BACKGROUND. Proteinuria is considered an unfavorable clinical condition that accelerates renal and cardiovascular disease. However, it is not clear whether all forms of proteinuria are damaging. Mutations in CUBN cause Imerslund-Gräsbeck syndrome (IGS), which is characterized by intestinal malabsorption of vitamin B12 and in some cases proteinuria. CUBN encodes for cubilin, an intestinal and proximal tubular uptake receptor containing 27 CUB domains for ligand binding. METHODS. We used next-generation sequencing for renal disease genes to genotype cohorts of patients with suspected hereditary renal disease and chronic proteinuria. CUBN variants were analyzed using bioinformatics, structural modeling, and epidemiological methods. RESULTS. We identified 39 patients, in whom biallelic pathogenic variants in the CUBN gene were associated with chronic isolated proteinuria and early childhood onset. Since the proteinuria in these patients had a high proportion of albuminuria, glomerular diseases such as steroid-resistant nephrotic syndrome or Alport syndrome were often the primary clinical diagnosis, motivating renal biopsies and the use of proteinuria-lowering treatments. However, renal function was normal in all cases. By contrast, we did not found any biallelic CUBN variants in proteinuric patients with reduced renal function or focal segmental glomerulosclerosis. Unlike the more N-terminal IGS mutations, 37 of the 41 proteinuria-associated CUBN variants led to modifications or truncations after the vitamin B12-binding domain. Finally, we show that 4 C-terminal CUBN variants are associated with albuminuria and slightly increased GFR in meta-analyses of large population-based cohorts. CONCLUSION. Collectively, our data suggest an important role for the C-terminal half of cubilin in renal albumin reabsorption. Albuminuria due to reduced cubilin function could be an unexpectedly common benign condition in humans that may not require any proteinuria-lowering treatment or renal biopsy.

BackgroundAutistic spectrum disorders (ASDs) with developmental delay and seizures are a genetically heterogeneous group of diseases caused by at least 700 different genes. Still, a number of cases remain genetically undiagnosed.ObjectiveThe objective of this study was to identify and characterise pathogenic variants in two individuals from unrelated families, both of whom presented a similar clinical phenotype that included an ASD, intellectual disability (ID) and seizures.MethodsWhole-exome sequencing was used to identify pathogenic variants in the two individuals. Functional studies performed in the Drosophila melanogaster model was used to assess the protein function in vivo.ResultsProbands shared a heterozygous de novo secretory carrier membrane protein (SCAMP5) variant (NM_001178111.1:c.538G>T) resulting in a p.Gly180Trp missense variant. SCAMP5 belongs to a family of tetraspanin membrane proteins found in secretory and endocytic compartments of neuronal synapses. In the fly SCAMP orthologue, the p.Gly302Trp genotype corresponds to human p.Gly180Trp. Western blot analysis of proteins overexpressed in the Drosophila fat body showed strongly reduced levels of the SCAMP p.Gly302Trp protein compared with the wild-type protein, indicating that the mutant either reduced expression or increased turnover of the protein. The expression of the fly homologue of the human SCAMP5 p.Gly180Trp mutation caused similar eye and neuronal phenotypes as the expression of SCAMP RNAi, suggesting a dominant-negative effect.ConclusionOur study identifies SCAMP5 deficiency as a cause for ASD and ID and underscores the importance of synaptic vesicular trafficking in neurodevelopmental disorders.

Purpose A personalized approach to prevention and early detection based on known risk factors should contribute to early diagnosis and treatment of breast cancer. We initiated a risk assessment clinic for all women wishing to undergo an individual breast cancer risk assessment. Methods Women underwent a complete breast cancer assessment including a questionnaire, mammogram with evaluation of breast density, collection of saliva sample, consultation with a radiologist, and a breast cancer specialist. Women aged 40 or older, with 0 or 1 first-degree relative with breast cancer diagnosed after the age of 40 were eligible for risk assessment using MammoRisk, a machine learning-based tool that provides an individual 5-year estimated risk of developing breast cancer based on the patient's clinical data and breast density, with or without polygenic risk scores (PRSs). DNA was extracted from saliva samples for genotyping of 76 single-nucleotide polymorphisms. The individual risk was communicated to the patient, with individualized screening and prevention recommendations. Results A total of 290 women underwent breast cancer assessment, among which 196 women (68%) were eligible for risk assessment using MammoRisk (median age 52, range 40-72). When PRS was added to MammoRisk, 40% (n = 78) of patients were assigned a different risk category, with 28% (n = 55) of patients changing from intermediate to moderate or high risk. Conclusion Individual risk assessment is feasible in the general population. Screening recommendations could be given based on individual risk. The use of PRS changed the risk score and screening recommendations in 40% of women.

Background: Polygenic risk scores (PRS) composed of single nucleotide polymorphisms (SNPs) known to increase breast cancer risk could improve the performance of existing breast cancer risk prediction tools. However, data is still limited on the feasibility of risk assessment including PRS in the general population of women undergoing routine screening mammography.Patients and Methods: Women, aged 40 or older and not previously identified as high risk, underwent a complete breast cancer assessment, including a questionnaire on personal and family history, mammogram with evaluation of breast density using DenSeeMammo®, and saliva-based testing of 76 SNPs. The PRS was calculated using published per-allele odds ratio corresponding to the SNP associations with breast cancer. We analyzed whether the addition of PRS in eligible women modified risk classification. PRS was not used for risk assessment in non-Caucasian women, but was calculated for comparison between ethnicities.Results: A total of 140 Caucasian women underwent a breast cancer assessment and 130 were eligible for MammoRisk® assessment, with a median age of 51 (38-71). With MammoRisk without PRS: 26 (20%) were found to have moderate risk (5-year risk <1%), 71 (55%) intermediate risk (between 1 and 1.67%), and 33 (25%) high risk (≥1.67%). When PRS was performed and integrated into MammoRisk score, 34 (26%) were found to have moderate risk, 45 (35%) intermediate risk, and 51 (39%) high risk. The use of PRS changed the risk classification in 57 women (44%), 32 (25%) to a higher category and 25 (19%) to a lower category. When PRS was assessed for women of sub-Saharan African origin (n=36) using allele frequencies and odd-ratio observed in Caucasian populations, mean PRS was much higher (mean=1.89, [0.65-5.33], median = 1.65; n=36) than in the group of Caucasian women (mean=0.97 [0.33-3.05], median = 1.02; n=130), which would overestimate the PRS and the risk of developing breast cancer in women of African origin. Conclusions: The use of PRS changed the risk classification in a large subset of women. Results of ongoing large-scale studies will inform on the benefits of personalized risk-based screening compared to annual screening (Wisdom [NCT02620852], MyPEBS [NCT03672331]). As current PRSs have been developed and validated in women of European ancestry, population-specific PRSs need to be developed with data from ongoing large-scale genome-wide association studies for improved risk assessment in women of other ethnicities (Confluence Project, Nigerian Breast Cancer Study). Number of women by risk categoryW/O PRSWith PRSModerate2634Intermediate7145High3351 Number of women with change in risk category when using PRSIntermediate to Moderate16Moderate to Intermediate5High to Intremediate9Moderate to High3Intermediate to high24 Citation Format: Mahasti Saghatchian, Marc Abehsera, Robert Sigal, Emilien Gauthier, Valerie Helin, Laure Villoing-Gaude, Cecile Reyes, Audrey Rapinat, David Gentien, Lisa Golmard, Dominique Stoppa-Lyonnet. Breast cancer risk assessment combined with a polygenic risk score in the general population for personalized screening [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS7-31.