Penetrance Of Mutations Research Articles

Exploring Neighborhood-Level Environmental Justice to Tackle County-Level Disparities in Breast Cancer Outcomes

Breast cancer is a disease in which cells, originating from the breast epithelium, grow out of control and form tumors. The progression of breast cancer can vary, and its severity is often categorized by stages ranging from early, localized forms to more advanced stages involving widespread dissemination. Breast cancer cases can be hereditary or non-hereditary; Hereditary cases are caused by a penetrant gene mutation: one that is pathogenic and has the potential to promote the development of cancer whereas non-hereditary cases can be caused by a variety of day-to-day exposures affected by socioeconomic disparities and health literacy rates. Despite scientific and technological advancements, researchers and health officials still do not know enough about the disease and breast cancer incidence rates in the United States have steadily increased. This literature review aims to synthesize the relationship between breast cancer health outcomes and environmental justice, health literacy, and socioeconomic disparities. This relationship was first examined from a county-level in the state of Florida. We first examined three Florida counties with varying socioeconomic profiles (Broward, Miami-Dade, and Palm Beach) and then examined neighborhoods within the county of Miami-Dade (selected because it has the highest breast cancer rates out of all Florida counties). This examination revealed higher incidences of breast cancer in Latinx and African American communities with high environmental exposures and lower socioeconomic statuses. The identification of specific neighborhoods primarily affected by environmental exposures and low socioeconomic statuses emphasizes the need for neighborhood level modeling to inform future breast cancer research and intervention strategies.

Cell Senescence and the Genetics of Melanoma Development.

Cutaneous malignant melanoma is an aggressive skin cancer with an approximate lifetime risk of 1 in 38 in the UK. While exposure to ultraviolet radiation is a key environmental risk factor for melanoma, up to ~10% of patients report a family history of melanoma, and ~1% have a strong family history. The understanding of causal mutations in melanoma has been critical to the development of novel targeted therapies that have contributed to improved outcomes for late-stage patients. Here, we review current knowledge of the genes affected by familial melanoma mutations and their partial overlap with driver genes commonly mutated in sporadic melanoma development. One theme linking a set of susceptibility loci/genes is the regulation of skin pigmentation and suntanning. The largest functional set of susceptibility variants, typically with high penetrance, includes CDKN2A, RB1, and telomerase reverse transcriptase (TERT) mutations, associated with attenuation of cell senescence. We discuss the mechanisms of action of these gene sets in the biology and progression of nevi and melanoma.

Abnormal synaptic architecture in iPSC-derived neurons from a multi-generational family with genetic Creutzfeldt-Jakob disease

Genetic prion diseases are caused by mutations in PRNP, which encodes the prion protein (PrPC). Why these mutations are pathogenic, and how they alter the properties of PrPC are poorly understood. We have consented and accessed 22 individuals of a multi-generational Israeli family harboring the highly penetrant E200K PRNP mutation and generated a library of induced pluripotent stem cells (iPSCs) representing nine carriers and four non-carriers. iPSC-derived neurons from E200K carriers display abnormal synaptic architecture characterized by misalignment of postsynaptic NMDA receptors with the cytoplasmic scaffolding protein PSD95. Differentiated neurons from mutation carriers do not produce PrPSc, the aggregated and infectious conformer of PrP, suggesting that loss of a physiological function of PrPC may contribute to the disease phenotype. Our study shows that iPSC-derived neurons can provide important mechanistic insights into the pathogenesis of genetic prion diseases and can offer a powerful platform for testing candidate therapeutics.

Enhanced motor noise in an autism subtype with poor motor skills

BackgroundMotor difficulties are common in many, but not all, autistic individuals. These difficulties can co-occur with other problems, such as delays in language, intellectual, and adaptive functioning. Biological mechanisms underpinning such difficulties are less well understood. Poor motor skills tend to be more common in individuals carrying highly penetrant rare genetic mutations. Such mechanisms may have downstream consequences of altering neurophysiological excitation-inhibition balance and lead to enhanced behavioral motor noise.MethodsThis study combined publicly available and in-house datasets of autistic (n = 156), typically-developing (TD, n = 149), and developmental coordination disorder (DCD, n = 23) children (age 3–16 years). Autism motor subtypes were identified based on patterns of motor abilities measured from the Movement Assessment Battery for Children 2nd edition. Stability-based relative clustering validation was used to identify autism motor subtypes and evaluate generalization accuracy in held-out data. Autism motor subtypes were tested for differences in motor noise, operationalized as the degree of dissimilarity between repeated motor kinematic trajectories recorded during a simple reach-to-drop task.ResultsRelatively ‘high’ (n = 87) versus ‘low’ (n = 69) autism motor subtypes could be detected and which generalize with 89% accuracy in held-out data. The relatively ‘low’ subtype was lower in general intellectual ability and older at age of independent walking, but did not differ in age at first words or autistic traits or symptomatology. Motor noise was considerably higher in the ‘low’ subtype compared to ‘high’ (Cohen’s d = 0.77) or TD children (Cohen’s d = 0.85), but similar between autism ‘high’ and TD children (Cohen’s d = 0.08). Enhanced motor noise in the ‘low’ subtype was also most pronounced during the feedforward phase of reaching actions.LimitationsThe sample size of this work is limited. Future work in larger samples along with independent replication is important. Motor noise was measured only on one specific motor task. Thus, a more comprehensive assessment of motor noise on many other motor tasks is needed.ConclusionsAutism can be split into at least two discrete motor subtypes that are characterized by differing levels of motor noise. This suggests that autism motor subtypes may be underpinned by different biological mechanisms.

Abstract Mo080: Clinically Variable Penetrant MYH7 G256E Mutation Shows Gene-Dose-Dependent HCM Disease Phenotype on a Transcriptomic, Proteomic, and Functional Level

Introduction: Hypertrophic cardiomyopathy (HCM) is a monogenic disorder caused by heterozygous (HET) mutations in sarcomere genes such as MYH7 . Recently, human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) carrying HET HCM mutations have shed new insights into the molecular mechanisms of HCM. However, the cause of phenotype variability and the role of allelic imbalance in phenotype penetrance of HET missense mutations such as MYH7 G256E remain unclear. Hypothesis: We hypothesize that hiPSC CMs carrying clinically variable penetrant HCM missense mutations such as MYH7 G256E show a gene dose-dependent disease phenotype indicating their susceptibility for allelic imbalance as a cause for variable disease phenotype penetrance. Methods: We generated HET and homozygous (HOM) hiPSC-lines for variable penetrant HCM mutation MYH7 G256E. We performed multiplexed single-cell RNA sequencing and quantitative proteomics analyses on wildtype (WT), HET, and HOM iPSC-CMs at day 30 of cardiac differentiation. Additional Digital Droplet PCR studies were performed to investigate the MYH7 mutant allele expression. The functional contractile phenotype was assessed with Sony SI8000 Cell motion imaging system. Results: We detected a large clone-to-clone and batch-to-batch variability in HET iPSC-CMs on a transcriptomic and proteomic level that obscured the identification of a consistent mutant phenotype in HET MYH7 G256E vs WT CMs. These phenotypes correlated with a 1:1 bulk ratio of mutant vs WT mRNA and protein expression, while overall MYH7 gene and protein expression remained comparable. Transcriptomic and proteomic analyses of WT, HET, and HOM CMs show a gene dose-dependent regulation of known hypertrophy response markers such as NPPB (mRNA: HET vs WT: +1.76x p .adj=7.0*10 -7 , HOM vs WT: +5.42x p.adj=1.5*10 -48 ; protein: HET vs WT: +1.15x, 95% CI [0.86, 1.58]; HOM vs WT: +1.51x, 95% CI [1.12, 2.01]) which functionally correlated with enhanced contractility (contraction velocity in μm/s: WT: 5.84 +/-2.24, HET: 6.04 +/-2.89, HOM: 7.77 +/-3.352, p=0.3*10 -2 ANOVA) and the more frequent occurrence of arrhythmias (WT: 1/46, HET: 0/55, HOM: 5/41). Conclusions: Hypertrophic disease phenotype in MYH7 G256E mutation iPSC-CMs shows a gene dose-dependent penetrance on a transcriptomic, proteomic, and functional level. This indicates susceptibility to allelic imbalance as a potential cause for variable disease penetrance.

Demographics and Clinical Decision Making in Patients with Germline Moderate Penetrance Non-BRCA Mutations in Breast Cancer Related Genes.

Management of pathogenic variants in high penetrance genes related to breast cancer (BC), such as BRCA1 and BRCA2, are well established. However, moderate penetrance mutations are understudied. We aim to compare risk reduction decision-making patterns in patients with a moderate penetrance BC-related genetic mutations, without a prior BC diagnosis. Female patients aged ≥ 18 years who tested positive for a BRCA1/2, high penetrance, or moderate penetrance mutation related to BC between 1996 and 2023 without a concurrent or prior BC diagnosis were retrospectively identified from a single academic center's database. Groups were stratified by mutation type: BRCA1/2 mutations (BRCA1, BRCA2), high penetrance mutations (HPM; CDH1, PALB2, PTEN, STK11, TP53), or moderate penetrance mutations (MPM; ATM, BARD1, CHEK2, NF1, RAD51C, RAD51D). Demographics and clinical outcomes were compared. A total of 528 patients met the inclusion criteria, with 66% (n = 350) having a BRCA1/2 mutation, 8% (n = 44) having HPM, and 25% (n = 134) having MPM; the median follow-up was 56.0 months. In our cohort, 20.9% of patients with BRCA mutations, 9.1% with HPM, and 7.5% with MPM chose to undergo risk-reducing mastectomies (RRM). Within the moderate penetrance cohort, patients who chose to undergo RRM were younger at the time of genetic testing (39.4 vs. 47.5 years, p = 0.03) and had a higher number of family members with BC (2 vs. 1, p = 0.05). Our findings provide insights into the demographic characteristics and family history of patients with moderate penetrance mutations and those who pursue risk-reducing surgery.

Optical coherence tomography assessment of disease activity in cryopyrin-associated periodic syndrome.

Cryopyrin-associated periodic syndrome is a rare autoinflammatory disease caused by gain-of-function mutations or variants in the NLRP3 gene. Clinically, patients suffer from a broad spectrum of both systemic and neurological symptoms. The aim of this study was to determine whether systemic inflammation demonstrated by serum amyloid A (SAA) elevation is associated with neuroinflammation assessed by optical coherence tomography (OCT). Thirty eyes of 15 patients with NLRP3 low penetrance mutations (PwNLRP3) and 20 eyes of 10 age- and sex-matched healthy controls were examined by spectral-domain OCT as part of routine clinical care. All retinal layers and clinical features were evaluated. At baseline no significant retinal neuroaxonal inflammation or degeneration was observed in all measured retinal layers amongst PwNLRP3 compared with healthy controls. In a pooled analysis of all individual OCT time points a significant difference regarding the macular retinal nerve fibre layer was detected. Increased levels of SAA showed a positive association with averaged combined outer plexiform layer and outer nuclear layer volumes (ρ < 0.0001, r2 = 0.35). In cryopyrin-associated periodic syndrome increased combined outer plexiform layer and outer nuclear layer volumes are mirrored by SAA increase, an acute phase reactant indicating systemic inflammation. Our findings identify OCT as a candidate biomarker to monitor subclinical neuroinflammation and to assess disease activity in PwNLRP3.

Abstract PO5-08-03: Breastfeeding and Breast Cancer Screening Among Carriers of Pathogenic Variants in BRCA 1 and BRCA 2 and Other High Penetrance Genes: Knowledge and Perspectives

Abstract Objectives: Carriers of pathogenic variants in high penetrance mutations, including BRCA 1 or BRCA 2 face higher lifetime risks of developing breast and tubo-ovarian cancers, and possibly endometrial cancers, than non-carriers. In particular, relative risks are higher among carriers than non-carriers at younger ages, suggesting the value of early initiation of breast cancer screening and the use of sensitive imaging methods, such as magnetic resonance imaging (MRI). Further, breastfeeding appears protective for these three cancers in the general population, and potentially among mutation carriers, albeit based on limited evidence. Given that data related to knowledge and perspectives of carriers about these issues are limited, we surveyed mutation carriers regarding breastfeeding, cancer risk, and the deferral of breast cancer screening coinciding with reproductive events. These data may guide future cancer prevention research and developing of targeted communication campaigns. Methods: Researchers at Mayo Clinic, in collaboration with Facing Our Risk of Cancer Empowered (FORCE) – a large, national non-profit organization that addresses the needs of people and families affected by inherited mutations linked to cancer – designed and conducted a survey using the Mayo Clinic’s external RedCap system. The survey covered genetic testing and results, history of live births and breastfeeding history for mothers, history of risk-reducing surgery, personal cancer history, sources of information about cancer screening, breastfeeding knowledge, and breast cancer screening at various times, including during pregnancy, while breastfeeding, and after weaning. The survey was disseminated through FORCE’s electronic newsletter, website, social media pages, and advocacy partners. Survey responses were collected anonymously and analyzed descriptively using standard descriptive statistics, including frequency and percentages for categorical responses and means (SD) or medians (IQR) for continuously scaled responses. The open-ended responses were analyzed qualitatively using standard qualitative methodology. Results: Respondents included 253 women, of whom 88.7% were U.S. residents and 92.9% were white. The mean age + SD was 47(13) years, 61.7% were parous, with a mean age at first birth of 22.58 (13.16) years. Approximately 60% of women were carriers of mutations in BRCA1 or BRCA2 or both genes and all but two of the remaining women reported mutations in other genes linked to increased cancer risk. At the time of the survey, 92% of women had undergone a mammogram, with first screen at a mean age of 35 (6.49) years, and 85.3% had undergone breast MRI, with first screen at a mean age of 43 (12.39) years. Among 34.3% of participants, their 1st postpartum mammogram occurred &amp;gt;3 years after the birth of their last child and 57% had 1st MRI 3 years postpartum. Preliminarily, our analysis shows that nearly 90% of women were unaware of their mutation status prior to pregnancy and approximately 1/3 did not undergo radiologic screening until 3 years postpartum. While 62.6% of respondents believed that breastfeeding lowers breast cancer risk, 74.2% of participants responded that nursing had no effect on tubo-ovarian cancer risk, and 78.2% considered that nursing did not impact endometrial cancer risk. Discussion and Conclusions: Preliminarily, we conclude that most women in the surveyed population were unaware of their mutation status when pregnant years earlier and many had not undergone screening until years after delivery. Many participants did not consider breastfeeding a potentially protective factor for women’s cancers. These data raise issues about the potential value of discussing genetic testing with women when considering family planning and mutation carriers, addressing complex issues about breast cancer screening while pregnant and breastfeeding. Citation Format: Laura Pacheco-Spann, Mark Sherman, Susan Friedman, Diane Rose, Miriam Levi, Alex Hochwald, Jennifer Ridgeway, Sophia Blumenfeld. Breastfeeding and Breast Cancer Screening Among Carriers of Pathogenic Variants in BRCA 1 and BRCA 2 and Other High Penetrance Genes: Knowledge and Perspectives [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-08-03.

Expression- and splicing-based multi-tissue transcriptome-wide association studies identified multiple genes for breast cancer by estrogen-receptor status

BackgroundAlthough several transcriptome-wide association studies (TWASs) have been performed to identify genes associated with overall breast cancer (BC) risk, only a few TWAS have explored the differences in estrogen receptor-positive (ER+) and estrogen receptor-negative (ER-) breast cancer. Additionally, these studies were based on gene expression prediction models trained primarily in breast tissue, and they did not account for alternative splicing of genes.MethodsIn this study, we utilized two approaches to perform multi-tissue TWASs of breast cancer by ER subtype: (1) an expression-based TWAS that combined TWAS signals for each gene across multiple tissues and (2) a splicing-based TWAS that combined TWAS signals of all excised introns for each gene across tissues. To perform this TWAS, we utilized summary statistics for ER + BC from the Breast Cancer Association Consortium (BCAC) and for ER- BC from a meta-analysis of BCAC and the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA).ResultsIn total, we identified 230 genes in 86 loci that were associated with ER + BC and 66 genes in 29 loci that were associated with ER- BC at a Bonferroni threshold of significance. Of these genes, 2 genes associated with ER + BC at the 1q21.1 locus were located at least 1 Mb from published GWAS hits. For several well-studied tumor suppressor genes such as TP53 and CHEK2 which have historically been thought to impact BC risk through rare, penetrant mutations, we discovered that common variants, which modulate gene expression, may additionally contribute to ER + or ER- etiology.ConclusionsOur study comprehensively examined how differences in common variation contribute to molecular differences between ER + and ER- BC and introduces a novel, splicing-based framework that can be used in future TWAS studies.

Multi-tissue transcriptome-wide association studies identified 235 genes for intrinsic subtypes of breast cancer.

Although genome-wide association studies (GWAS) of breast cancer (BC) identified common variants which differ between intrinsic subtypes, genes through which these variants act to impact BC risk have not been fully established. Transcriptome-wide association studies (TWAS) have identified genes associated with overall BC risk, but subtype-specific differences are largely unknown. We performed two multi-tissue TWAS for each BC intrinsic subtype, including an expression-based approach that collated TWAS signals from expression quantitative trait loci (eQTLs) across multiple tissues and a novel splicing-based approach that collated signals from splicing QTLs (sQTLs) across intron clusters and subsequently across tissues. We used summary statistics for five intrinsic subtypes including Luminal A-like, Luminal B-like, Luminal B/HER2-negative-like, HER2-enriched-like, and triple-negative BC, generated from 106 278 BC cases and 91 477 controls in the Breast Cancer Association Consortium. Overall, we identified 235 genes in 88 loci that were associated with at least one of the five intrinsic subtypes. Most genes were subtype-specific, and many have not been reported in previous TWAS. We discovered common variants that modulate expression of CHEK2 confer increased risk to Luminal A-like BC, in contrast to the viewpoint that CHEK2 primarily harbors rare, penetrant mutations. Additionally, our splicing-based TWAS provided population-level support for MDM4 splice variants that increased the risk of triple-negative BC. Our comprehensive, multi-tissue TWAS corroborated previous GWAS loci for overall BC risk and intrinsic subtypes, while underscoring how common variation that impacts expression and splicing of genes in multiple tissue types can be used to further elucidate the etiology of BC.

Generation of a TMEM43 knockout human induced pluripotent stem cell line (HDZi003-A-1) using CRISPR/Cas9

TMEM43 (LUMA) is a ubiquitously expressed protein with unknown function. The protein is phylogenetically highly conserved and also found in Drosophila melanogaster (Klinke et al., 2022). TMEM43-p.S358L is a rare, fully penetrant mutation that leads to arrhythmogenic right ventricular cardiomyopathy type 5 (ARVC5). To understand the function of the ARVC5-associated mutation it is first important to understand the function of the TMEM43 protein. Therefore, a TMEM43 knockout induced pluripotent stem cell (iPSC) line was generated using the CRISPR/Cas9 genome editing system.The resulting cell line had a deficiency of TMEM43 and showed normal morphology and a stable karyotype. The colonies were positive for pluripotency markers and could be differentiated into the three germ layers.

A highly penetrant ACTA2 mutation of thoracic aortic disease

BackgroundThe role of ACTA2 mutations in Familial Aortic Disease has been increasingly recognized. We describe a highly penetrant variant (R118Q) in a family with aortic disease.Case reportA patient presented to us for elective repair of an ascending aortic aneurysm with a family history of his mother expiring after aortic dissection. Genetic testing revealed he was a heterozygous carrier of the ACTA2 missense mutation R118Q. Subsequently, all living family members were tested for this variant and a full medical history was obtained to compile a family tree for the variant and penetrance of an aortic event (defined as lifetime occurrence of aortic surgery / dissection). In total 9 family members were identified and underwent genetic testing with 7/9 showing presence of the ACTA2 R118Q mutation or an aortic event. All patients over the age of 50 (n = 4) had an aortic event. Those events occurred at ages 54, 55, 60, and 62 (mean event at 57.8 ± 3.9 years). Three family members with the variant under the age of 40 have not had an aortic event and most are undergoing regular aortic surveillance via CT scan.ConclusionsExisting studies of known ACTA2 mutations describe a 76% aortic event rate by 85 years old. The R118Q missense mutation is a less common ACTA2 variant, estimated to be found in about 5% of patients with known mutations. Prior studies have predicted the R118Q mutation to have a slightly decreased risk of aortic events compared to other ACTA2 mutations. In this family, however, we demonstrate 100% penetrance of aortic disease above age 50. In today’s era of excellent outcomes in elective aortic surgery, our team aggressively offers elective repair. We advocate for strict aortic surveillance for patients with this variant and would consider elective aortic replacement at 4.5 cm, or at an even smaller diameter in patients with a strong family history of dissection who are identified with this mutation.

Abstract 15426: Stress-Induced Transcriptomic Shift in Human iPSC-Derived Cardiomyocytes Carrying Hypertrophic Cardiomyopathy Associated MYH7 G256E Mutation

Introduction: Hypertrophic cardiomyopathy (HCM) is a monogenic disorder caused by heterozygous (HET) mutations in sarcomere genes such as MYH7. Recently, human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) carrying HET HCM mutations have shed new insights into the molecular mechanisms of HCM. However, it remains unclear whether the cellular phenotypes of low penetrant mutations such as MYH7 G256E and others, can be adequately elucidated. Hypothesis: We hypothesize that the incorporation of cellular stressors can enhance the manifestation of pathogenic HCM phenotypes in low penetrant MYH7 mutations. Methods: We generated HET and homozygous (HOM) hiPSC-lines for mutation G256E in the MYH7 locus, which is associated with HCM. We performed single-cell RNA sequencing (scRNAseq) with CellPlex technology on wildtype (WT), HET, and HOM iPSC-CMs at day 30 and 60 of cardiac differentiation to establish baseline cellular transcriptional phenotype. We then treated day 30 hiPSC-CMs with 1μM isoproterenol treatment for 5 days or glucose starvation for 10 days and performed scRNAseq to assess their transcriptional shift. Additional Digital Droplet PCR studies were performed to investigate the MYH7 mutant allele expression. Results: In day 30 iPSC-CMs we detected a large clone-to-clone and batch-to-batch variability transcriptionally that obscured the identification of a consistent mutant phenotype in HET MYH G256E vs WT hiPSC lines. These phenotypes correlated with a 1:1 ratio of mutant vs WT allele expression. Implementation of long-term culture or treatment with isoproterenol or glucose starvation led to enhanced hypertrophic and oxidative phosphorylation gene expression in HET hiPSC-CMs. Intriguingly, the expression of MYH6 increased in MYH7-mutant hiPSC-CMs. Conclusions: The application of cellular stressors can enhance the manifestation of hypertrophic phenotypes in HET MYH G256E hiPSC-CMs and suggests a potential mechanism for the variable penetrance of MYH7 mutations in HCM patients.

Familial Mediterranean fever and microRNAs.

Familial Mediterranean fever (FMF) is an inherited disorder caused by the gain of function mutations in MEFV (MEditerranean FeVer) gene loci. FMF affects more than 100,000 people worldwide and generally seen in the eastern Mediterranean region and causes the lifelong diseases which have a significant effect on the patient's life quality and health systems. The identification of low penetrant or heterozygous MEFV gene mutations in clinically diagnosed FMF patients was considered that epigenetic or environmental factors may display a role in FMF pathogenesis. Epigenetics might be defined as heritable changes that affect gene expression without any changes in the genome. MicroRNAs (miRNAs) are the main group of small noncoding RNAs, and an important element of epigenetic mechanisms and their discoveries revolutionized our knowledge about biological processes, such as malignant, infectious and autoimmune mechanisms, and contributed to the development of the epigenetic areas. In this review, the studies focusing on the roles of miRNAs in FMF pathogenesis in the last decades were examined and the importance of miRNAs as therapeutic agents which are promising for diagnosis and treatment was discussed.

The amyotrophic lateral sclerosis exposome: recent advances and future directions.

Amyotrophic lateral sclerosis (ALS) is a fatal disease of motor neuron degeneration with typical survival of only 2-5 years from diagnosis. The causes of ALS are multifactorial: known genetic mutations account for only around 70% of cases of familial ALS and 15% of sporadic cases, and heritability estimates range from 8% to 61%, indicating additional causes beyond genetics. Consequently, interest has grown in environmental contributions to ALS risk and progression. The gene-time-environment hypothesis posits that ALS onset occurs through an interaction of genes with environmental exposures during ageing. An alternative hypothesis, the multistep model of ALS, suggests that several hits, at least some of which could be environmental, are required to trigger disease onset, even in the presence of highly penetrant ALS-associated mutations. Studies have sought to characterize the ALS exposome - the lifetime accumulation of environmental exposures that increase disease risk and affect progression. Identifying the full scope of environmental toxicants that enhance ALS risk raises the prospect of preventingdisease by eliminating or mitigating exposures. In this Review, we summarize the evidence for an ALS exposome, discussing the strengths and limitations of epidemiological studies that have identified contributions from various sources. We also consider potential mechanisms of exposure-mediated toxicity and suggest future directions for ALS exposome research.

Genetic and ultrasonographic analyses of fetuses with 1q21.1q21.2 microdeletion/microduplication: a retrospective study

Background1q21.1q21.2 microdeletions/microduplications are rare and incompletely penetrant genetic mutations, and only a few reports regarding their prenatal diagnosis are currently available. Here, we analyzed the ultrasonographic phenotypic characteristics of fetuses with these mutations to improve the understanding, diagnosis, and screening of these mutations during gestation.MethodsWe retrospectively analyzed 8700 cases of pregnant women who underwent invasive prenatal screening by karyotyping and chromosomal microarray analysis (CMA) between November 2016 and November 2021.ResultsCMA revealed copy number changes in the 1q21.1q21.2 region of eleven fetuses, of which five had microdeletions and six had microduplications. These eleven fetuses exhibited variable ultrasonographic phenotypes. Of the five fetuses with the microdeletion, one exhibited a right-dominant heart, permanent right umbilical vein, and mild tricuspid regurgitation, another showed thickened nuchal translucency, and the remaining three had normal ultrasound phenotypes. Two of the six cases with 1q21.1q21.2 microduplication had structural malformations; one of them had a bilateral subependymal cyst, neck mass, and enlarged cardiothoracic ratio, while the other had right ventricular hypoplasia. Of the remaining four cases, two exhibited nasal bone dysplasia, one showed measurement slower than that during menopause and mild tricuspid regurgitation, and another did not show any notable abnormality in ultrasound examination. Among the eleven cases of 1q21.1q21.2 microdeletion/microduplication, only the parents of two fetuses underwent pedigree verification. The parents of these two fetuses with 1q21.1q21.2 microdeletion syndrome chose to continue the pregnancy, and all aspects of postnatal follow-up were normal. The parents of the other nine fetuses refused pedigree verification; of these cases, four cases terminated, and five cases continued the pregnancies. The five continued pregnancies were followed up after birth; no abnormalities were found.ConclusionsFetuses with 1q21.1q21.2 microdeletion/microduplication show different ultrasound characteristics and may have congenital heart disease, thickened nuchal translucency, and nasal bone dysplasia or show no notable abnormalities in an ultrasound examination. Our study highlights that CMA as a powerful diagnostic tool for these diseases can provide an accurate genetic diagnosis, while improving prenatal diagnosis standards.

Hereditary predisposition to kidney cancer: cancer syndromes, multisystemic disorders, and nephropathies

Kidney cancer (KC) is a common disease characterized by extreme heterogeneity. There are nine known monogenic diseases associated with a significantly elevated KC risk: von Hippel-Lindau disease, MET-associated papillary renal cancer, familial multiple leiomyomatosis and renal cell cancer, SDHx-associated familial pheochromocytoma/ paraganglioma, Birt-Hogg-Dube syndrome, tuberous sclerosis, Cowden syndrome, BAP1- and MITF-associated melanoma-KC predisposition. These syndromes differ in the degree of cancer risk, the quantity, growth and progression rates of associated precancerous lesions, the morphology, and clinical presentations of malignancy itself, and in the response to therapy. Identification of causative germline lesion allows planning the surveillance of a mutation carrier, choosing the right time and extent of surgery, and optimizing treatment regimen. Hereditary KC research often brings forward novel approaches to the management of sporadic “phenocopies” of hereditary syndromes, i.e. sporadic cancers with somatic mutations in similar genes. The main directions for further study of genetic factors of KC are to find novel KC genes, to study risk modifiers in carriers of highly penetrant mutations, to clarify the involvement of hereditary nephropathies in the occurrence of renal cancers.

Ex Vivo Chromosomal Radiosensitivity Testing in Patients with Pathological Germline Variants in Breast Cancer High-Susceptibility Genes BReast CAncer 1 and BReast CAncer 2.

Individual radiosensitivity is an important factor in the occurrence of undesirable consequences of radiotherapy. The potential for increased radiosensitivity has been linked to highly penetrant heterozygous mutations in DNA repair genes such as BRCA1 and BRCA2. By studying the chromosomal radiosensitivity of BRCA1/2 mutation carriers compared to the general population, we study whether increased chromosomal radiation sensitivity is observed in patients with BRCA1/2 variants. Three-color-fluorescence in situ hybridization was performed on ex vivo-irradiated peripheral blood lymphocytes from 64 female patients with a heterozygous germline BRCA1 or BRCA2 mutation. Aberrations in chromosomes #1, #2 and #4 were analyzed. Mean breaks per metaphase (B/M) served as the parameter for chromosomal radiosensitivity. The results were compared with chromosomal radiosensitivity in a cohort of generally healthy individuals and patients with rectal cancer or breast cancer. Patients with BRCA1/2 mutations (n = 64; B/M 0.47) overall showed a significantly higher chromosomal radiosensitivity than general healthy individuals (n = 211; B/M 0.41) and patients with rectal cancer (n = 379; B/M 0.44) and breast cancer (n = 147; B/M 0.45) without proven germline mutations. Chromosomal radiosensitivity varied depending on the locus of the BRCA1/2 mutation. BRCA1/2 mutations result in slightly increased chromosomal sensitivity to radiation. A few individual patients have a marked increase in radiation sensitivity. Therefore, these patients are at a higher risk for adverse therapeutic consequences.

Challenges of Diagnosing Mendelian Susceptibility to Mycobacterial Diseases in South Africa.

Inborn errors of immunity (IEI) are genetic disorders with extensive clinical presentations. They can range from increased susceptibility to infections to significant immune dysregulation that results in immune impairment. While IEI cases are individually rare, they collectively represent a significant burden of disease, especially in developing countries such as South Africa, where infectious diseases like tuberculosis (TB) are endemic. This is particularly alarming considering that certain high penetrance mutations that cause IEI, such as Mendelian Susceptibility to Mycobacterial Disease (MSMD), put individuals at higher risk for developing TB and other mycobacterial diseases. MSMD patients in South Africa often present with different clinical phenotypes than those from the developed world, therefore complicating the identification of disease-associated variants in this setting with a high burden of infectious diseases. The lack of available data, limited resources, as well as variability in clinical phenotype are the reasons many MSMD cases remain undetected or misdiagnosed. This article highlights the challenges in diagnosing MSMD in South Africa and proposes the use of transcriptomic analysis as a means of potentially identifying dysregulated pathways in affected African populations.

Detection of germline variants with pathogenic potential in 48 patients with familial colorectal cancer by using whole exome sequencing

BackgroundHereditary genetic mutations causing predisposition to colorectal cancer are accountable for approximately 30% of all colorectal cancer cases. However, only a small fraction of these are high penetrant mutations occurring in DNA mismatch repair genes, causing one of several types of familial colorectal cancer (CRC) syndromes. Most of the mutations are low-penetrant variants, contributing to an increased risk of familial colorectal cancer, and they are often found in additional genes and pathways not previously associated with CRC. The aim of this study was to identify such variants, both high-penetrant and low-penetrant ones.MethodsWe performed whole exome sequencing on constitutional DNA extracted from blood of 48 patients suspected of familial colorectal cancer and used multiple in silico prediction tools and available literature-based evidence to detect and investigate genetic variants.ResultsWe identified several causative and some potentially causative germline variants in genes known for their association with colorectal cancer. In addition, we identified several variants in genes not typically included in relevant gene panels for colorectal cancer, including CFTR, PABPC1 and TYRO3, which may be associated with an increased risk for cancer.ConclusionsIdentification of variants in additional genes that potentially can be associated with familial colorectal cancer indicates a larger genetic spectrum of this disease, not limited only to mismatch repair genes. Usage of multiple in silico tools based on different methods and combined through a consensus approach increases the sensitivity of predictions and narrows down a large list of variants to the ones that are most likely to be significant.