To date, all but one reported DHNA structures are octameric complexes. As the only exception, ligand-free Mycobacterium tuberculosis DHNA (apo-MtDHNA) forms a tetramer in crystal, but its active sites are only partially formed. In contrast, the tetrameric HpDHNA:Pterin complex has well-formed active sites. Each active site accommodates one pterin molecule, but the exit of active site is blocked by two amino acid residues exhibiting a contact distance of 5.2 â€‹Å. In contrast, the corresponding contact distance in Staphylococcus aureus DHNA (SaDHNA) is twice the size, ranging from 9.8 to 10.5 â€‹Å, for ligand-free enzyme, the substrate complex, the product complex, and an inhibitor complex. This large contact distance indicates that the active site of SaDHNA is wide open. We propose that this isozyme-specific contact distance (ISCD) is a characteristic feature of DHNA active site. Comparative analysis of HpDHNA and SaDHNA structures suggests a fragment-based strategy for the development of isozyme-specific inhibitors.

An Asian case of combined 17α-hydroxylase/17,20-lyase deficiency due to homozygous p.R96Q mutation: A case report and review of the literature.

Background: Combined 17α-hydroxylase/17,20-lyase deficiency (17-OHD) is a very rare form of congenital adrenal hyperplasia (CAH) caused by mutations in the CYP17A1 gene. Almost 100 different mutations of the CYP17A1 gene have been reported, including p.R96Q mutation, but no case of p.R96Q mutation has been described in Asian populations. Case presentation: We describe a 22-year-old female patient of 46,XY karyotype, who presented with pseudohermaphrodism, primary amenorrhea, underdeveloped secondary sexual characteristics, delayed epiphyseal healing, hypertension, and hypokalemia. The diagnosis of 17-OHD was reached by measurement of steroid hormones and abdominal CT scan and confirmed by genetic sequencing, which revealed a homozygous p.R96Q missense mutation in the CYP17A1 gene. The patient received treatment with dexamethasone and estradiol, and 4 months of follow-up showed that both blood pressure and potassium were well controlled. Conclusions: This is the first Asian case of CAH caused by a homozygous p.R96Q missense mutation in the CYP17A1 gene. Herein, we highlight the role of inguinal hernia in the early diagnosis of female 17-OHD and the necessity of removing the ectopic testis.

Association Between NPHS2 p.R229Q and Focal Segmental Glomerular Sclerosis/Steroid-Resistant Nephrotic Syndrome.

Aim: NPHS2 is the coding gene of podocin. This study aims to investigate the association between NPHS2 p.R229Q (rs61747728), the most frequently reported missense variant of NPHS2, and focal segmental glomerular sclerosis (FSGS) or steroid-resistant nephrotic syndrome (SRNS) based on typing the variant in a Chinese FSGS/SRNS cohort and conducting a meta-analysis. Method: We recruited patients with FSGS or SRNS and healthy individuals. To conduct a meta-analysis, all studies on p.R229Q and FSGS/SRNS were searched from public databases. Results: In total, we enrolled 204 patients with FSGS, 61 patients with SRNS [46 with FSGS, 9 with minimal change disease (MCD), and six patients with IgA nephropathy (IgAN)], and 100 healthy controls. Unexpectedly, p.R229Q was absent in the patients from our cohort. By meta-analysis of 21 studies including 2,489 patients with FSGS/SRNS and 6,004 healthy controls, we confirmed that the A allele of p.R229Q was significantly associated with increased risk of FSGS/SRNS (allelic OR = 1.9, 95% CI = 1.44-2.52, P < 0.001). However, the subgroup analysis showed that the association between p.R229Q and FSGS/SRNS was true only in Caucasians (allelic OR = 2.14, 95%CI = 1.54-2.98, P < 0.001) and in early-onset patients (allelic OR: 2.13, 95% CI = 1.21-3.76, P = 0.009). Conclusion: NPHS2 p.R229Q may play an important role in enhancing the susceptibility of FSGS/SRNS, especially in ethnicity of Caucasian and age of early-onset patients.