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Breast cancer is the most frequent cancer in women and represents the second leading cause of cancer death among women (after lung cancer). The etiology of breast cancer is still poorly understood with known breast cancer risk factors explaining only a small proportion of cases. Risk factors that modulate the development of breast cancer discussed in this review include: age, geographic location (country of origin) and socioeconomic status, reproductive events, exogenous hormones, lifestyle risk factors (alcohol, diet, obesity and physical activity), familial history of breast cancer, mammographic density, history of benign breast disease, ionizing radiation, bone density, height, IGF‐1 and prolactin levels, chemopreventive agents. Additionally, we summarized breast cancer risk associated with the following genetic factors: breast cancer susceptibility high‐penetrance genes (BRCA1, BRCA2, p53, PTEN, ATM, NBS1 or LKB1) and low‐penetrance genes such as cytochrome P450 genes (CYP1A1, CYP2D6, CYP19), glutathione S‐transferase family (GSTM1, GSTP1), alcohol and one‐carbon metabolism genes (ADH1C and MTHFR), DNA repair genes (XRCC1, XRCC3, ERCC4/XPF) and genes encoding cell signaling molecules (PR, ER, TNFα or HSP70). All these factors contribute to a better understanding of breast cancer risk. Nonetheless, in order to evaluate more accurately the overall risk of breast tumorigenesis, novel genetic and phenotypic traits need to be identified.

Purpose: The aim of this study was to determine the clinical and molecular characteristics of 2,079 patients who underwent hereditary cancer multigene panel testing. Methods: Panels included comprehensive analysis of 14–22 cancer susceptibility genes ( BRCA1 and BRCA2 not included), depending on the panel ordered (BreastNext, OvaNext, ColoNext, or CancerNext). Next-generation sequencing and deletion/duplication analyses were performed for all genes except EPCAM (deletion/duplication analysis only). Clinical histories of ColoNext patients harboring mutations in genes with well-established diagnostic criteria were assessed to determine whether diagnostic/testing criteria were met. Results: Positive rates were defined as the proportion of patients with a pathogenic mutation/likely pathogenic variant(s) and were as follows: 7.4% for BreastNext, 7.2% for OvaNext, 9.2% for ColoNext, and 9.6% for CancerNext. Inconclusive results were found in 19.8% of BreastNext, 25.6% of OvaNext, 15.1% of ColoNext, and 23.5% of CancerNext tests. Based on information submitted by clinicians, 30% of ColoNext patients with mutations in genes with well-established diagnostic criteria did not meet corresponding criteria. Conclusion: Our data point to an important role for targeted multigene panels in diagnosing hereditary cancer predisposition, particularly for patients with clinical histories spanning several possible diagnoses and for patients with suspicious clinical histories not meeting diagnostic criteria for a specific hereditary cancer syndrome. Genet Med 16 11, 830–837.

Spinocerebellar ataxia type 8 (SCA8), a dominantly inherited neurodegenerative disorder caused by a CTG•CAG expansion, is unusual because most individuals that carry the mutation do not develop ataxia. To understand the variable penetrance of SCA8, we studied the molecular differences between highly penetrant families and more common sporadic cases (82%) using a large cohort of SCA8 families ( n  = 77). We show that repeat expansion mutations from individuals with multiple affected family members have CCG•CGG interruptions at a higher frequency than sporadic SCA8 cases and that the number of CCG•CGG interruptions correlates with age at onset. At the molecular level, CCG•CGG interruptions increase RNA hairpin stability, and in cell culture experiments, increase p‐eIF2α and polyAla and polySer RAN protein levels. Additionally, CCG•CGG interruptions, which encode arginine interruptions in the polyGln frame, increase toxicity of the resulting proteins. In summary, SCA8 CCG•CGG interruptions increase polyAla and polySer RAN protein levels, polyGln protein toxicity, and disease penetrance and provide novel insight into the molecular differences between SCA8 families with high vs. low disease penetrance. SYNOPSIS This study shows CCG•CGG interruptions within the ATXN8OS/ATXN8 CTG•CAG repeat are an important genetic modifier of disease penetrance in spinocerebellar ataxia type 8 (SCA8). CCG CGG interruptions in the ATXN8OS/ATXN8 CTG•CAG repeat expansion are more frequent in families with multiple affected individuals. The number of CCG•CGG interruptions, and not repeat length, correlates with age of onset in SCA8. CGG interrupted ATXN8 repeat expansions are more toxic to cells than pure ATXN8 repeat expansions. CGG interruptions increase RNA stability, p‐eIF2α levels and the levels of toxic polyAla and polySer repeat‐associated non‐AUG (RAN) proteins. Arginine‐interrupted polyGln expansion proteins expressed from CGG interrupted expansions are more toxic than pure polyGln expansion proteins. Graphical Abstract This study shows CCG•CGG interruptions within the ATXN8OS/ATXN8 CTG•CAG repeat are an important genetic modifier of disease penetrance in spinocerebellar ataxia type 8 (SCA8).

Premature fusion of the cranial sutures (craniosynostosis), affecting 1 in 2000 newborns, is treated surgically in infancy to prevent adverse neurologic outcomes. To identify mutations contributing to common non-syndromic midline (sagittal and metopic) craniosynostosis, we performed exome sequencing of 132 parent-offspring trios and 59 additional probands. Thirteen probands (7%) had damaging de novo or rare transmitted mutations in SMAD6, an inhibitor of BMP – induced osteoblast differentiation (p<10−20). SMAD6 mutations nonetheless showed striking incomplete penetrance (<60%). Genotypes of a common variant near BMP2 that is strongly associated with midline craniosynostosis explained nearly all the phenotypic variation in these kindreds, with highly significant evidence of genetic interaction between these loci via both association and analysis of linkage. This epistatic interaction of rare and common variants defines the most frequent cause of midline craniosynostosis and has implications for the genetic basis of other diseases. The bones in the front, back and sides of the human skull are not fused to one another at birth in order to allow the brain to double in size during the first year of life and continue growing into adulthood. However, one in 2,000 infants is born with a condition called craniosynostosis in which some of these bones have already fused. This fusion prevents the skull from growing properly, and can lead to the brain becoming compressed. As such, surgeons routinely undo the fusion in these infants to allow the brain and skull to grow normally. Eighty-five percent of craniosynostosis cases occur in infants with no other abnormalities, (called non-syndromic cases) and most have no other affected family member. It has therefore been unclear whether these infants have craniosynostosis due to a genetic or non-genetic cause. If the cause is genetic, it is also not clear whether a mutation in a single gene, the combined effects of many genes, or something in between is responsible. Now, by focusing on a group of 191 infants with premature fusion of bones joined at the midline of the skull, Timberlake et al. asked if any of the approximately 20,000 genes in the human genome were altered more frequently in these infants than would be expected by chance. This search revealed that rare mutations that disable one copy of a gene called SMAD6 in combination with a common DNA variant near another gene called BMP2 account for about 7% of infants with midline forms of craniosynostosis. These genes are both known to regulate how bones form, which explains how the mutation of these genes could lead to craniosynostosis. In all cases, the parents of these children were unaffected. This was typically because one parent had only the SMAD6 mutation while the other had only the common BMP2 variant; the transmission of both to their offspring resulted in craniosynostosis. The finding that a rare mutation’s effect is strongly modified by a common variant from another site in the genome is unprecedented. These findings will allow doctors to counsel families about the risk of having additional children with craniosynostosis. Timberlake et al. next plan to study more patients with craniosynostosis to identify additional genes that contribute to this disease. They will also look at other diseases to see whether the combination of rare mutation and common DNA variant could be behind other unexplained disorders.

Purpose In some Huntington disease (HD) patients, the “loss of interruption” (LOI) variant eliminates an interrupting codon in the HTT CAG-repeat tract, which causes earlier age of onset (AOO). The magnitude of this effect is uncertain, since previous studies included few LOI carriers, and the variant also causes CAG size misestimation. We developed a rapid LOI detection screen, enabling unbiased frequency estimation among manifest HD patients. Additionally, we combined published data with clinical data from newly identified patients to accurately characterize the LOI’s effect on AOO. Methods We developed a LOI detection polymerase chain reaction (PCR) assay, and screened patients to estimate the frequency of the LOI variant and its effect on AOO. Results Mean onset for LOI carriers ( n  = 49) is 20.4 years earlier than expected based on diagnosed CAG size. After correcting for CAG size underestimation, the variant is still associated with onset 9.5 years earlier. The LOI is present in 1.02% of symptomatic HD patients, and in 32.2% of symptomatic reduced penetrance (RP) range patients (36–39 CAGs). Conclusion The LOI causes significantly earlier onset, greater than expected by CAG length, particularly in persons with 36–39 CAG repeats. Detection of this variant has implications for HD families, especially for those in the RP range.

IntroductionPredictive genetic testing allows the identification of at-risk first-degree relatives of patients with genetic cardiomyopathies. Data on the penetrance of genetic variants associated with cardiomyopathies is limited. The aim of this study was to investigate disease penetrance in asymptomatic carriers of familial cardiomyopathy variants associated with hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM) and arrhythmogenic right ventricular cardiomyopathy (ARVC).MethodsWe included asymptomatic individuals referred to the Royal Brompton Hospital for predictive testing after the finding of a pathogenic or likely pathogenic genetic variant in a first-degree relative with cardiomyopathy between January 2017 and December 2019. Cardiomyopathy diagnosis was defined by international guidelines. Those with a prior diagnosis or signs or symptoms of heart disease at the time of testing were excluded.Results:A total of 105 genotype-positive individuals from 80 families were evaluated (median age 24.9 years [interquartile range: 16.1 to 45.0 years], 51 [48.6%] males). Variants in genes associated with DCM included: TTN n = 16 (51.6%), MYH7 n = 5 (16.1%), LMNA n = 3 (9.7%), TNNI3 n = 3 (9.7%), RBM20 n = 2 (6.5%), BAG3 n = 1 (3.2%), DMD n = 1 (3.2%); variants in genes associated with HCM included: MYBPC3 n = 31 (47.7%), MYH7 n = 25 (38.5%), TPM1 n = 5 (7.7%), PLN n = 1 (1.5%), TNNC1 n = 1 (1.5%), TNNI3 n = 1 (1.5%), TNNT2 n = 1 (1.5%); and variants in genes associated with ARVC included: PKP2 n = 4 (44.4%), DSP n = 4 (44.4%), FLNC n = 1 (11.1%). On first clinical evaluation 2 of 31 carriers of DCM variants were diagnosed with DCM, 5 with hypokinetic non-dilated cardiomyopathy (HNDC) and 4 with isolated left ventricular (LV) dilatation; 10 of 65 carriers of HCM variants were diagnosed with HCM; and 0 of 9 carriers of ARVC variants were diagnosed with ARVC. Over a median follow-up of 2.4 years (interquartile range: 1.0 to 4.3 years) an additional 13 of 84 carriers developed cardiomyopathy phenotypes (0 of 20 DCM, 3 of 20 HNDC, 3 of 20 isolated LV dilatation, 7 of 55 HCM, 0 of 9 ARVC). Furthermore, 2 individuals with DCM/HCM received implantable cardioverter defibrillators and 2 individuals with DCM/HCM received implantable loop recorders.ConclusionsApproximately one-third of asymptomatic carriers of familial cardiomyopathy variants were diagnosed with a cardiomyopathy phenotype at initial screen or during a short follow-up period. This confirms the importance of predictive testing and the need for follow-up of genotype-positive, phenotype-negative individuals.Conflict of InterestNone

Genetic variation can predispose to disease both through (i) monogenic risk variants that disrupt a physiologic pathway with large effect on disease and (ii) polygenic risk that involves many variants of small effect in different pathways. Few studies have explored the interplay between monogenic and polygenic risk. Here, we study 80,928 individuals to examine whether polygenic background can modify penetrance of disease in tier 1 genomic conditions — familial hypercholesterolemia, hereditary breast and ovarian cancer, and Lynch syndrome. Among carriers of a monogenic risk variant, we estimate substantial gradients in disease risk based on polygenic background — the probability of disease by age 75 years ranged from 17% to 78% for coronary artery disease, 13% to 76% for breast cancer, and 11% to 80% for colon cancer. We propose that accounting for polygenic background is likely to increase accuracy of risk estimation for individuals who inherit a monogenic risk variant. Genetic variation predisposes to disease via monogenic and polygenic risk variants. Here, the authors assess the interplay between these types of variation on disease penetrance in 80,928 individuals. In carriers of monogenic variants, they show that disease risk is a gradient influenced by polygenic background.

De novo mutations in protein-coding genes are a well-established cause of developmental disorders 1 . However, genes known to be associated with developmental disorders account for only a minority of the observed excess of such de novo mutations 1 , 2 . Here, to identify previously undescribed genes associated with developmental disorders, we integrate healthcare and research exome-sequence data from 31,058 parent–offspring trios of individuals with developmental disorders, and develop a simulation-based statistical test to identify gene-specific enrichment of de novo mutations. We identified 285 genes that were significantly associated with developmental disorders, including 28 that had not previously been robustly associated with developmental disorders. Although we detected more genes associated with developmental disorders, much of the excess of de novo mutations in protein-coding genes remains unaccounted for. Modelling suggests that more than 1,000 genes associated with developmental disorders have not yet been described, many of which are likely to be less penetrant than the currently known genes. Research access to clinical diagnostic datasets will be critical for completing the map of genes associated with developmental disorders. By integrating healthcare and exome-sequencing data from parent–offspring trios of patients with developmental disorders, 28 genes that had not previously been associated with developmental disorders were identified.

Purpose Pathogenic variants affecting MLH1 , MSH2 , MSH6 , and PMS2 cause Lynch syndrome and result in different but imprecisely known cancer risks. This study aimed to provide age and organ-specific cancer risks according to gene and gender and to determine survival after cancer. Methods We conducted an international, multicenter prospective observational study using independent test and validation cohorts of carriers of class 4 or class 5 variants. After validation the cohorts were merged providing 6350 participants and 51,646 follow-up years. Results There were 1808 prospectively observed cancers. Pathogenic MLH1 and MSH2 variants caused high penetrance dominant cancer syndromes sharing similar colorectal, endometrial, and ovarian cancer risks, but older MSH2 carriers had higher risk of cancers of the upper urinary tract, upper gastrointestinal tract, brain, and particularly prostate. Pathogenic MSH6 variants caused a sex-limited trait with high endometrial cancer risk but only modestly increased colorectal cancer risk in both genders. We did not demonstrate a significantly increased cancer risk in carriers of pathogenic PMS2 variants. Ten-year crude survival was over 80% following colon, endometrial, or ovarian cancer. Conclusion Management guidelines for Lynch syndrome may require revision in light of these different gene and gender-specific risks and the good prognosis for the most commonly associated cancers.

This review gives an account of the molecular mechanisms that underlie various forms of inherited cardiomyopathies. Numerous, rare mutations occur in each category, and different mutations in the same genes can produce different phenotypes. Inherited cardiomyopathies are a major cause of heart disease in all age groups, often with an onset in adolescence or early adult life. Not only the patients but also their families can be severely burdened by these illnesses. More than 20 years ago, the first “disease gene” for hypertrophic cardiomyopathy was identified. 1 , 2 This finding led to the concept that hypertrophic cardiomyopathy is a disease of the sarcomere. 3 Similar advances in the elucidation of the genetic basis of other forms of cardiomyopathy, as well as in other inherited cardiovascular diseases, soon followed. The identification of disease genes in numerous inherited . . .