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Background: To study BRCA1/2 gene variants in La Rioja in the northcentral area of Spain. Methods: We performed a molecular analysis of BRCA1 and BRCA2 in 642 individuals from 427 different families from June 2008 to December 2019. Results: We identified 71 families with pathogenic variants in these genes, 32 families with BRCA1 variants and 39 families with BRCA2 variants. The pathogenic variants c.959delG in BRCA1 and c.1363_1369delTCAGAGA, c.1397dupA, c.4234_4236delACTinsC and c.8387delC in BRCA2 have not been previously described. The c.81–2 A > T variant in BRCA1, detected in two unrelated families, has not been reported previously in the Spanish population. Two large genomic deletions were found in the BRCA1 gene in exons (Ex) 23–24 and Ex1A-1B-2, and one deletion was found in the BRCA2 gene in Ex2. The pathogenic variant c.5123 C > A in BRCA1 was detected in 8 unrelated families and was the most frequent pathogenic variant in our population. The c.6024dupG mutation in BRCA2 was detected in 6 unrelated families; the c.2808_2011delACAA mutation in BRCA2 was found in 5 different families; the c.211 A > G mutation in BRCA1 was found in three different families; and the c.68_69delAG, c81-2 A > T, c.4038_4039delAA, and c.5266dupC variants in BRCA1 and the c.2457delA, c.2701delC, c.5116_5119delAATA, c.6275delTT, c.7558 C > T and c.7617 + 1G > A variants in BRCA2 were found in two different families. Conclusions: The spectrum of pathogenic variants in the BRCA1/2 genes in La Rioja is similar to that in other Spanish regions, with some unique characteristics. The pathogenic c.6024dupG variant in the BRCA2 gene was detected in a large number of families and could have a founding effect in the Ebro riverside areas in the regions of La Rioja and Navarra. Trial registration: Not applicable. [ABSTRACT FROM AUTHOR]

Background: This study aimed to screen southern and southwestern Chinese individuals using expanded carrier screening (ECS), which explores the carrier status of recessively inherited diseases in southern and southwestern China, evaluates the clinical effectiveness of ECS application, and helps recognize high-risk fetuses that may have genetic disorders early in pregnancy, to provide better reproductive guidance. Methods: ECS for 220 diseases based on next-generation sequencing was performed on 3024 southern and southwestern Chinese individuals (1512 couples). Carrier status was analyzed; genes and loci with high frequencies of variants and on high-risk couples (ARCs) were focused to evaluate the clinical utility of our ECS technology and provide them precise fertility guidance. Results: In total, Pathogenic/likely pathogenic(P/LP) variants were found in 1885 individuals, so the carrier frequency was 62.3%, and 23.2% of the individuals were carriers of multiple diseases. furthermore, 2837 variants were detected, and the average number of P/LP variants carried per subject was 0.938. Additionally, 128 ARCs carried P/LP variants of the same gene, and the theoretical incidence rate in their offspring was as high as 2.12%. Conclusion: This study validated the application of our ECS technique for carrier screening in southern China, identifying carrier status and providing accurate carrier frequencies for hundreds of genetic diseases. [ABSTRACT FROM AUTHOR]

Germline (GL) predisposition to acute myeloid leukemia (AML) has been established as an independent disease entity in the latest World Health Organization classification. Following the American College of Medical Genetics and Genomics guidelines, GL variants were interpreted as causal if they were classified as "pathogenic." GL predisposition can be divided into three groups with different phenotypes, and play an important role in the pathogenesis of adult-onset AML. The clinical course and age of onset of myeloid neoplasms varied considerably for each gene. For example, patients with GATA2 GL variants develop AML before the age of 30 along with bone marrow failure, whereas those with DDX41 GL variants tend to develop AML after the age of 50 without any preceding hematological abnormalities or organ dysfunction. A comprehensive analysis of adult-onset myelodysplastic syndromes in transplant donors showed a 7% frequency of pathogenic GL variants, with DDX41 being the most frequent gene mutation at approximately 3.8%. Future research on GL predisposition at any age of myeloid neoplasm onset will assist in early and accurate diagnosis, development of effective treatment strategies, and selection of suitable donors for stem cell transplantation. [ABSTRACT FROM AUTHOR]

Background: The variant call format (VCF) file is a structured and comprehensive text file crucial for researchers and clinicians in interpreting and understanding genomic variation data. It contains essential information about variant positions in the genome, along with alleles, genotype calls, and quality scores. Analyzing and visualizing these files, however, poses significant challenges due to the need for diverse resources and robust features for in-depth exploration. Results: To address these challenges, we introduce variant graph craft (VGC), a VCF file visualization and analysis tool. VGC offers a wide range of features for exploring genetic variations, including extraction of variant data, intuitive visualization, and graphical representation of samples with genotype information. VGC is designed primarily for the analysis of patient cohorts, but it can also be adapted for use with individual probands or families. It integrates seamlessly with external resources, providing insights into gene function and variant frequencies in sample data. VGC includes gene function and pathway information from Molecular Signatures Database (MSigDB) for GO terms, KEGG, Biocarta, Pathway Interaction Database, and Reactome. Additionally, it dynamically links to gnomAD for variant information and incorporates ClinVar data for pathogenic variant information. VGC supports the Human Genome Assembly Hg37 and Hg38, ensuring compatibility with a wide range of data sets, and accommodates various approaches to exploring genetic variation data. It can be tailored to specific user needs with optional phenotype input data. Conclusions: In summary, VGC provides a comprehensive set of features tailored to researchers working with genomic variation data. Its intuitive interface, rapid filtering capabilities, and the flexibility to perform queries using custom groups make it an effective tool in identifying variants potentially associated with diseases. VGC operates locally, ensuring data security and privacy by eliminating the need for cloud-based VCF uploads, making it a secure and user-friendly tool. It is freely available at https://github.com/alperuzun/VGC. [ABSTRACT FROM AUTHOR]

There are more than 260 million people of Slavic descent worldwide, who reside mainly in Eastern Europe but also represent a noticeable share of the population in the USA and Canada. Slavic populations, particularly Eastern Slavs and some Western Slavs, demonstrate a surprisingly high degree of genetic homogeneity, and, consequently, remarkable contribution of recurrent alleles associated with hereditary diseases. Along with pan-European pathogenic variants with clearly elevated occurrence in Slavic people (e.g., ATP7B c.3207C>A and PAH c.1222C>T), there are at least 52 pan-Slavic germ-line mutations (e.g., NBN c.657_661del and BRCA1 c.5266dupC) as well as several disease-predisposing alleles characteristic of the particular Slavic communities (e.g., Polish SDHD c.33C>A and Russian ARSB c.1562G>A variants). From a clinical standpoint, Slavs have some features of a huge founder population, thus providing a unique opportunity for efficient genetic studies. [ABSTRACT FROM AUTHOR]

Abstract Background To study BRCA1/2 gene variants in La Rioja in the northcentral area of Spain. Methods We performed a molecular analysis of BRCA1 and BRCA2 in 642 individuals from 427 different families from June 2008 to December 2019. Results We identified 71 families with pathogenic variants in these genes, 32 families with BRCA1 variants and 39 families with BRCA2 variants. The pathogenic variants c.959delG in BRCA1 and c.1363_1369delTCAGAGA, c.1397dupA, c.4234_4236delACTinsC and c.8387delC in BRCA2 have not been previously described. The c.81–2 A > T variant in BRCA1, detected in two unrelated families, has not been reported previously in the Spanish population. Two large genomic deletions were found in the BRCA1 gene in exons (Ex) 23–24 and Ex1A-1B-2, and one deletion was found in the BRCA2 gene in Ex2. The pathogenic variant c.5123 C > A in BRCA1 was detected in 8 unrelated families and was the most frequent pathogenic variant in our population. The c.6024dupG mutation in BRCA2 was detected in 6 unrelated families; the c.2808_2011delACAA mutation in BRCA2 was found in 5 different families; the c.211 A > G mutation in BRCA1 was found in three different families; and the c.68_69delAG, c81-2 A > T, c.4038_4039delAA, and c.5266dupC variants in BRCA1 and the c.2457delA, c.2701delC, c.5116_5119delAATA, c.6275delTT, c.7558 C > T and c.7617 + 1G > A variants in BRCA2 were found in two different families. Conclusions The spectrum of pathogenic variants in the BRCA1/2 genes in La Rioja is similar to that in other Spanish regions, with some unique characteristics. The pathogenic c.6024dupG variant in the BRCA2 gene was detected in a large number of families and could have a founding effect in the Ebro riverside areas in the regions of La Rioja and Navarra. Trial registration Not applicable.

Abstract Background This study aimed to screen southern and southwestern Chinese individuals using expanded carrier screening (ECS), which explores the carrier status of recessively inherited diseases in southern and southwestern China, evaluates the clinical effectiveness of ECS application, and helps recognize high-risk fetuses that may have genetic disorders early in pregnancy, to provide better reproductive guidance. Methods ECS for 220 diseases based on next-generation sequencing was performed on 3024 southern and southwestern Chinese individuals (1512 couples). Carrier status was analyzed; genes and loci with high frequencies of variants and on high-risk couples (ARCs) were focused to evaluate the clinical utility of our ECS technology and provide them precise fertility guidance. Results In total, Pathogenic/likely pathogenic(P/LP) variants were found in 1885 individuals, so the carrier frequency was 62.3%, and 23.2% of the individuals were carriers of multiple diseases. furthermore, 2837 variants were detected, and the average number of P/LP variants carried per subject was 0.938. Additionally, 128 ARCs carried P/LP variants of the same gene, and the theoretical incidence rate in their offspring was as high as 2.12%. Conclusion This study validated the application of our ECS technique for carrier screening in southern China, identifying carrier status and providing accurate carrier frequencies for hundreds of genetic diseases.

21-hydroxylase deficiency (21-OHD) represents the most common form of congenital adrenal hyperplasia (CAH) due to CYP21A2 gene pathogenic variants. Τhe aim of this study was the identification of CYP21A2 variants in 500 subjects of Greek origin with a suspicion of 21-OHD and, by using the existing hormonal assessment and genotypes of the 500 subjects tested, to identify a biomarker that could differentiate between the heterozygotes and the cases with no pathogenic variants identified. Five hundred subjects with clinical suspicion of 21-OHD underwent CYP21A2 gene sequencing and Multiplex Ligation Dependent Probe Amplification (MLPA). Genetic diagnosis was achieved in 27.4% of the subjects tested, most of which presented with the non-classic form (NC) of 21-OHD. Heterozygotes accounted for 42.6% of cases, whereas no pathogenic variants were identified in 27% of cases. De novo aberrations, duplications, and five novel variants were also identified. Statistical analysis revealed that the difference between the basal and 60′ post-ACTH stimulation 17-hydroxyprogesterone concentrations (Δ17-OHP60-0) could be a potential biomarker (p < 0.05) distinguishing the heterozygotes from the cases with no pathogenic variants identified, although no clear cut-off value could be set. Further analysis revealed overlapping clinical manifestations among all the subjects tested. The presented phenotypic traits of the subjects tested and the inability to identify a discriminative biochemical marker highlight the importance of comprehensive CYP21A2 genotyping to ascertain the correct genetic diagnosis and proper genetic counselling.

Background: Hypermanganesemia with dystonia 1 (HMNDYT1) is a rare genetic disorder characterized by elevated blood manganese levels. This condition is associated with polycythemia, motor neurodegeneration with extrapyramidal features, and hepatic dysfunction, which can progress to cirrhosis in some patients. Materials and Methods: In this study, a consanguineous Saudi family with two affected individuals exhibiting symptoms of severe motor impairment, spastic paraparesis, postural instability, and dystonia was studied. Clinical and radiographic evaluations were conducted on the affected individuals. Whole exome sequencing (WES) was performed to diagnose the disease and to determine the causative variant underlying the phenotype. Moreover, Sanger sequencing was used for validation and segregation analysis of the identified variant. Bioinformatics tools were utilized to predict the pathogenicity of candidate variants based on ACMG criteria. Results: Exome sequencing detected a recurrent homozygous missense variant (c.266T>C; p.L89P) in exon 1 of the SLC30A10 gene. Sanger sequencing was employed to validate the segregation of the discovered variant in all available family members. Bioinformatics tools predicted that the variant is potentially pathogenic. Moreover, conservation analysis showed that the variant is highly conserved in vertebrates. Conclusions: This study shows that exome sequencing is instrumental in diagnosing undiagnosed neurodevelopmental disorders. Moreover, this study expands the mutation spectrum of SLC30A10 in distinct populations. [ABSTRACT FROM AUTHOR]

Aims: Primary pigmented nodular adrenocortical disease (PPNAD), as a rare kind of Cushing's syndrome, is frequently misdiagnosed. To get a better understanding of the disease, we analyzed the clinical characteristics and pathogenic variants of PPNAD. Methods: Databases were searched, and the pathogenic variants and clinical manifestations of patients were summarized from the relevant articles. Results: A total of 210 patients in 86 articles were enrolled with a median age of 22 and a female-to-male ratio of 2:1. Sixty-six (31.43%) patients were combined with Carney complex (CNC) and 94.29% were combined with osteoporosis/osteopenia. Among 151 patients who underwent genetic testing, 87.42% (132/151) had pathogenic variants. Six gene mutations (PRKAR1A, PDE11A, PRKACA, CTNNB1, PDE8B, and ARMC5) were detected in the patients. The most common mutation was PKAR1A, accounting for 79.47% (120/151). There was a significant correlation between PRKAR1A pathogenic variant and spotty skin pigmentation in CNC concurrent with PPNAD (p < 0.05). Among pregnant patients with PPNAD, those without surgical treatment and with bilateral adrenalectomy suffered from a high-risk perinatal period. However, patients with unilateral adrenalectomy presented a safe perinatal period. Conclusions: For young patients with Cushing's syndrome, especially female patients with spotty skin pigmentation and osteoporosis/osteopenia, PPNAD should be considered. Unilateral adrenal resection may be considered as an option for women with fertility needs. In view of the difficulty of PPNAD diagnosis, genetic testing before surgery might be a reasonable option. Patients with PPNAD with spotty skin pigmentation should consider the PRKAR1A pathogenic variant and pay attention to CNC. [ABSTRACT FROM AUTHOR]

Introduction: Approximately 10% of breast cancer (BC) cases result from hereditary causes. Genetic testing has been widely implemented in BC care to determine hereditary cancer syndromes and personalized medicine. Thus, identification of individuals carrying germline pathogenic variants could be useful to provide appropriate prophylactic or screening measures for each BC subtype, however, there are few formal recommendations for genetic testing in this sense so far. In this study, we assessed rare germline variants in a specific group of genes in order to determine the association with human epidermal growth factor 2 enriched (HER2+) BC phenotype through a systematic review and meta-analysis comparing subtypes overexpressing HER2 with other clinically recognized subtypes of BC. This review was registered with PROSPERO (ID: CRD42023447571). Methods: We conducted an online literature search in PubMed (MEDLINE), Scopus, and EMBASE databases. We included original studies that investigated germline variants in HER2+ BC patients and selected the studies that reported only rare and/or pathogenic germline variants. We assessed the risk of bias and quality of the studies using the Joanna Briggs Institute Critical Appraisal checklists and the Modified Newcastle-Ottawa Scale for Genetic Studies, respectively. Considering hormone receptor and HER2 expression status, we compared gene-based risks initially in HR-HER2-, HR+HER2-, HR+HER2+, and HR-HER2+ groups, conducting separate meta-analyses using the random effects model for each comparison, and within them for each gene. Results: Of the total 36 studies describing germline variants, 11 studies provided information on the prevalence of variants in the different clinically relevant BC subtypes and allowed comparisons. Germline variants within eight genes showed significant differences when meta-analyzed between the BC groups: BRCA1, BRCA2, TP53, ATM, CHEK2, PALB2, RAD51C, and BARD1. Notably, TP53, ATM, and CHEK2 germline variants were identified as predisposing factors for HER2+ subtypes, whereas BRCA1, BRCA2, PALB2, RAD51C, and BARD1 germline variants were associated with a predisposition to low HER2 expression. Main concerns about bias and quality assessment were the lack of confounding factors control; and comparability or outcome assessment, respectively. Discussion: Our findings underscore the connection between germline variants and differential expression of the HER2 protein and BC subtypes. [ABSTRACT FROM AUTHOR]

Summary: Thrombocytopenia 4 (THC4) is an autosomal‐dominant thrombocytopenia caused by mutations in CYCS, the gene encoding cytochrome c (CYCS), a small haeme protein essential for electron transport in mitochondria and cell apoptosis. THC4 is considered an extremely rare condition since only a few patients have been reported so far. These subjects presented mild thrombocytopenia and no or mild bleeding tendency. In this study, we describe six Italian families with five different heterozygous missense CYCS variants: p.Gly42Ser and p.Tyr49His previously associated with THC4, and three novel variants (p.Ala52Thr, p.Arg92Gly, and p.Leu99Val), which have been classified as pathogenic by bioinformatics and segregation analyses. Moreover, we supported functional effects of p.Ala52Thr and p.Arg92Gly on oxidative growth and respiratory activity in a yeast model. The clinical characterization of the 22 affected individuals, the largest series of THC4 patients ever reported, showed that this disorder is characterized by mild‐to‐moderate thrombocytopenia, normal platelet size, and function, low risk of bleeding, and no additional clinical phenotypes associated with reduced platelet count. Finally, we describe a significant correlation between the region of CYCS affected by mutations and the extent of thrombocytopenia, which could reflect different degrees of impairment of CYCS functions caused by different pathogenetic variants. [ABSTRACT FROM AUTHOR]

Introduction: The DNA damage repair (DDR) system in human genome is pivotal in maintaining genomic integrity. Pathogenic variation (PV) in DDR genes impairs their function, leading to genome instability and increased susceptibility to diseases, especially cancer. Understanding the evolution origin and arising time of DDR PV is crucial for comprehending disease susceptibility in modern humans. Methods: We used big data approach to identify the PVs in DDR genes in modern humans. We mined multiple genomic databases derived from 251,214 modern humans of African and non-Africans. We compared the DDR PVs between African and non-African. We also mined the DDR PVs in the genomic data derived from 5,031 ancient humans. We used the DDR PVs from ancient humans as the intermediate to further the DDR PVs between African and non-African. Results and discussion: We identified 1,060 single-base DDR PVs across 77 DDR genes in modern humans of African and non-African. Direct comparison of the DDR PVs between African and non-African showed that 82.1% of the non-African PVs were not present in African. We further identified 397 single-base DDR PVs in 56 DDR genes in the 5,031 ancient humans dated between 45,045 and 100 years before present (BP) lived in Eurasian continent therefore the descendants of the latest out-of-Africa human migrants occurred 50,000-60,000 years ago. By referring to the ancient DDR PVs, we observed that 276 of the 397 (70.3%) ancient DDR PVs were exclusive in non-African, 106 (26.7%) were shared between non-African and African, and only 15 (3.8%) were exclusive in African. We further validated the distribution pattern by testing the PVs in BRCA and TP53, two of the important genes in genome stability maintenance, in African, non-African, and Ancient humans. Our study revealed that DDR PVs in modern humans mostly emerged after the latest out-of-Africa migration. The data provides a foundation to understand the evolutionary basis of disease susceptibility, in particular cancer, in modern humans. [ABSTRACT FROM AUTHOR]

Hereditary breast and ovarian cancer (HBOC) syndrome is a genetic condition that increases the risk of breast cancer by 80% and that of ovarian cancer by 40%. The most common pathogenic variants (PVs) causing HBOC occur in the BRCA1 gene, with more than 3850 reported mutations in the gene sequence. The prevalence of specific PVs in BRCA1 has increased across populations due to the effect of founder mutations. Therefore, when a founder mutation is identified, it becomes key to improving cancer risk characterization and effective screening protocols. The only founder mutation described in the Mexican population is the deletion of exons 9 to 12 of BRCA1 (BRCA1Δ9–12), and its description focuses on the gene sequence, but no transcription profiles have been generated for individuals who carry this gene. In this study, we describe the transcription profiles of cancer patients and healthy individuals who were heterozygous for PV BRCA1Δ9–12 by analyzing the differential expression of both alleles compared with the homozygous BRCA1 control group using RT–qPCR, and we describe the isoforms produced by the BRCA1 wild-type and BRCA1Δ9–12 alleles using nanopore long-sequencing. Using the Kruskal–Wallis test, our results showed a similar transcript expression of the wild-type allele between the healthy heterozygous group and the homozygous BRCA1 control group. An association between the recurrence and increased expression of both alleles in HBOC patients was also observed. An analysis of the sequences indicated four wild-type isoforms with diagnostic potential for discerning individuals who carry the PV BRCA1Δ9–12 and identifying which of them has developed cancer. [ABSTRACT FROM AUTHOR]

Purpose: Recruit and sequence breast cancer subjects in Guatemalan and US Hispanic populations. Identify optimum strategies to recruit Latin American and Hispanic women into genetic studies of breast cancer. Methods: We used targeted gene sequencing to identify pathogenic variants in 19 familial breast cancer susceptibility genes in DNA from unselected Hispanic breast cancer cases in the US and Guatemala. Recruitment across the US was achieved through community-based strategies. In addition, we obtained patients receiving cancer treatment at major hospitals in Texas and Guatemala. Results: We recruited 287 Hispanic US women, 38 (13%) from community-based and 249 (87%) from hospital-based strategies. In addition, we ascertained 801 Guatemalan women using hospital-based recruitment. In our experience, a hospital-based approach was more efficient than community-based recruitment. In this study, we sequenced 103 US and 137 Guatemalan women and found 11 and 10 pathogenic variants, respectively. The most frequently mutated genes were BRCA1, BRCA2, CHEK2, and ATM. In addition, an analysis of 287 US Hispanic patients with pathology reports showed a significantly higher percentage of triple-negative disease in patients with pathogenic variants (41% vs. 15%). Finally, an analysis of mammography usage in 801 Guatemalan patients found reduced screening in women with a lower socioeconomic status (p < 0.001). Conclusion: Guatemalan and US Hispanic women have rates of hereditary breast cancer pathogenic variants similar to other populations and are more likely to have early age at diagnosis, a family history, and a more aggressive disease. Patient recruitment was higher using hospital-based versus community enrollment. This data supports genetic testing in breast cancer patients to reduce breast cancer mortality in Hispanic women. [ABSTRACT FROM AUTHOR]

The genetic bases of Alzheimer's disease (AD) and frontotemporal dementia (FTD) have been comprehensively studied, which is not the case for atypical cases not classified into these diagnoses. In the present study, we aim to contribute to the molecular understanding of the development of non-AD and non-FTD dementia due to hyperammonemia caused by mutations in urea cycle genes. The analysis was performed by pooled whole-exome sequencing (WES) of 90 patients and by searching for rare pathogenic variants in autosomal genes for enzymes or transporters of the urea cycle pathway. The survey returned two rare pathogenic coding mutations leading to citrullinemia type I: rs148918985, p.Arg265Cys, C>T; and rs121908641, p.Gly390Arg, G>A in the argininosuccinate synthase 1 (ASS1) gene. The p.Arg265Cys variant leads to enzyme deficiency, whereas p.Gly390Arg renders the enzyme inactive. These variants found in simple or compound heterozygosity can lead to the late-onset form of citrullinemia type I, associated with high ammonia levels, which can lead to cerebral dysfunction and thus to the development of dementia. The presence of urea cycle disorder-causing mutations can be used for the early initiation of antihyperammonemia therapy in order to prevent the neurotoxic effects. [ABSTRACT FROM AUTHOR]

Abstract Background Admixture occurs between different ethnic human populations. The global colonization in recent centuries by Europeans led to the most significant admixture in human history. While admixture may enhance genetic diversity for better fitness, it may also impact on human health by transmitting genetic variants for disease susceptibility in the admixture population. The admixture by Portuguese global exploration initiated in the 15th century has reached over 20 million of Portuguese-heritage population worldwide. It provides a valuable model to study the impact of admixture on human health. BRCA1 and BRCA2 (BRCA) are two of the important tumor suppressor genes. The pathogenic variation (PV) in BRCA is well determined to cause high risk of hereditary breast and ovarian cancer. Tracing the distribution of Portuguese BRCA PV in Portuguese-heritage population will help to understand the impact of admixture on cancer susceptibility in modern humans. In this study, we analyzed the distribution of the Portuguese-originated BRCA variation in Brazilian population, which has high degree Portuguese-heritage. Methods By comprehensive data mining, standardization and annotation, we generated a Portuguese-derived BRCA variation dataset and a Brazilian-derived BRCA variation dataset. We compared the two BRCA variation datasets to identify the BRCA variants shared between the two populations. Results The Portuguese-derived BRCA variation dataset consists of 220 BRCA variants including 78 PVs from 11,482 Portuguese cancer patients, 93 (42.2%) in BRCA1 and 127 (57.7%) in BRCA2. Of the 556 Portuguese BRCA PV carriers carrying the 78 PVs, 331 (59.5%) carried the three Portuguese-BRCA founder PVs of BRCA1 c.2037delinsCC, BRCA1 c.3331_3334del and BRCA2 c.156_157insAlu. The Brazilian-derived BRCA variation dataset consists of 255 BRCA PVs from 7,711 cancer patients, 136 (53.3%) in BRCA1 and 119 (46.6%) in BRCA2. We developed an open database named dbBRCA-Portuguese ( https://genemutation.fhs.um.edu.mo/dbbrca-portuguese/ ) and an open database named dbBRCA-Brazilian ( https://genemutation.fhs.um.edu.mo/dbbrca-brazilian ) to host the BRCA variation data from Portuguese and Brazilian populations. We compared the BRCA PV datasets between Portuguese and Brazilian populations, and identified 29 Portuguese-specific BRCA PVs shared between Portuguese and Brazilian populations, 14 in BRCA1 including the Portuguese founder BRCA1 c.3331_3334del and BRCA1 c.2037delinsCC, and 15 in BRCA2 including the Portuguese founder BRCA2 c.156_157insAlu. Searching the 78 Portuguese BRCA PVs in over 5,000 ancient human genomes identified evolution origin for only 8 PVs in Europeans dated between 37,470 and 3,818 years before present, confirming the Portuguese-specificity of Portuguese BRCA PVs; comparing the 78 Portuguese BRCA PVs Portuguese, 255 Brazilian BRCA PVs, and 134 African BRCA PVs showed little overlapping, ruling out the possibility that the BRCA PVs shared between Portuguese and Brazilian may also be contributed by African. Conclusion Our study provides evidence that the admixture in recent human history contributed to cancer susceptibility in modern humans.

Abstract Background Genome stability is maintained by the DNA damage repair (DDR) system composed of multiple DNA repair pathways of hundreds of genes. Germline pathogenic variation (PV) in DDR genes damages function of the affected DDR genes, leading to genome instability and high risk of diseases, in particular, cancer. Knowing evolutionary origin of the PVs in human DDR genes is essential to understand the etiology of human diseases. However, answer to the issue remains largely elusive. In this study, we analyzed evolutionary origin for the PVs in human DDR genes. Methods We identified 169 DDR genes by referring to various databases and identified PVs in the DDR genes of modern humans from ClinVar database. We performed a phylogenetic analysis to analyze the conservation of human DDR PVs in 100 vertebrates through cross-species genomic data comparison using the phyloFit program of the PHAST package and visualized the results using the GraphPad Prism software and the ggplot module. We identified DDR PVs from over 5000 ancient humans developed a database to host the DDR PVs ( https://genemutation.fhs.um.edu.mo/dbDDR-AncientHumans ). Using the PV data, we performed a molecular archeological analysis to compare the DDR PVs between modern humans and ancient humans. We analyzed evolution selection of DDR genes across 20 vertebrates using the CodeML in PAML for phylogenetic analysis. Results Our phylogenic analysis ruled out cross-species conservation as the origin of human DDR PVs. Our archeological approach identified rich DDR PVs shared between modern and ancient humans, which were mostly dated within the last 5000 years. We also observed similar pattern of quantitative PV distribution between modern and ancient humans. We further detected a set of ATM, BRCA2 and CHEK2 PVs shared between human and Neanderthals. Conclusions Our study reveals that human DDR PVs mostly arose in recent human history. We propose that human high cancer risk caused by DDR PVs can be a by-product of human evolution.

Abstract Background 21-hydroxylase deficiency is present in 90–95% of cases of congenital adrenal hyperplasia (CAH). Eleven major pathogenic variants account for 93% of all identified variants in the CYP21A2 gene in various clinical forms of the disease. Each population has its own range of significant pathogenic variants. We aimed to study the frequency of pathogenic variants in the CYP21A2 gene using NGS technology and real-time PCR in Surgut patients with different clinical forms of CAH. NGS was performed on 70 patients with salt-wasting and non-classical clinical forms of 21-hydroxylase deficiency, verified by direct Sanger sequencing and PCR–RFLP analysis. Results Eleven different pathogenic variants were found in 68.57% (48/70) of patients. Among 92.86% (13/14) of patients with salt-wasting CAH, variants were found to be homozygous, with CYP21A2 gene deletion as the most frequent mutation (46.4% or 13/28 alleles). In the group with non-classical CAH, pathogenic variants were identified only in 60.71% (34/56) of patients. V282L was discovered to be the most common variant in heterozygous carriers (45.45%, 15/33). NGS method identified 2 variants that were not determined by the standard method for major mutations detection: p.C170* and p.W22X, accounting for 3% of all known pathogenic variants. Conclusion Our data make it possible to clarify the specific spectrum of CYP21A2 gene pathogenic variants in CAH patients from Surgut. The NGS method allows for the identification of rare pathogenic variants (3%) in the CYP21A2 gene that are not included in the conventional PCR–RFLP analysis.

The management of elderly patients diagnosed with acute myelogenous leukemia (AML) is complicated by high relapse risk and comorbidities that often preclude access to allogeneic hematopoietic cellular transplantation (allo-HCT). In recent years, fast-paced FDA drug approval has reshaped the therapeutic landscape, with modest, albeit promising improvement in survival. Still, AML outcomes in elderly patients remain unacceptably unfavorable highlighting the need for better understanding of disease biology and tailored strategies. In this review, we discuss recent modifications suggested by European Leukemia Network 2022 (ELN-2022) risk stratification and review recent aging cell biology advances with the discussion of four AML cases. While an older age, >60 years, does not constitute an absolute contraindication for allo-HCT, the careful patient selection based on a detailed and multidisciplinary risk stratification cannot be overemphasized. [ABSTRACT FROM AUTHOR]

Due to the low number of patients, rare genetic diseases are a special challenge for the development of therapies, especially for diseases that result from numerous, patient‐specific pathogenic variants. Precision medicine makes use of various kinds of molecular information about a specific variant, so that the possibilities for an effective therapy based on the molecular features of the variants can be elucidated. The attention to personalized precision therapies has increased among scientists and clinicians, since the "single drug for all patients" approach does not allow the classification of individuals in subgroups according to the differences in the disease genotype or phenotype. This review article summarizes some approaches of personalized precision medicine that can be used for a cost‐effective and fast development of therapies, even for single patients. We have focused on specific examples on inborn errors of metabolism, with special attention on drug repurposing. Furthermore, we provide an overview of cell culture models that are suitable for precision medicine approaches. [ABSTRACT FROM AUTHOR]

Background: Admixture occurs between different ethnic human populations. The global colonization in recent centuries by Europeans led to the most significant admixture in human history. While admixture may enhance genetic diversity for better fitness, it may also impact on human health by transmitting genetic variants for disease susceptibility in the admixture population. The admixture by Portuguese global exploration initiated in the 15th century has reached over 20 million of Portuguese-heritage population worldwide. It provides a valuable model to study the impact of admixture on human health. BRCA1 and BRCA2 (BRCA) are two of the important tumor suppressor genes. The pathogenic variation (PV) in BRCA is well determined to cause high risk of hereditary breast and ovarian cancer. Tracing the distribution of Portuguese BRCA PV in Portuguese-heritage population will help to understand the impact of admixture on cancer susceptibility in modern humans. In this study, we analyzed the distribution of the Portuguese-originated BRCA variation in Brazilian population, which has high degree Portuguese-heritage. Methods: By comprehensive data mining, standardization and annotation, we generated a Portuguese-derived BRCA variation dataset and a Brazilian-derived BRCA variation dataset. We compared the two BRCA variation datasets to identify the BRCA variants shared between the two populations. Results: The Portuguese-derived BRCA variation dataset consists of 220 BRCA variants including 78 PVs from 11,482 Portuguese cancer patients, 93 (42.2%) in BRCA1 and 127 (57.7%) in BRCA2. Of the 556 Portuguese BRCA PV carriers carrying the 78 PVs, 331 (59.5%) carried the three Portuguese-BRCA founder PVs of BRCA1 c.2037delinsCC, BRCA1 c.3331_3334del and BRCA2 c.156_157insAlu. The Brazilian-derived BRCA variation dataset consists of 255 BRCA PVs from 7,711 cancer patients, 136 (53.3%) in BRCA1 and 119 (46.6%) in BRCA2. We developed an open database named dbBRCA-Portuguese (https://genemutation.fhs.um.edu.mo/dbbrca-portuguese/) and an open database named dbBRCA-Brazilian (https://genemutation.fhs.um.edu.mo/dbbrca-brazilian) to host the BRCA variation data from Portuguese and Brazilian populations. We compared the BRCA PV datasets between Portuguese and Brazilian populations, and identified 29 Portuguese-specific BRCA PVs shared between Portuguese and Brazilian populations, 14 in BRCA1 including the Portuguese founder BRCA1 c.3331_3334del and BRCA1 c.2037delinsCC, and 15 in BRCA2 including the Portuguese founder BRCA2 c.156_157insAlu. Searching the 78 Portuguese BRCA PVs in over 5,000 ancient human genomes identified evolution origin for only 8 PVs in Europeans dated between 37,470 and 3,818 years before present, confirming the Portuguese-specificity of Portuguese BRCA PVs; comparing the 78 Portuguese BRCA PVs Portuguese, 255 Brazilian BRCA PVs, and 134 African BRCA PVs showed little overlapping, ruling out the possibility that the BRCA PVs shared between Portuguese and Brazilian may also be contributed by African. Conclusion: Our study provides evidence that the admixture in recent human history contributed to cancer susceptibility in modern humans. [ABSTRACT FROM AUTHOR]

SORLA, the protein encoded by the SORL1 gene, has an important role in recycling cargo proteins to the cell surface. While SORLA loss-of-function variants occur almost exclusively in Alzheimer's disease cases, the majority of SORL1 variants are missense variants that are individually rare and can have individual mechanisms how they impair SORLA function as well as have individual effect size on disease risk. However, since carriers mostly come from small pedigrees, it is challenging to determine variant penetrance, leaving clinical significance associated with most missense variants unclear. In this article, we present functional approaches to evaluate the pathogenicity of a SORL1 variant, p.D1105H. First, we generated our mutant receptor by inserting the D1105H variant into the full-length SORLA-WT receptor. Then using western blot analysis we quantified the effect of the mutation on maturation and shedding of the receptor for transfected cells, and finally applied a flow cytometry approach to quantify SORLA expression at the cell surface. The results showed decreased maturation, decreased shedding, and decreased cell surface expression of D1105H compared with wild-type SORLA. We propose how these approaches can be used to functionally assess the pathogenicity of SORL1 variants in the future. This article is part of a discussion meeting issue 'Understanding the endo-lysosomal network in neurodegeneration'. [ABSTRACT FROM AUTHOR]

Introduction: RRAS2, a member of the R-Ras subfamily of Ras-like lowmolecular-weight GTPases, is considered to regulate cell proliferation and differentiation via the RAS/MAPK signaling pathway. Seven RRAS2 pathogenic variants have been reported in patients with Noonan syndrome; however, few functional analyses have been conducted. Herein, we report two patients who presented with a Noonan-like phenotype with recurrent and novel RRAS2 pathogenic variants (p.Gly23Val and p.Gly24Glu, respectively) and the results of their functional analysis. Materials and methods: Wild-type (WT) and mutant RRAS2 genes were transiently expressed in Human Embryonic Kidney293 cells. Expression of RRAS2 and phosphorylation of ERK1/2 were confirmed by Western blotting, and the RAS signaling pathway activity was measured using a reporter assay system with the serum response element-luciferase construct. WT and p.Gly23Val RRAS2 were expressed in Drosophila eye using the glass multiple reporter-Gal4 driver. Mutant mRNA microinjection into zebrafish embryos was performed, and the embryo jaws were observed. Results: No obvious differences in the expression of proteins WT, p.Gly23Val, and p.Gly24Glu were observed. The luciferase reporter assay showed that the activity of p.Gly23Val was 2.45 ± 0.95-fold higher than WT, and p.Gly24Glu was 3.06 ± 1.35-fold higher than WT. For transgenic flies, the p.Gly23Val expression resulted in no adults flies emerging, indicating lethality. For mutant mRNA-injected zebrafish embryos, an oval shape and delayed jaw development were observed compared with WT mRNA-injected embryos. These indicated hyperactivity of the RAS signaling pathway. Discussion: Recurrent and novel RRAS2 variants that we reported showed increased in vitro or in vivo RAS signaling pathway activity because of gain-offunction RRAS2 variants. Clinical features are similar to those previously reported, suggesting that RRAS2 gain-of-function variants cause this disease in patients. [ABSTRACT FROM AUTHOR]

Introduction: The objective of this study was to reclassify published germline CDH1 variants identified in gastric cancer (GC) in accordance with the latest ClinVar definition and to correlate their pathogenicity with the established international clinical criteria for genetic testing. Methods: The relevant literature dating from 1998 to 2019 was systematically searched for data on CDH1 germline mutations in accord with PRISMA guidelines. The collected variants were classified according to the latest ClinVar definition into the following classes: benign (B), likely benign (LB), pathogenic (P), likely pathogenic (LP), and variant of unknown significance (VUS). The McNemar test was used to compare the adequacy of current versus previous International GC Linkage Consortium (IGCLC) criteria. Results: We reclassified a total of 247 CDH1 variants, and we identified that about 70% of B/LB variant carriers were not fulfilling the defined clinical criteria. Instead, all P/LP variants (100%) were associated with the hereditary diffuse gastric cancer (HDGC) phenotype fulfilling the 2020 ILGCC criteria, with a significant improvement (p = 0.025) compared to previous version. Conclusions: We conclude that germline CDH1 genetic testing is indicated only in families meeting the clinical criteria for the HDGC syndrome. This observation suggests that clinical phenotypes that do not clearly fulfill these criteria should not be considered for CDH1 genetic testing. [ABSTRACT FROM AUTHOR]

We aim to report the ocular phenotype and molecular genetic findings in two Czech families with Sorsby fundus dystrophy and to review all the reported TIMP3 pathogenic variants. Two probands with Sorsby fundus dystrophy and three first-degree relatives underwent ocular examination and retinal imaging, including optical coherence tomography angiography. The DNA of the first proband was screened using a targeted ocular gene panel, while, in the second proband, direct sequencing of the TIMP3 coding region was performed. Sanger sequencing was also used for segregation analysis within the families. All the previously reported TIMP3 variants were reviewed using the American College of Medical Genetics and the Association for Molecular Pathology interpretation framework. A novel heterozygous variant, c.455A>G p.(Tyr152Cys), in TIMP3 was identified in both families and potentially de novo in one. Optical coherence tomography angiography documented in one patient the development of a choroidal neovascular membrane at 54 years. Including this study, 23 heterozygous variants in TIMP3 have been reported as disease-causing. Application of gene-specific criteria denoted eleven variants as pathogenic, eleven as likely pathogenic, and one as a variant of unknown significance. Our study expands the spectrum of TIMP3 pathogenic variants and highlights the importance of optical coherence tomography angiography for early detection of choroidal neovascular membranes. [ABSTRACT FROM AUTHOR]

Iron resistance iron deficiency anaemia is a rare autosomal recessive disorder characterized by hypochromic microcytic anaemia, low transferrin saturation and inappropriately high hepcidin levels. The aetiology of this condition is rooted in genetic variations within the transmembrane serine protease 6 (TMPRSS6) genes, responsible for encoding matriptase-2, a pivotal negative regulator of hepcidin. We conducted a systematic search across four electronic databases, yielding 538 articles in total out of which 25 were finally included and were preceded further, aiming to prognosticate prevalent single nucleotide polymorphisms (SNPs) and detrimental genetic alterations. This review aims to elucidate the effects of various SNPs and pathogenic mutations on both haematological and biochemical parameters, as well as their potential interethnic correlation. Employing bioinformatics tools, we subjected over 100 SNPs to scrutiny, discerning their potential functional ramifications. We found rs1373272804, rs1430692214 and rs855791 variants to be most frequent and were having a significant impact on haematological and biochemical profile. We found that individuals of European ancestry were more prone to have these variants compared to other ethnic groups. In conclusion, this review not only sheds light on the association of TMPRSS6 polymorphism in iron resistance iron deficiency anaemia (IRIDA), but also highlights the critical need for further investigations involving larger sample size and more diverse ethnic groups around the globe. These future studies will be vital for gaining a stronger and more reliable understanding of how these genetic differences are linked to the development of IRIDA. [ABSTRACT FROM AUTHOR]

Lymphangioleiomyomatosis (LAM) represents a rare, insidiously progressive disease of the pulmonary system, marked by cystic degradation of lung tissues leading to respiratory compromise. Pulmonary LAM has been identified as being associated with tuberous sclerosis complex (TSC) in its pulmonary manifestation (TSC-LAM), a multisystem genetic disorder resulting from mutations in either the TSC1 or TSC2 genes. Herein, we describe an early 20s female admitted to the hospital with dyspnea, chest pain, hypopigmented macules, and facial fibroadenomas. She has a medical history of renal angiomyolipomas (ALMs) and pneumothoraces. Diagnosis with LAM was confirmed through high-resolution computed tomography (HRCT) scan and histopathology of lung biopsy. Whole exome sequencing analysis identified a frameshift mutation c.4504del (p.L1502Cfs*74) in the patient's TSC2 gene. This variant was de novo due to its absence in the patient's parents. This is the first report on the clinical and genetic etiology of TSC-LAM in Vietnam. [ABSTRACT FROM AUTHOR]

Objectives : Novel or rare damaging mutations have been implicated in the developmental pathogenesis of nonsyndromic cleft lip with or without cleft palate (nsCL ± P). Thus, we investigated the human genome for high-impact mutations that could explain the risk of nsCL ± P in our cohorts. Materials and Methods: We conducted next-generation sequencing (NGS) analysis of 130 nsCL ± P case-parent African trios to identify pathogenic variants that contribute to the risk of clefting. We replicated this analysis using whole-exome sequence data from a Brazilian nsCL ± P cohort. Computational analyses were then used to predict the mechanism by which these variants could result in increased risks for nsCL ± P. Results : We discovered damaging mutations within the AFDN gene, a cell adhesion molecule (CAMs) that was previously shown to contribute to cleft palate in mice. These mutations include p.Met1164Ile, p.Thr453Asn, p.Pro1638Ala, p.Arg669Gln, p.Ala1717Val, and p.Arg1596His. We also discovered a novel splicing p.Leu1588Leu mutation in this protein. Computational analysis suggests that these amino acid changes affect the interactions with other cleft-associated genes including nectins (PVRL1, PVRL2, PVRL3, and PVRL4) CDH1, CTNNA1, and CTNND1. Conclusion : This is the first report on the contribution of AFDN to the risk for nsCL ± P in humans. AFDN encodes AFADIN, an important CAM that forms calcium-independent complexes with nectins 1 and 4 (encoded by the genes PVRL1 and PVRL4). This discovery shows the power of NGS analysis of multiethnic cleft samples in combination with a computational approach in the understanding of the pathogenesis of nsCL ± P. [ABSTRACT FROM AUTHOR]

Deciphering the structural effects of gene variants is essential for understanding the pathophysiological mechanisms of genetic diseases. Using a neurodevelopmental disorder called Bosch‐Boonstra‐Schaaf Optic Atrophy Syndrome (BBSOAS) as a genetic disease model, we applied structural bioinformatics and Genetic Code Expansion (GCE) strategies to assess the pathogenic impact of human NR2F1 variants and their binding with known and novel partners. While the computational analyses of the NR2F1 structure delineated the molecular basis of the impact of several variants on the isolated and complexed structures, the GCE enabled covalent and site‐specific capture of transient supramolecular interactions in living cells. This revealed the variable quaternary conformations of NR2F1 variants and highlighted the disrupted interplay with dimeric partners and the newly identified co‐factor, CRABP2. The disclosed consequence of the pathogenic mutations on the conformation, supramolecular interplay, and alterations in the cell cycle, viability, and sub‐cellular localization of the different variants reflect the heterogeneous disease spectrum of BBSOAS and set up novel foundation for unveiling the complexity of neurodevelopmental diseases. [ABSTRACT FROM AUTHOR]

Background: 21-hydroxylase deficiency is present in 90–95% of cases of congenital adrenal hyperplasia (CAH). Eleven major pathogenic variants account for 93% of all identified variants in the CYP21A2 gene in various clinical forms of the disease. Each population has its own range of significant pathogenic variants. We aimed to study the frequency of pathogenic variants in the CYP21A2 gene using NGS technology and real-time PCR in Surgut patients with different clinical forms of CAH. NGS was performed on 70 patients with salt-wasting and non-classical clinical forms of 21-hydroxylase deficiency, verified by direct Sanger sequencing and PCR–RFLP analysis. Results: Eleven different pathogenic variants were found in 68.57% (48/70) of patients. Among 92.86% (13/14) of patients with salt-wasting CAH, variants were found to be homozygous, with CYP21A2 gene deletion as the most frequent mutation (46.4% or 13/28 alleles). In the group with non-classical CAH, pathogenic variants were identified only in 60.71% (34/56) of patients. V282L was discovered to be the most common variant in heterozygous carriers (45.45%, 15/33). NGS method identified 2 variants that were not determined by the standard method for major mutations detection: p.C170* and p.W22X, accounting for 3% of all known pathogenic variants. Conclusion: Our data make it possible to clarify the specific spectrum of CYP21A2 gene pathogenic variants in CAH patients from Surgut. The NGS method allows for the identification of rare pathogenic variants (3%) in the CYP21A2 gene that are not included in the conventional PCR–RFLP analysis. [ABSTRACT FROM AUTHOR]

Background: Although proteinuria is long recognized as an independent risk factor for progressive chronic kidney diseases, not all forms of proteinuria are detrimental to kidney function, one of which is isolated proteinuria caused by cubilin (CUBN)‐specific mutations. CUBN encodes an endocytic receptor, initially found to be responsible for the Imerslund–Gräsbeck syndrome (IGS; OMIM #261100) characterized by a combined phenotype of megaloblastic anemia and proteinuria. Methods: After analyzing their clinical and pathological characterizations, next‐generation sequencing for renal disease genes or whole‐exome sequencing (WES) was performed on four patients with non‐progressive isolated proteinuria. CUBN biallelic pathogenic variants were identified and further analyzed by cDNA‐PCR sequencing, immunohistochemistry, minigene assay, and multiple in silico prediction tools, including 3D protein modeling. Results: Here, we present four patients with isolated proteinuria caused by CUBN C‐terminal biallelic pathogenic variants, all of which showed no typical IGS symptoms, such as anemia and vitamin B12 deficiency. Their urine protein levels fluctuated between +~++ and estimated glomerular filtration rate (eGFR) were normal or slightly higher. Mild mesangial hypercellularity was found in three children's renal biopsies. A homozygous splice‐site variant of CUBN (c.6821+3 (IVS44) A>G) was proven to result in the exon 44 skipping and premature translation termination by cDNA sequencing and immunohistochemistry. Compound heterozygous mutations were identified among the other three children, including another novel splice‐site variant (c.10764+1 (IVS66) G>A) causing the retention of first 4 nucleotides in intron 66 by minigene assay, two unreported missense mutations (c.4907G>A (p.R1636Q); c. 9095 A>G (p.Y3032C)), and two reported missense mutations in China (c.8938G>A (p.D2980N); c. 9287T>C (p.L3096P)), locating behind the vitamin B12‐binding domain, affecting CUB11, CUB16, CUB22, CUB23, and CUB27 domains, respectively. Conclusion: These results demonstrate that above CUBN mutations may cause non‐progressive and isolated proteinuria, expanding the variant spectrum of CUBN and benefiting our understanding of proteinuria and renal function. [ABSTRACT FROM AUTHOR]

IntroductionApproximately 10% of breast cancer (BC) cases result from hereditary causes. Genetic testing has been widely implemented in BC care to determine hereditary cancer syndromes and personalized medicine. Thus, identification of individuals carrying germline pathogenic variants could be useful to provide appropriate prophylactic or screening measures for each BC subtype, however, there are few formal recommendations for genetic testing in this sense so far. In this study, we assessed rare germline variants in a specific group of genes in order to determine the association with human epidermal growth factor 2 enriched (HER2+) BC phenotype through a systematic review and meta-analysis comparing subtypes overexpressing HER2 with other clinically recognized subtypes of BC. This review was registered with PROSPERO (ID: CRD42023447571).MethodsWe conducted an online literature search in PubMed (MEDLINE), Scopus, and EMBASE databases. We included original studies that investigated germline variants in HER2+ BC patients and selected the studies that reported only rare and/or pathogenic germline variants. We assessed the risk of bias and quality of the studies using the Joanna Briggs Institute Critical Appraisal checklists and the Modified Newcastle-Ottawa Scale for Genetic Studies, respectively. Considering hormone receptor and HER2 expression status, we compared gene-based risks initially in HR-HER2-, HR+HER2-, HR+HER2+, and HR-HER2+ groups, conducting separate meta-analyses using the random effects model for each comparison, and within them for each gene.ResultsOf the total 36 studies describing germline variants, 11 studies provided information on the prevalence of variants in the different clinically relevant BC subtypes and allowed comparisons. Germline variants within eight genes showed significant differences when meta-analyzed between the BC groups: BRCA1, BRCA2, TP53, ATM, CHEK2, PALB2, RAD51C, and BARD1. Notably, TP53, ATM, and CHEK2 germline variants were identified as predisposing factors for HER2+ subtypes, whereas BRCA1, BRCA2, PALB2, RAD51C, and BARD1 germline variants were associated with a predisposition to low HER2 expression. Main concerns about bias and quality assessment were the lack of confounding factors control; and comparability or outcome assessment, respectively. DiscussionOur findings underscore the connection between germline variants and differential expression of the HER2 protein and BC subtypes.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO, identifier CRD42023447571.

AbstractIn an effort to better understand the complex genetic background of Alzheimer’s disease (AD) we performed high-coverage whole-exome sequencing of a DNA pool assembled of 66 Bulgarian AD patients. We focused our analysis on genes demonstrated to have association with AD in previous studies, i.e. PSEN1, PSEN2, APP, APOE, TREM2, HFE, CLU and CR1. In these genes, we established six pathogenic/likely pathogenic variants in the sequenced pool, three common and three rare. Two of these variants showed statically non-significant difference between Bulgarian AD patients and Bulgarian control exomes, the hemochromatosis variant rs104894002 (HFE) and rs7412 (APOE), which, notwithstanding its pathogenicity score, has putative protective role against AD. Three of the remaining four pathogenic/likely pathogenic variants were estimated to significantly differ in frequency between the analyzed AD patient pool and controls. These are the rs429358 (APOE) polymorphism, a well-established risk factor for Alzheimer’s disease, the rs28936380 (PSEN2) and rs104894002 (TREM2), also ascertained to be associated with AD. The performed study validates the role of three pathogenic/likely pathogenic variants in AD related genes in the multifaceted genetic etiology of Alzheimer’s disease.

• Largest series from south India on Dravet syndrome genotype phenotype correlations. • Truncating and missense variants appeared to be equally prevalent. • Developmental outcomes did not differ between phenotypes. • Truncating variants increased the risk of multiple seizure types and ASM resistance. • 28.6% patients with missense variants were seizure free versus none with truncating. We aimed to compare the electroclinical correlates of truncating and missense variants of SCN1A variants in children with Dravet syndrome (DS) and to determine phenotypic features in relation to variants identified and seizure outcomes. A single center prospective study was carried out on a South Indian cohort. Patients below 18 years of age who met the clinical criteria for DS who had undergone genetic testing and completed a minimum of one year follow up were included. We compared the differences in clinical profile, seizure outcome, developmental characteristics and anti-seizure medication (ASM) responsiveness profiles between patients with missense and truncating variants. Out of a total of 3967 children with drug-resistant epilepsy during the period 2015–2021, 49 patients who fulfilled the inclusion criteria were studied. Thirty-seven had positive genetic tests, out of which 29 were SCN1A variants and 9 were other novel variants. The proportion of missense (14; 48.3%) and truncating SCN1A variants (15; 51.7%) was similar. A significant trend for developing multiple seizure types was noted among children with truncating variants (p = 0.035) and seizure freedom was more likely among children with missense variants (p = 0.042). All patients with truncating variants had ASM resistant epilepsy (p = 0.020). Developmental outcomes did not differ between the variant subtypes. Our results show that children harbouring missense variants demonstrated a significantly lower propensity for multiple seizure subtypes and a higher proportion with seizure freedom. However developmental implications appear to be independent of variant subtype. [ABSTRACT FROM AUTHOR]

The identification of causal BRCA1/2 pathogenic variants (PVs) in epithelial ovarian carcinoma (EOC) aids the selection of patients for genetic counselling and treatment decision‐making. Current recommendations therefore stress sequencing of all EOCs, regardless of histotype. Although it is recognised that BRCA1/2 PVs cluster in high‐grade serous ovarian carcinomas (HGSOC), this view is largely unsubstantiated by detailed analysis. Here, we aimed to analyse the results of BRCA1/2 tumour sequencing in a centrally revised, consecutive, prospective series including all EOC histotypes. Sequencing of n = 946 EOCs revealed BRCA1/2 PVs in 125 samples (13%), only eight of which were found in non‐HGSOC histotypes. Specifically, BRCA1/2 PVs were identified in high‐grade endometrioid (3/20; 15%), low‐grade endometrioid (1/40; 2.5%), low‐grade serous (3/67; 4.5%), and clear cell (1/64; 1.6%) EOCs. No PVs were identified in any mucinous ovarian carcinomas tested. By re‐evaluation and using loss of heterozygosity and homologous recombination deficiency analyses, we then assessed: (1) whether the eight 'anomalous' cases were potentially histologically misclassified and (2) whether the identified variants were likely causal in carcinogenesis. The first 'anomalous' non‐HGSOC with a BRCA1/2 PV proved to be a misdiagnosed HGSOC. Next, germline BRCA2 variants, found in two p53‐abnormal high‐grade endometrioid tumours, showed substantial evidence supporting causality. One additional, likely causal variant, found in a p53‐wildtype low‐grade serous ovarian carcinoma, was of somatic origin. The remaining cases showed retention of the BRCA1/2 wildtype allele, suggestive of non‐causal secondary passenger variants. We conclude that likely causal BRCA1/2 variants are present in high‐grade endometrioid tumours but are absent from the other EOC histotypes tested. Although the findings require validation, these results seem to justify a transition from universal to histotype‐directed sequencing. Furthermore, in‐depth functional analysis of tumours harbouring BRCA1/2 variants combined with detailed revision of cancer histotypes can serve as a model in other BRCA1/2‐related cancers. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Background: Mountain areas of the North Caucasus host several large ethnic communities that have preserved their national identity over the centuries. Methods: This study involved high-grade serous ovarian cancer (HGSOC) and breast cancer (BC) patients from Dagestan (HGSOC: 37; BC: 198), Kabardino-Balkaria (HGSOC: 68; BC: 155), North Ossetia (HGSOC: 51; BC: 104), Chechnya (HGSOC: 68; BC: 79), Ingushetia (HGSOC: 19; BC: 103), Karachay-Cherkessia (HGSOC: 13; BC: 47), and several Armenian settlements (HGSOC: 16; BC: 101). The group of BC patients was enriched by young-onset and/or family history-positive and/or bilateral and/or receptor triple-negative cases. The entire coding region of BRCA1, BRCA2, PALB2, and ATM genes was analyzed by next-generation sequencing. Results: A significant contribution of BRCA1/2 pathogenic variants (PVs) to HGSOC and BC development was observed across all North Caucasus regions (HGSOC: 19–39%; BC: 6–13%). Founder alleles were identified in all ethnic groups studied, e.g., BRCA1 c.3629_3630delAG in Chechens, BRCA2 c.6341delC in North Ossetians, BRCA2 c.5351dupA in Ingush, and BRCA1 c.2907_2910delTAAA in Karachays. Some BRCA1/2 alleles, particularly BRCA2 c.9895C > T, were shared by several nationalities. ATM PVs were detected in 14 patients, with c.1673delG and c.8876_8879delACTG alleles occurring twice each. PALB2 heterozygosity was observed in 5 subjects, with one variant seen in 2 unrelated women. Conclusion: This study adds to the evidence for the global-wide contribution of BRCA1/2 genes to HGSOC and BC morbidity, although the spectrum of their PVs is a subject of ethnicity-specific variations. The data on founder BRCA1/2 alleles may be considered when adjusting the BRCA1/2 testing procedure to the ethnic origin of patients. [ABSTRACT FROM AUTHOR]

Purpose: Up to 10% of all breast cancers (BC) are attributed to inherited pathogenic variants (PV) in BC susceptibility genes; however, most carriers of PVs remain unidentified. Here, we sought to determine the yield of hereditary cancer gene PVs among diverse women attending breast imaging centers, who could benefit from enhanced surveillance and/or risk reduction interventions. Methods: This cross-sectional retrospective cohort study included consecutive women, unselected for personal or family cancer history, who were offered genetic testing for hereditary cancer genes at the time of breast imaging at three centers (November 2020–March 2022). Results: Among 1943 patients (median age: 66 years), self-reported race/ethnicity was White (34.5%), Hispanic (27.7%), African American (17.9%), Asian (4.5%), Ashkenazi Jewish (0.6%), Other (3.5%), and missing (13.0%). Thirty-nine patients (2%) were identified as carriers of a PV in an autosomal dominant clinically actionable hereditary breast and ovarian cancer (HBOC)-related or Lynch syndrome gene, most frequently, BRCA2 (6/39; 15.4%), PALB2 (8/39; 20.5%), CHEK2 (10/39; 25.6%), and PMS2 (5/39; 12.8%). Of the 34 PVs with known race/ethnicity, 47% were detected among non-White patients. Overall, 354/1,943 (18.2%) of patients met NCCN guidelines for HBOC gene testing and only 15/39 (38.5%) patients with an autosomal dominant clinically actionable PV met guidelines. Conclusion: This population health approach extended the reach of genetic cancer risk assessment in a diverse population and highlighted the limits of a guideline-based approach. This may help address inequity in access to risk-appropriate screening and cancer prevention. [ABSTRACT FROM AUTHOR]

Purpose: The etiology of 46, XY disorders of sex development (46, XY DSD) is complex, and studies have shown that different series of patients with 46, XY DSD has different genetic spectrum. In this study, we aimed to investigate the underlying genetic etiology in a Chinese series of patients with 46, XY DSD by whole exome sequencing (WES). Methods: Seventy patients with 46, XY DSD were enrolled from the Peking Union Medical College Hospital (Beijing, China). The detailed clinical characteristics were evaluated, and peripheral blood was collected for WES to find the patients' rare variants (RVs) of genes related to 46, XY DSD. The clinical significance of the RVs was annotated according to American College of Medical Genetics and Genomics (ACMG) guidelines. Results: A total of 57 RVs from nine genes were identified in 56 patients with 46, XY DSD, which include 21 novel RVs and 36 recurrent RVs. Based on the American ACMG guidelines, 43 variants were classified as pathogenic(P) or likely pathogenic (LP) variants and 14 variants were defined as variants of uncertain significance (VUS). P or LP variants were identified in 64.3% (45/70) patients of the series. Thirty‐nine, 14, and 4 RVs were involved in the process of androgen synthesis and action, testicular determination and developmental process, and syndromic 46, XY DSD, respectively. The top three genes most frequently affected to cause 46, XY DSD were AR, SRD5A2, and NR5A1. Seven patients were found harboring RVs of the 46, XY DSD pathogenic genes identified in recent years, namely DHX37 in four patients, MYRF in two patients, and PPP2R3C in one patient. Conclusion: We identified 21 novel RVs of nine genes, which extended the genetic spectrum of 46, XY DSD pathogenic variants. Our study showed that 60% of the patients were caused by AR, SRD5A2 or NR5A1 P/LP variants. Therefore, polymerase chain reaction (PCR) amplification and Sanger sequencing of these three genes could be performed first to identify the pathogeny of the patients. For those patients whose pathogenic variants had not been found, whole‐exome sequencing could be helpful in determining the etiology. [ABSTRACT FROM AUTHOR]

The Protection of Telomere 1 (POT1) gene was identified as a melanoma predisposition candidate nearly 10 years ago. Thereafter, various cancers have been proposed as associated with germline POT1 variants in the context of the so-called POT1 Predisposition Tumor Syndrome (POT1–TPD). While the key role, and related risks, of the alterations in POT1 in melanoma are established, the correlation between germline POT1 variants and the susceptibility to other cancers partially lacks evidence, due also to the rarity of POT1–TPD. Issues range from the absence of functional or segregation studies to biased datasets or the need for a revised classification of variants. Furthermore, a proposal of a surveillance protocol related to the cancers associated with POT1 pathogenic variants requires reliable data to avoid an excessive, possibly unjustified, burden for POT1 variant carriers. We propose a critical perspective regarding data published over the last 10 years that correlate POT1 variants to various types of cancer, other than cutaneous melanoma, to offer food for thought for the specialists who manage cancer predisposition syndromes and to stimulate a debate on the grey areas that have been exposed. [ABSTRACT FROM AUTHOR]

Familial adenomatous polyposis (FAP) is an autosomal dominant colorectal cancer syndrome that is characterized by the development of multiple adenomas in the colon and rectum with high penetrance rates. This disease has specific features like the occurrence of pathogenic variations in the APC gene and diverse FAP phenotypes due to the occurrence region. In this study we aimed to evaluate pathogenic variants in exons of the APC gene in Iranian patients with FAP. A total of 35 FAP individuals were referred to the gastroenterology ward of Taleghani Hospital. As the aim of the study was to study the germline variations in the participants, the peripheral blood was collected and after the DNA extraction, PCR, and Sanger sequencing processes for the APC gene, the results were evaluated by the ACMG classification guidelines to report their pathogenicity. Accordingly, out of eight specific detected variants, three of them were novel, and the rest were reported previously. These eight variants were all truncating protein and pathogenic, and they were limited to 849-1378 codons. Overall, detected variants revealed discrepancies and parallels with previous reported cases in terms of quantity, occurrence region, and association with demographic and clinicopathological characteristics of patients. The spectrum of detected variants and the patient's phenotype showed distinct characteristics, such as occurrence in specific regions and the absence of extracolonic symptoms like Congenital hypertrophy of the retinal pigment epithelium (CHRPE). These findings open the path to comprehending the typical symptoms, their rarity, and their occurrence in the Iranian population and also due to the facts, we found that the studying of the APC gene alone for diagnosing FAP disease is not sufficient, and considering other genes are completely rational in the case of sequencing and studying the variants. [ABSTRACT FROM AUTHOR]

Mutations in the MYBPC3 gene are currently believed to lead to the development of hypertrophic cardiomyopathy (HCM) in the majority of genetically determined cases. However, despite many years of research, both in worldwide and in Russia in particular, the genetic landscape of HCM is still insufficiently studied. Moreover, the insufficient study of genetically determined cases of HCM in the Russian population does not allow us to study the possible relation of the phenotypic characteristics of HCM patients with certain pathogenic variants of the genome of these patients. In this regard, the purpose of our work was to study the prevalence of rare pathogenic variants rs730880711 and rs397515974 of the MYBPC3 gene in HCM patients from Russia and to assess the effect of these mutations on the severity of this disease. The sample included 180 patients with moderate HCM and 137 patients with severe HCM. Analysis of the genotypes of rs730880711 (NC_000011.10:g.47342928_47342929insG; V453X) and rs397515974 (NC_000011.10:g.47337452G>C; Y847X) variants in the MYBPC3 gene was carried out in genomic DNA samples isolated from peripheral blood by real-time PCR. The performed analysis of the prevalence of rare pathogenic variants rs730880711 and rs397515974 in the MYBPC3 gene in patients with moderate and severe forms of HCM from Russia showed that the frequency of each mutation was 0.003. Both pathogenic variants were identified in individuals with the moderate disease. Thus, the indicated mutations are extremely rare in HCM patients from Russia and do not make a significant contribution to the development of this disease in the Russian population. [ABSTRACT FROM AUTHOR]

Background We aimed to correlate alterations in the rat sarcoma virus (RAS)/mitogen‐activated protein kinase pathway in vascular anomalies to the clinical phenotype for improved patient and treatment stratification. Methods and Results This retrospective multicenter cohort study included 29 patients with extracranial vascular anomalies containing mosaic pathogenic variants (PVs) in genes of the RAS/mitogen‐activated protein kinase pathway. Tissue samples were collected during invasive treatment or clinically indicated biopsies. PVs were detected by the targeted sequencing of panels of genes known to be associated with vascular anomalies, performed using DNA from affected tissue. Subgroup analyses were performed according to the affected genes with regard to phenotypic characteristics in a descriptive manner. Twenty‐five vascular malformations, 3 vascular tumors, and 1 patient with both a vascular malformation and vascular tumor presented the following distribution of PVs in genes: Kirsten rat sarcoma viral oncogene (n=10), neuroblastoma ras viral oncogene homolog (n=1), Harvey rat sarcoma viral oncogene homolog (n=5), V‐Raf murine sarcoma viral oncogene homolog B (n=8), and mitogen‐activated protein kinase kinase 1 (n=5). Patients with RAS PVs had advanced disease stages according to the Schobinger classification (stage 3–4: RAS, 9/13 versus non‐RAS, 3/11) and more frequent progression after treatment (RAS, 10/13 versus non‐RAS, 2/11). Lesions with Kirsten rat sarcoma viral oncogene PVs infiltrated more tissue layers compared with the other PVs including other RAS PVs (multiple tissue layers: Kirsten rat sarcoma viral oncogene, 8/10 versus other PVs, 6/19). Conclusions This comparison of patients with various PVs in genes of the RAS/MAPK pathway provides potential associations with certain morphological and clinical phenotypes. RAS variants were associated with more aggressive phenotypes, generating preliminary data and hypothesis for future larger studies.

Background: Molecular diagnosis of cystic fibrosis (CF) is challenging in Mexico due to the population's high genetic heterogeneity. To date, 46 pathogenic variants (PVs) have been reported, yielding a detection rate of 77%. We updated the spectrum and frequency of PVs responsible for this disease in mexican patients. Methods: We extracted genomic DNA from peripheral blood lymphocytes obtained from 297 CF patients and their parents. First, we analyzed the five most frequent PVs in the Mexican population using PCR-mediated site-directed mutagenesis. In patients with at least one identified allele, CFTR sequencing was performed using next-generation sequencing tools and multiplex ligation-dependent probe amplification. For variants not previously classified as pathogenic, we used a combination of in silico prediction, CFTR modeling, and clinical characteristics to determine a genotype–phenotype correlation. Results: We identified 95 PVs, increasing the detection rate to 87.04%. The most frequent variants were p.(PheF508del) (42.7%), followed by p.(Gly542*) (5.6%), p.(Ser945Leu) (2.9%), p.(Trp1204*) and p.(Ser549Asn) (2.5%), and CFTRdel25–26 and p.(Asn386Ilefs*3) (2.3%). The remaining variants had frequencies of

Abstract Background Although proteinuria is long recognized as an independent risk factor for progressive chronic kidney diseases, not all forms of proteinuria are detrimental to kidney function, one of which is isolated proteinuria caused by cubilin (CUBN)‐specific mutations. CUBN encodes an endocytic receptor, initially found to be responsible for the Imerslund–Gräsbeck syndrome (IGS; OMIM #261100) characterized by a combined phenotype of megaloblastic anemia and proteinuria. Methods After analyzing their clinical and pathological characterizations, next‐generation sequencing for renal disease genes or whole‐exome sequencing (WES) was performed on four patients with non‐progressive isolated proteinuria. CUBN biallelic pathogenic variants were identified and further analyzed by cDNA‐PCR sequencing, immunohistochemistry, minigene assay, and multiple in silico prediction tools, including 3D protein modeling. Results Here, we present four patients with isolated proteinuria caused by CUBN C‐terminal biallelic pathogenic variants, all of which showed no typical IGS symptoms, such as anemia and vitamin B12 deficiency. Their urine protein levels fluctuated between +~++ and estimated glomerular filtration rate (eGFR) were normal or slightly higher. Mild mesangial hypercellularity was found in three children's renal biopsies. A homozygous splice‐site variant of CUBN (c.6821+3 (IVS44) A>G) was proven to result in the exon 44 skipping and premature translation termination by cDNA sequencing and immunohistochemistry. Compound heterozygous mutations were identified among the other three children, including another novel splice‐site variant (c.10764+1 (IVS66) G>A) causing the retention of first 4 nucleotides in intron 66 by minigene assay, two unreported missense mutations (c.4907G>A (p.R1636Q); c. 9095 A>G (p.Y3032C)), and two reported missense mutations in China (c.8938G>A (p.D2980N); c. 9287T>C (p.L3096P)), locating behind the vitamin B12‐binding domain, affecting CUB11, CUB16, CUB22, CUB23, and CUB27 domains, respectively. Conclusion These results demonstrate that above CUBN mutations may cause non‐progressive and isolated proteinuria, expanding the variant spectrum of CUBN and benefiting our understanding of proteinuria and renal function.

Hereditary breast and ovarian cancer (HBOC) syndrome is a genetic condition that increases the risk of breast cancer by 80% and that of ovarian cancer by 40%. The most common pathogenic variants (PVs) causing HBOC occur in the BRCA1 gene, with more than 3850 reported mutations in the gene sequence. The prevalence of specific PVs in BRCA1 has increased across populations due to the effect of founder mutations. Therefore, when a founder mutation is identified, it becomes key to improving cancer risk characterization and effective screening protocols. The only founder mutation described in the Mexican population is the deletion of exons 9 to 12 of BRCA1 (BRCA1Δ9–12), and its description focuses on the gene sequence, but no transcription profiles have been generated for individuals who carry this gene. In this study, we describe the transcription profiles of cancer patients and healthy individuals who were heterozygous for PV BRCA1Δ9–12 by analyzing the differential expression of both alleles compared with the homozygous BRCA1 control group using RT–qPCR, and we describe the isoforms produced by the BRCA1 wild-type and BRCA1Δ9–12 alleles using nanopore long-sequencing. Using the Kruskal–Wallis test, our results showed a similar transcript expression of the wild-type allele between the healthy heterozygous group and the homozygous BRCA1 control group. An association between the recurrence and increased expression of both alleles in HBOC patients was also observed. An analysis of the sequences indicated four wild-type isoforms with diagnostic potential for discerning individuals who carry the PV BRCA1Δ9–12 and identifying which of them has developed cancer.

Chunyun Fu,1,&ast; Jingsi Luo,2,&ast; Jiasun Su,2 Shujie Zhang,2 Qi Yang,2 Yue Zhang2 1Medical Science Laboratory, Children’s Hospital, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530003, People’s Republic of China; 2Department of Genetic Metabolism, Children’s Hospital, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530003, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Chunyun Fu, Email fuchunyun2008@sina.comObjective: Congenital central hypothyroidism (CCH) is a rare disorder poorly described in childhood and adolescence. The current knowledge on the genetic bases of CCH is scarce. The purpose of this study was to analyze the clinical characteristics and molecular genetic basis of CCH in children.Methods: We conducted a thorough evaluation of the clinical features in children diagnosed with CCH. Genomic DNA was extracted from peripheral blood of both children and their parents, and chromosomal microarray analysis and whole-exome sequencing were performed. Candidates for single nucleotide variants were validated using Sanger sequencing and were classified according to the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) guidelines.Results: Two cases with likely pathogenic variants were detected by whole-exome sequencing. Individual 1 carried a novel homozygous ATP6V0A4 c.1418C>T (p.Ser473Phe) variant and a novel heterozygous POU1F1 c.416G>A. (p.Arg139Gln) variant. Individual 2 had a novel homozygous POU1F1 c.212C>T (p.Ala71Val) variant. The chromosomal microarray detected the presence of a 24 Mb heterozygous deletion (LOH: loss of heterozygosity) in the p12.1p13.13 region of chromosome 2 in individual 3, and the copy number variant was unknown of clinical significance.Conclusion: Our study employed chromosomal microarray and whole-exome sequencing to investigate central hypothyroidism in seven children, leading to the detection of genetic anomalies in three individuals. The identification of novel variants has contributed to the expanded genetic spectrum of POU1F1 and ATP6V0A4 associated with pediatric central hypothyroidism.Keywords: congenital central hypothyroidism, genetic, chromosomal microarray, whole-exome sequencing, pathogenic variants

Abstract Background Approximately 5% of colorectal cancers (CRCs) are hereditary. Lynch syndrome (LS), also known as hereditary nonpolyposis colorectal cancer (HNPCC), is the most common form of recognized hereditary CRC. Although Iran, as a developing country, has a high incidence of CRC, the spectrum of variants has yet to be thoroughly investigated. Aims This study aimed to investigate pathogenic and non‐pathogenic variants in MLH1 and MSH2 genes in Iranian patients with suspected Lynch syndrome (sLS). Methods and results In the present study, 25 peripheral blood samples were collected from patients with sLS and high microsatellite instability (MSI‐H). After DNA extraction, all samples underwent polymerase chain reaction and Sanger sequencing to identify the variants in the exons of MLH1 and MSH2 genes. The identified variants were interpreted using prediction tools, and were finally reported under ACMG guidelines. In our study population, 13 variants were found in the MLH1 gene and 8 in the MSH2 gene. Interestingly, 7 of the 13 MLH1 variants and 3 of the 8 MSH2 variants were novel, whereas the remaining variants were previously reported or available in databases. In addition, some patients with sLS did not have variants in the exons of the MLH1 and MSH2 genes. The variants detected in the MLH1 and MSH2 genes had specific characteristics regarding the number, area of occurrence, and their relationship with demographic and clinicopathologic features. Conclusion Overall, our results suggest that analysis of MLH1 and MSH2 genes alone is insufficient in the Iranian population, and more comprehensive tests are recommended for detecting LS.