From variant of uncertain significance to likely pathogenic in two siblings with atypical RAG2 Deficiency: a case report and review of the literature.

BACKGROUND: Severe combined immunodeficiencies (SCIDs) are hereditary disorders characterized by impaired T and B cell function, resulting in significant immune system dysfunction. Recombination-activating gene (RAG) mutations account for a substantial proportion of SCID cases. Here, we present two sibling cases of SCID caused by a novel RAG2 gene mutation. CASE PRESENTATION: The index case was an 8-year-old boy who had a history of recurring infections. After a comprehensive immunological workup, the initial diagnosis of agammaglobulinemia was revised to combined immunodeficiency (CID). The patient underwent hematopoietic stem cell transplantation (HSCT) but succumbed to cytomegalovirus (CMV) infection. His brother, a 4-month-old boy, presented with CMV chorioretinitis. Leaky SCID was diagnosed based on genetic tests and immunological findings. The patient received appropriate treatment and was considered for HSCT. Both siblings had a homozygous RAG2 gene variant, with the first case classified as a variant of uncertain significance (VUS). The presence of the same mutation in the second brother, and the clinical phenotype, supports considering the mutation as likely pathogenic. CONCLUSIONS: This case report highlights a novel RAG2 gene mutation associated with CID. The classification of a VUS may evolve with accumulating evidence, and additional studies are warranted to establish its pathogenicity. Proper communication between genetic counselors and immunologists, accurate documentation of patient information, increased public awareness, and precise utilization of genetic techniques are essential for optimal patient management.

Defining the scope of extended NIPS in Western China: evidence from a large cohort of fetuses with normal ultrasound scans.

BACKGROUND: Standard noninvasive prenatal screening(NIPS) is an accurate and reliable method to screen for common chromosome aneuploidies, such as trisomy 21, 18 and 13. Extended NIPS has been used in clinic for not only aneuploidies but also copy number variants(CNVs). Here we aim to define the range of chromosomal abnormalities that should be able to identify by NIPS in order to be an efficient extended screening test for chromosomal abnormalities. METHODS: A prospective study was conducted, involving pregnant women without fetal sonographic structural abnormalities who underwent amniocentesis. Prenatal samples were analyzed using copy number variation sequencing(CNV-seq) to identify fetal chromosomal abnormalities. RESULTS: Of 28,469 pregnancies included 1,022 (3.59%) were identified with clinically significant fetal chromosome abnormalities, including 587 aneuploidies (2.06%) and 435 (1.53%) pathogenic (P) / likely pathogenic (LP) CNVs. P/LP CNVs were found in all chromosomes, but the distribution was not uniform. Among them, P/LP CNVs in chromosomes 16, 22, and X exhibited the highest frequencies. In addition, P/LP CNVs were most common on distal ends of the chromosomes and in low copy repeat regions. Recurrent microdeletion/microduplication syndromes (MMS) accounted for 40.69% of total P/LP CNVs. The size of most P/LP CNVs (77.47%) was < 3 Mb. CONCLUSIONS: In addition to aneuploidies, the scope of extended NIPS should include the currently known P/LP CNVs, especially the regions with recurrent MMS loci, distal ends of the chromosomes, and low copy repeat regions. To be effective detection should include CNVs of < 3 Mb. Meanwhile, sufficient preclinical validation is still needed to ensure the clinical effect of extended NIPS.

Lynch-like syndrome with germline WRN mutation in Bulgarian patient with synchronous endometrial and ovarian cancer.

BACKGROUND: Synchronous endometrial and ovarian cancer (SEOC) accounts for 50-70% of all synchronous gynecology cancers in women. Approximately 14% of SEOC cases are caused by Lynch syndrome (LS). The widespread introduction of "universal screening" at LS (all cases with CRC and all EC cases diagnosed before age 60 should be tested for MMR deficiency) has led to an increasing number of suspected LS cases- MMR-deficient tumors without germline mutation in the MMR genes. These cases are attributed to the so-called Lynch-like syndrome (LLS). CASE PRESENTATION: We present a case of LLS with a detected germline, likely pathogenic variant in the WRN gene. The proband was a woman diagnosed with SEOC at the age of 51 years. Histology of both tumors (endometrium and ovary) was endometroid and showed loss of MLH1 and PMS protein expression. Genetic testing by next generation sequencing (NGS) detected a germline mutation (in the heterozygous state) in the WRN gene - c.4109del, p.(Asn1370ThrfsTer23) in the proband. CONCLUSIONS: The presented case contributes to the etiology of LLS and confirms the need for specific genetic testing, together with genetic counseling, in hereditary cancer syndromes. The use of combined information from clinicians, pathologists, genetic counselors, and data from NGS testing for cancer predisposition, clinical surveillance, and follow-up management in women with gynecology cancers, especially SEOC, could be improved.

Molecular Profiling of Tumor Tissue in Mexican Patients with Colorectal Cancer.

Colorectal cancer is a heterogeneous disease with multiple genomic changes that influence the clinical management of patients; thus, the search for new molecular targets remains necessary. The aim of this study was to identify genetic variants in tumor tissues from Mexican patients with colorectal cancer, using massive parallel sequencing. A total of 4813 genes were analyzed in tumoral DNA from colorectal cancer patients, using the TruSight One Sequencing panel. From these, 192 variants with clinical associations were found distributed in 168 different genes, of which 46 variants had not been previous reported in the literature or databases, although genes harboring those variants had already been described in colorectal cancer. Enrichment analysis of the affected genes was performed using Reactome software; pathway over-representation showed significance for disease, signal transduction, and immune system subsets in all patients, while exclusive subsets such as DNA repair, autophagy, and RNA metabolism were also found. Those characteristics, whether individual or shared, could give tumors specific capabilities for survival, aggressiveness, or response to treatment. Our results can be useful for future investigations targeting specific characteristics of tumors in colorectal cancer patients. The identification of exclusive or common pathways in colorectal cancer patients could be important for better diagnosis and personalized cancer treatment.

Segmental aneuploidies with 1 Mb resolution in human preimplantation blastocysts.

PURPOSE: This study aimed to investigate the spectrum and characteristics of segmental aneuploidies (SAs) of <10 megabase (Mb) length in human preimplantation blastocysts. METHODS: Preimplantation genetic testing for aneuploidy was performed in 15,411 blastocysts from 5171 patients using a validated 1 Mb resolution platform. The characteristics and spectrum of SAs, including the incidence, sizes, type, inheritance pattern, clinical significance, and embryo distribution, were studied. RESULTS: In total, 6.4% of the 15,411 blastocysts carried SAs of >10 Mb, 4.9% of embryos had SAs ranging between 1 to 10 Mb, and 84.3% of 1 to 10 Mb SAs were <5 Mb in size. Inheritance pattern analysis indicated that approximately 63.8% of 1 to 10 Mb SAs were inherited and were predominantly 1 to 3 Mb in size. Furthermore, 18.4% of inherited SAs and 51.9% de novo 1 to 10 Mb SAs were pathogenic or likely pathogenic (P/LP). Different from whole-chromosome aneuploidies, reanalysis indicated that 50% of the de novo 1 to 10 Mb SAs and 70% of the >10 Mb SAs arose from mitotic errors. CONCLUSION: Based on the established platform, 1 to 10 Mb SAs are common in blastocysts and include a subset of P/LP SAs. Inheritance pattern analysis and clinical interpretation based on the American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines contributed to determine the P/LP SAs.

Clinical application of liquid biopsy in cancer patients.

BACKGROUND: This study was to determine the prevalence and clinical significance of clonal hematopoiesis (CH)-related variants, and somatic and germline mutations in cancer patients and healthy individuals. METHODS: We performed next-generation sequencing of 275 cancer-related genes be-tween plasma and white blood cells in 92 cancer patients and 47 controls without cancer. Blood samples were recruited from May 2017 to July 2021, and blood cancer patients were excluded. For all statistical analysis in this study, p < 0.05 was considered statistically significant. RESULTS: Overall, 38.04% of patients and 46.81% of controls harbored at least one CH-related mutation in plasma cell-free DNA. Based on our results, older cancer patients exhibited a CH phenomenon more frequently than younger patients (p = 0.0024). A total of 39 somatic pathogenic (P)/likely pathogenic (LP) mutations were identified in 17 genes in 21 of 92 patients. We found that the presence of P/LP variants in cancer-related gene predicted shorter overall survival (OS) (p = 0.001). Multivariate analysis adjusted for CH-related mutations, germline mutations, and tumor stage, also indicated that somatic mutations correlated significantly with OS (p = 0.022). Moreover, the frequency of a germline P/LP variant was that of seven of 92 individuals in the cancer group and one of 42 individuals in the control group. CONCLUSIONS: We characterized the CH-related variants, and somatic and germline mutations in cancer patients and healthy individuals, and the results have important clinical significance.

Whole genome sequencing of 45 Japanese patients with intellectual disability.

Intellectual disability (ID) is characterized by significant limitations in both intellectual functioning and adaptive behaviors, originating before the age of 18 years. However, the genetic etiologies of ID are still incompletely elucidated due to the wide range of clinical and genetic heterogeneity. Whole genome sequencing (WGS) has been applied as a single-step clinical diagnostic tool for ID because it detects genetic variations with a wide range of resolution from single nucleotide variants (SNVs) to structural variants (SVs). To explore the causative genes for ID, we employed WGS in 45 patients from 44 unrelated Japanese families and performed a stepwise screening approach focusing on the coding variants in the genes. Here, we report 12 pathogenic and likely pathogenic variants: seven heterozygous variants of ADNP, SATB2, ANKRD11, PTEN, TCF4, SPAST, and KCNA2, three hemizygous variants of SMS, SLC6A8, and IQSEC2, and one homozygous variant in AGTPBP1. Of these, four were considered novel. Furthermore, a novel 76 kb deletion containing exons 1 and 2 in DYRK1A was identified. We confirmed the clinical and genetic heterogeneity and high frequency of de novo causative variants (8/12, 66.7%). This is the first report of WGS analysis in Japanese patients with ID. Our results would provide insight into the correlation between novel variants and expanded phenotypes of the disease.

The role of genetics in Parkinson's disease: a large cohort study in Chinese mainland population.

This study aimed to determine the mutational spectrum of familial Parkinson's disease and sporadic early-onset Parkinson's disease (sEOPD) in a mainland Chinese population and the clinical features of mutation carriers. We performed multiplex ligation-dependent probe amplification assays and whole-exome sequencing for 1676 unrelated patients with Parkinson's disease in a mainland Chinese population, including 192 probands from families with autosomal-recessive Parkinson's disease, 242 probands from families with autosomal-dominant Parkinson's disease, and 1242 sEOPD patients (age at onset ≤ 50). According to standards and guidelines from the American College of Medical Genetics and Genomics, pathogenic/likely pathogenic variants in 23 known Parkinson's disease-associated genes occurred more frequently in the autosomal-recessive Parkinson's disease cohort (65 of 192, 33.85%) than in the autosomal-dominant Parkinson's disease cohort (10 of 242, 4.13%) and the sEOPD cohort (57 of 1242, 4.59%), which leads to an overall molecular diagnostic yield of 7.88% (132 of 1676). We found that PRKN was the most frequently mutated gene (n = 83, 4.95%) and present the first evidence of an SNCA duplication and LRRK2 p.N1437D variant in mainland China. In addition, several novel pathogenic/likely pathogenic variants including LRRK2 (p.V1447M and p.Y1645S), ATP13A2 (p.R735X and p.A819D), FBXO7 (p.G67E), LRP10 (c.322dupC/p.G109Rfs*51) and TMEM230 (c.429delT/p.P144Qfs*2) were identified in our cohort. Furthermore, the age at onset of the 132 probands with genetic diagnoses (median, 31.5 years) was about 14.5 years earlier than that of patients without molecular diagnoses (i.e. non-carriers, median 46.0 years). Specifically, the age at onset of Parkinson's disease patients with pathogenic/likely pathogenic variants in ATP13A2, PLA2G6, PRKN, or PINK1 was significantly lower than that of non-carriers, while the age at onset of carriers with other gene pathogenic/likely pathogenic variants was similar to that of non-carriers. The clinical spectrum of Parkinson's disease-associated gene carriers in this mainland Chinese population was similar to that of other populations. We also detected 61 probands with GBA possibly pathogenic variants (3.64%) and 59 probands with GBA p.L444P (3.52%). These results shed insight into the genetic spectrum and clinical manifestations of Parkinson's disease in mainland China and expand the existing repertoire of pathogenic or likely pathogenic variants involved in known Parkinson's disease-associated genes. Our data highlight the importance of genetic testing in Parkinson's disease patients with age at onset < 40 years, especially in those from families with a recessive inheritance pattern, who may benefit from early diagnosis and treatment.

Exon splicing analysis of intronic variants in multigene cancer panel testing for hereditary breast/ovarian cancer.

The use of multigene panel testing for patients with a predisposition to breast/ovarian cancer is increasing as the identification of variants is useful for diagnosis and disease management. We identified pathogenic and likely pathogenic (P/LP) variants of high-and moderate-risk genes using a 23-gene germline cancer panel in 518 patients with hereditary breast and ovarian cancers (HBOC). The frequency of P/LP variants was 12.4% (64/518) for high- and moderate-penetrant genes, namely, BRCA2 (5.6%), BRCA1 (3.3%), CHEK2 (1.2%), MUTYH (0.8%), PALB2 (0.8%), MLH1 (0.4%), ATM (0.4%), BRIP1 (0.4%), TP53 (0.2%), and PMS2 (0.2%). Five patients possessed two P/LP variants in BRCA1/2 and other genes. We also compared the results from in silico splicing predictive tools and exon splicing patterns from patient samples by analyzing RT-PCR product sequences in six P/LP intronic variants and two intronic variants of unknown significance (VUS). Altered transcriptional fragments were detected for P/LP intronic variants in BRCA1, BRIP1, CHEK2, PARB2, and PMS2. Notably, we identified an in-frame deletion of the BRCA1 C-terminal (BRCT) domain by exon skipping in BRCA1 c.5152+6T>C-as known VUS-indicating a risk for HBOC. Thus, exon splicing analysis can improve the identification of veiled intronic variants that would aid decision making and determination of hereditary cancer risk.

Prevalence and spectrum of MLH1, MSH2, and MSH6 pathogenic germline variants in Pakistani colorectal cancer patients.

BACKGROUND: Pathogenic germline variants in MLH1, MSH2 and MSH6 genes account for the majority of Lynch syndrome (LS). In this first report from Pakistan, we investigated the prevalence of pathogenic MLH1/MSH2/MSH6 variants in colorectal cancer (CRC) patients. METHODS: Consecutive cases (n = 212) were recruited at the Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH&RC), between November 2007 to March 2011. Patients with a family history of > 3 or 2 HNPCC-associated cancers were classified as HNPCC (n = 9) or suspected-HNPCC (n = 20), respectively (group 1; n = 29). Cases with no family history were designated as non-HNPCC (group 2; n = 183). MLH1/MSH2/MSH6 genes were comprehensively screened in group 1. Pathogenic/likely pathogenic variants identified in group 1 were subsequently evaluated in group 2. RESULTS: Eight distinct pathogenic/likely pathogenic MLH1/MSH2 variants were found in group 1 (10/29; 34.5%), belonging to HNPCC (5/9; 55.6%) and suspected-HNPCC (5/20; 25%) families and in group 2 (2/183; 1.1%) belonging to non-HNPCC. Overall, three recurrent variants (MSH2 c.943-1G > C, MLH1 c.1358dup and c.2041G > A) accounted for 58.3% (7/12) of all families harboring pathogenic/likely pathogenic MLH1/MSH2 variants. Pathogenic MSH6 variants were not detected. CONCLUSION: Pathogenic/likely pathogenic MLH1/MSH2 variants account for a substantial proportion of CRC patients with HNPCC/suspected-HNPCC in Pakistan. Our findings suggest that HNPCC/suspected-HNPCC families should be tested for these recurrent variants prior to comprehensive gene screening in this population.

Variety of genetic defects in GnRH and hypothalamic-pituitary signaling and development in normosmic patients with IHH.

Introduction: Normosmic isolated hypogonadotropic hypogonadism (nIHH) is a clinically and genetically heterogeneous disorder. Deleterious variants in over 50 genes have been implicated in the etiology of IHH, which also indicates a possible role of digenicity and oligogenicity. Both classes of genes controlling GnRH neuron migration/development and hypothalamic/pituitary signaling and development are strongly implicated in nIHH pathogenesis. The study aimed to investigate the genetic background of nIHH and further expand the genotype-phenotype correlation. Methods: A total of 67 patients with nIHH were enrolled in the study. NGS technology and a 38-gene panel were applied. Results: Causative defects regarded as at least one pathogenic/likely pathogenic (P/LP) variant were found in 23 patients (34%). For another 30 individuals, variants of unknown significance (VUS) or benign (B) were evidenced (45%). The most frequently mutated genes presenting P/LP alterations were GNRHR (n = 5), TACR3 (n = 3), and CHD7, FGFR1, NSMF, BMP4, and NROB1 (n = 2 each). Monogenic variants with solid clinical significance (P/LP) were observed in 15% of subjects, whereas oligogenic defects were detected in 19% of patients. Regarding recurrence, 17 novel pathogenic variants affecting 10 genes were identified for 17 patients. The most recurrent pathogenic change was GNRHR:p.Arg139His, detected in four unrelated subjects. Another interesting observation is that P/LP defects were found more often in genes related to hypothalamic-pituitary pathways than those related to GnRH. Conclusions: The growing importance of the neuroendocrine pathway and related genes is drawing increasing attention to nIHH. However, the underestimated potential of VUS variants in IHH etiology, particularly those presenting recurrence, should be further elucidated.

Prevalence of pathogenic or likely pathogenic germline variants in cancer predisposition genes among selected patients with lung adenocarcinoma: The GERMLUNG study.

INTRODUCTION: Pathogenic or likely pathogenic germline variants (PGVs) in cancer predisposition genes may play a role in lung cancer (LC) susceptibility. However, determining an eligible population for genetic testing remains uncertain. This study aimed to assess the prevalence of PGVs in a selected cohort of individuals with lung adenocarcinoma. METHODS: A cross-sectional cohort study was conducted to assess the PGVs rate in lung adenocarcinoma patients with a family history of LC, young-onset presentation, history of never/light smoking, or actionable genomic alterations (AGAs). Sequencing was performed using Sophia Hereditary Cancer Solution panel F, including 144 cancer predisposition genes. Variants classified as pathogenic or likely pathogenic were included for further analysis. RESULTS: Of 201 patients, 43 (21.4 %) exhibited PGVs, among which 64.5 % were DNA damage repair genes, and 86.1 % were clinically actionable. The main PGVs were in ATM (9.3 %), TP53 (6.9 %), BRCA2 (6.9 %), and CHEK2 (6.9 %) genes. PGVs were associated with male sex (adjusted odds ratio [aOR] 2.46, 95 % CI 1.15-5.32, p = 0.021), along with a trend toward association with AGAs (aOR 6.04, 95 % CI 0.77-49.74, p = 0.094). CONCLUSIONS: In this study, a high PGVs prevalence was identified based on our selection criteria, which represents an effective strategy to identify candidates for germline genomic testing, potential screening strategies in close relatives, and personalized therapeutic modalities. Our results warrant further exploration in other populations to confirm them.

Comparing Cancer Risk Management between Females with Truncating CHEK2 1100delC versus Missense CHEK2 I157T Variants.

Breast cancer (BC) risks imparted by CHEK2 c.1100delC ("1100delC") germline pathogenic/likely pathogenic variant (GPV) are 20-30%, compared to CHEK2 c.470T>C ("I157T") GPV with <20%, leading to different breast screening recommendations through MRI. We compared cancer risk management (CRM) across these two GPVs. Study participants were adult females with an 1100delC or I157T GPV drawn from the Inherited Cancer Registry (ICARE) across the United States. Cancer history, clinical characteristics, and CRM were compared using chi-squared tests, t-tests, and logistic regression. Of 150 CHEK2 carriers, 40.7% had BC, with a mean age of 50. Comparing 1100delC and I157T GPVs, there were no differences in rates of (1) breast MRI among those with (65.2% versus 55.6% of 23 and 9; p = 0.612) and without (44.0% versus 44.8% of 50 and 29; p = 0.943) BC; (2) risk-reducing mastectomy among those with (50% versus 38.9% of 46 and 15; p = 0.501) and without (13.8% versus 6.5% of 58 and 31; p = 0.296) BC; and (3) risk-reducing salpingo-oophorectomy among those with (24.2% versus 22.2% of 45 and 18; p = 0.852) and without (17.5% versus 16.7% of 57 and 30; p = 0.918) BC. The results suggest over-screening with breast MRI among CHEK2 I157T GPV carriers and possible overuse of risk-reducing surgeries among CHEK2 carriers.

Whole exome sequencing identifies MAP3K1, MSH2, and MLH1 as potential cancer-predisposing genes in familial early-onset colorectal cancer.

The incidence of early-onset colorectal cancer (CRC), which affects people under 50, is increasing for unknown reasons. Additionally, no underlying genetic cause is found in 20%-30% of patients suspected of having familial CRC syndrome. Whole exome sequencing (WES) has generated evidence for new genes associated with CRC susceptibility, but many patients remain undiagnosed. This study applied WES in five early-onset CRC patients from three unrelated families to identify novel genetic variants that could be linked to rapid disease development. Furthermore, the candidate variants were validated using Sanger sequencing. Two heterozygote variations, c.1077-2A>G and c.199G>A, were found in the MSH2 and the MLH1 genes, respectively. Sanger sequencing analysis confirmed that these (likely) pathogenic mutations segregated in all the affected families' members. In addition, we identified a rare heterozygote variant (c.175C>T) with suspected pathogenic potential in the MAP3K1 gene; formally the variant is of uncertain significance (VUS). Our findings support the hypothesis that CRC onset may be oligogenic and molecularly heterogeneous. Larger and more robust studies are needed to understand the genetic basis of early-onset CRC development, combined with novel functional analyses and omics approaches.

Exome sequencing identifies novel genes and variants in patients with Hirschsprung disease.

BACKGROUND: Hirschsprung disease (HSCR) is a complex genetic disease characterized by the absence of ganglion cells in the intestines, leading to a functional obstruction in infants. At least 24 genes have been identified for the pathogenesis of HSCR. They contributed to approximately 72% of HSCR cases. We aimed to elucidate further the genetic basis of HSCR in Indonesia using the whole-exome sequencing (WES) approach. METHODS: WES was performed in 39 sporadic non-syndromic HSCR patients and 16 non-HSCR subjects as controls. Variants presented in controls were excluded, followed by in silico prediction tools and population allele frequency databases to select rare variants. We determined the minor allele frequency (MAF) using gnomAD (MAF <0.1%). RESULTS: We involved 24 (61.5%) males and 15 (38.5%) females. Most patients (62%) had short-segment aganglionosis and underwent the Duhamel procedure (41%). We identified several candidate novel variants in HSCR-related genes, including UBR4, GDNF, and ECE1. Moreover, we also identified some novel candidate genes, including a possible compound heterozygous variant in the MUTYH gene: the first variant, a known protein-truncating variant associated with colorectal cancer (CRC), p.Glu452Ter and the second variant is novel, p.Ala39Val. Moreover, the type of variants was not associated with the aganglionosis type. CONCLUSIONS: We identified several novel genes and variants, including the variant associated with CRC, that might contribute to the pathogenesis of HSCR. No genotype-phenotype associations were noted. Our study further confirms the complex network involved in enteric nervous system development and HSCR pathogenesis. LEVEL OF EVIDENCE: Level III.

Novel homozygous GLDC variant causing late-onset glycine encephalopathy: A case report and updated review of the literature.

Glycine encephalopathy (MIM #605899) is an autosomal recessive inborn error of metabolism caused by pathogenic variants in three genes GLDC, AMT, GCSH encoding glycine cleavage enzyme system. We report an 8-year-old boy with late-onset glycine encephalopathy who harbors a novel homozygous GLDC likely pathogenic variant c.707G > A p.(Arg236Gln). Polyhydramnios was noted at fetal ultrasound. He displayed global developmental delay, craniofacial dysmorphism, convulsions. Our report expands the phenotypic and genetic spectrum of late-onset nonketotic hyperglycinemia.

Differences among a Portuguese cohort of BRCA pathogenic/likely pathogenic variants carriers choosing risk-reducing mastectomy or intensive breast surveillance.

PURPOSE: Women with BRCA1 and BRCA2 (BRCA1/2) pathogenic/likely pathogenic (P/LP) variants have a higher risk to develop breast and ovarian cancer. In structured high-risk clinics, risk-reducing measures are adopted. This study aimed at characterizing these women and identify factors that may have influenced their choice between risk reduction mastectomy (RRM) and intensive breast surveillance (IBS). METHODS: This study reviewed retrospectively 187 clinical records of affected and unaffected women with P/LP variants of the BRCA1/2 genes, from 2007 to 2022, of which 50 chose RRM, while 137 chose IBS. The research focused on personal and family history and tumor characteristics and their relation with the preventive option chosen. RESULTS: Among women with personal history of breast cancer, a higher proportion opted for RRM compared to those asymptomatic (34.2% vs 21.3%, p = 0.049), with younger age determining the option for RRM (38.5 years vs 44.0 years, p < 0.001). Among women with personal history of ovarian cancer, a higher proportion opted for RRM compared to those without that history (62.5% vs 25.1%, p = 0.033), with younger age determining the option for RRM (42.6 years vs 62.7 years, p = 0.009). Women who had bilateral salpingo-oophorectomy were more likely to choose RRM than those who did not (37.3% vs 18.3%, p = 0.003). Family history was not associated with preventive option (33.3% vs 25.3, p = 0.346). CONCLUSIONS: The decision for the preventive option is multifactorial. In our study, personal history of breast or ovarian cancer, younger age at diagnosis, and previous bilateral salpingo-oophorectomy were associated with the choice of RRM. Family history was not associated with the preventive option.

Lynch syndrome-associated endometrial cancer patient with a rare novel germline likely pathogenic variant of MSH2 gene: A case report.

The Lynch syndrome (LS) is an autosomal dominant condition usually characterized by germline pathogenic variants in DNA mismatch repair (MMR) genes. Despite the guidelines now available, determining the pathogenicity of rare variants remains challenging, as the clinical significance of a genetic variant could be uncertain, but it may represent a disease-associated variation in the aforementioned genes. In this case report we will describe the case of a 47 years-old female affected by endometrial cancer (EC) with an extremely rare germline heterozygous variant in the MSH2 gene (c.562G > T p. (Glu188Ter), exon 3) that is likely pathogenic, and a family history consistent with LS.

Targeted next-generation sequencing of 21 candidate genes in hereditary ovarian cancer patients from the Republic of Bashkortostan.

About 5-10% of all ovarian cancer cases show familial clustering, and some 15-25% of familial ovarian cancer cases are mediated by high-penetrance mutations in the BRCA1 and BRCA2 genes. Only few other genes have been identified for familial ovarian cancer.We conducted targeted next-generation sequencing of the protein coding region of 21 candidate genes, including UTR regions, in genomic DNA samples of 48 patients with familial ovarian cancer from the Republic of Bashkortostan. We identified deleterious variants in BRCA1, BRCA2, CHEK2, MSH6 and NBN in a total of 16 patients (33%). The NBN truncating variant, p.W143X, had not previously been reported. Seven patients (15%) were carriers of the c.5266dupC variant in BRCA1, supporting a Russian origin of this founder allele. An additional 15 variants of uncertain clinical significance were observed. We conclude that our gene panel explains about one-third of familial ovarian cancer risk in the Republic of Bashkortostan.

Association analysis between chromosomal abnormalities and fetal ultrasonographic soft markers based on 15,263 fetuses.

BACKGROUND: Soft markers are common prenatal ultrasonographic findings that indicate an increased risk for fetal aneuploidy. However, the association between soft markers and pathogenic or likely pathogenic copy number variations is still unclear, and clinicians lack clarity on which soft markers warrant a recommendation for invasive prenatal genetic testing of the fetus. OBJECTIVE: This study aimed to provide guidance on ordering prenatal genetic testing for fetuses with different soft markers and to elucidate the association between specific types of chromosomal abnormalities and specific ultrasonographic soft markers. STUDY DESIGN: Low-pass genome sequencing was performed for 15,263 fetuses, including 9123 with ultrasonographic soft markers and 6140 with normal ultrasonographic findings. The detection rate of pathogenic or likely pathogenic copy number variants among fetuses with various ultrasonographic soft markers were compared with that of fetuses with normal ultrasonography. The association of soft markers with aneuploidy and pathogenic or likely pathogenic copy number variants were investigated using Fisher exact tests with Bonferroni correction. RESULTS: The detection rate of aneuploidy and pathogenic or likely pathogenic copy number variants was 3.04% (277/9123) and 3.40% (310/9123), respectively, in fetuses with ultrasonographic soft markers. An absent or a hypoplastic nasal bone was the soft marker in the second trimester with the highest diagnostic rate for aneuploidy of 5.22% (83/1591) among all isolated groups. Four types of isolated ultrasonographic soft markers, namely a thickened nuchal fold, single umbilical artery, mild ventriculomegaly, and absent or hypoplastic nasal bone, had higher diagnostic rates for pathogenic or likely pathogenic copy number variants (P<.05; odds ratio, 1.69-3.31). Furthermore, this study found that the 22q11.2 deletion was associated with an aberrant right subclavian artery, whereas the 16p13.11 deletion, 10q26.13-q26.3 deletion, and 8p23.3-p23.1 deletion were associated with a thickened nuchal fold, and the 16p11.2 deletion and 17p11.2 deletion were associated with mild ventriculomegaly (P<.05). CONCLUSION: Ultrasonographic phenotype-based genetic testing should be considered in clinical consultations. Copy number variant analysis is recommended for fetuses with an isolated thickened nuchal fold, a single umbilical artery, mild ventriculomegaly, and an absent or a hypoplastic nasal bone. A comprehensive definition of genotype-phenotype correlations in aneuploidy and pathogenic or likely pathogenic copy number variants could provide better information for genetic counseling.