Uterine leiomyomas (ULs) constitute a considerable health burden in the general female population. The fumarate hydratase (FH) deficient subtype is found in up to 1.6% and can occur in hereditary ...leiomyomatosis and renal cell carcinoma (HLRCC) syndrome. We sequenced 13 FH deficient ULs from a previous immunohistochemical screen using a targeted panel and identified biallelic FH variants in all. In eight, we found an FH point mutation (two truncating, six missense) with evidence for loss of the second allele. Variant allele-frequencies in all cases with a point mutation pointed to somatic variants. Spatial clustering of the identified missense variants in the lyase domain indicated altered fumarase oligomerization with subsequent degradation as explanation for the observed FH deficiency. Biallelic FH deletions in five tumors confirm the importance of copy number loss as mutational mechanism. By curating all pathogenic FH variants and calculating their population frequency, we estimate a carrier frequency of up to 1/2,563. Comparing with the prevalence of FH deficient ULs, we conclude that most are sporadic and estimate 2.7–13.9% of females with an FH deficient UL to carry a germline FH variant. Further prospective tumor/normal sequencing studies are needed to develop a reliable screening strategy for HLRCC in women with ULs.
An increasing number of genes involved in chromatin structure and epigenetic regulation has been implicated in a variety of developmental disorders, often including intellectual disability. By trio ...exome sequencing and subsequent mutational screening we now identified two de novo frameshift mutations and one de novo missense mutation in CTCF in individuals with intellectual disability, microcephaly, and growth retardation. Furthermore, an individual with a larger deletion including CTCF was identified. CTCF (CCCTC-binding factor) is one of the most important chromatin organizers in vertebrates and is involved in various chromatin regulation processes such as higher order of chromatin organization, enhancer function, and maintenance of three-dimensional chromatin structure. Transcriptome analyses in all three individuals with point mutations revealed deregulation of genes involved in signal transduction and emphasized the role of CTCF in enhancer-driven expression of genes. Our findings indicate that haploinsufficiency of CTCF affects genomic interaction of enhancers and their regulated gene promoters that drive developmental processes and cognition.
Two percent of patients with Wilms tumors have a positive family history. In many of these cases the genetic cause remains unresolved. By applying germline exome sequencing in two families with two ...affected individuals with Wilms tumors, we identified truncating mutations in TRIM28. Subsequent mutational screening of germline and tumor DNA of 269 children affected by Wilms tumor was performed, and revealed seven additional individuals with germline truncating mutations, and one individual with a somatic truncating mutation in TRIM28. TRIM28 encodes a complex scaffold protein involved in many different processes, including gene silencing, DNA repair and maintenance of genomic integrity. Expression studies on mRNA and protein level showed reduction of TRIM28, confirming a loss‐of‐function effect of the mutations identified. The tumors showed an epithelial‐type histology that stained negative for TRIM28 by immunohistochemistry. The tumors were bilateral in six patients, and 10/11 tumors are accompanied by perilobar nephrogenic rests. Exome sequencing on eight tumor DNA samples from six individuals showed loss‐of‐heterozygosity (LOH) of the TRIM28‐locus by mitotic recombination in seven tumors, suggesting that TRIM28 functions as a tumor suppressor gene in Wilms tumor development. Additionally, the tumors showed very few mutations in known Wilms tumor driver genes, suggesting that loss of TRIM28 is the main driver of tumorigenesis. In conclusion, we identified heterozygous germline truncating mutations in TRIM28 in 11 children with mainly epithelial‐type Wilms tumors, which become homozygous in tumor tissue. These data establish TRIM28 as a novel Wilms tumor predisposition gene, acting as a tumor suppressor gene by LOH.
What's new?
About 2% of Wilms tumors run in families, and some of the mutations remain unknown. These authors identified a new Wilms tumor mutation, a truncation on the TRIM28 gene. They started by performing exome sequencing on tumors in pairs of affected children from 2 families. In these 4 patients, they found mutations in TRIM28, which encodes a scaffold protein involved in DNA repair and genome stability. They then screened a cohort of 269 cases and found 8 more patients bearing TRIM28 loss‐of‐function mutations. The gene appears to function as a tumor suppressor with loss of heterozygosity in the tumor cells.
Parkinson’s disease (PD) is a progressive neurological disorder and appears to have gender-specific symptoms. Studies have observed a higher frequency for development of PD in male than in female. In ...the current study, we evaluated the gender-based changes in cortical thickness and structural connectivity in PD patients. With informed consent, 64 PD (43 males and 21 females) patients, and 46 (12 males and 34 females) age-matched controls underwent clinical assessment including Mini-Mental State Examination (MMSE) and magnetic resonance imaging on a 1.5 Tesla clinical MR scanner. Whole brain high-resolution T1-weighted images were acquired from all subjects and used to measure cortical thickness and structural network connectivity. No significant difference in MMSE score was observed between male and female both in control and PD subjects. Male PD patients showed significantly reduced cortical thickness in multiple brain regions including frontal, parietal, temporal, and occipital lobes as compared with those in female PD patients. The graph theory-based network analysis depicted lower connection strengths, lower clustering coefficients, and altered network hubs in PD male than in PD female. Male-specific cortical thickness changes and altered connectivity in PD patients may derive from behavioral, physiological, environmental, and genetical differences between male and female, and may have significant implications in diagnosing and treating PD among genders.
Breast cancer is the most common cancer in women. 12-15% of all tumors are triple-negative breast cancers (TNBC). So far, TNBC has been mainly associated with mutations in BRCA1. The presence of ...other predisposing genes seems likely since DNA damage repair is a complex process that involves several genes. Therefore we investigated if mutations in other genes are involved in cancer development and whether TNBC is an additional indicator of mutational status besides family history and age of onset.
We performed a germline panel-based screening of 10 high and low-moderate penetrance breast cancer susceptibility genes (BRCA1, BRCA2, ATM, CDH1, CHEK2, NBN, PALB2, RAD51C, RAD51D and TP53) in 229 consecutive individuals affected with TNBC unselected for age, family history or bilateral disease. Within this cohort we compared the number of mutation carriers fulfilling clinical selection criteria with the total number of carriers identified.
Age at diagnosis ranged from 23 to 80 years with an average age of 50.2 years. In 57 women (24.9%) we detected a pathogenic mutation, with a higher frequency (29.7%) in the group manifesting cancer before 60 years. Deleterious BRCA1 mutations occurred in 14.8% of TNBC patients. These were predominantly recurrent frameshift mutations (24/34, 70.6%). Deleterious BRCA2 mutations occurred in 5.7% of patients, all but one (c.1813dupA) being unique. While no mutations were found in CDH1 and TP53, 10 mutations were detected in one of the six other predisposition genes. Remarkably, neither of the ATM, RAD51D, CHEK2 and PALB2 mutation carriers had a family history. Furthermore, patients with non-BRCA1/2 mutations were not significantly younger than mutation negative women (p = 0.3341). Most importantly, among the 57 mutation carriers, ten (17.5%) would be missed using current clinical testing criteria including five (8%) with BRCA1/2 mutations.
In summary, our data confirm and expand previous studies of a high frequency of germline mutations in genes associated with ineffective repair of DNA damage in women with TNBCs. Neither age of onset, contralateral disease nor family history were able to discern all mutation positive individuals. Therefore, TNBC should be considered as an additional criterion for panel based genetic testing.
Biallelic variants in the AEBP1 gene cause a novel autosomal-recessive connective tissue disorder (CTD) reminiscent of Ehlers-Danlos Syndrome (EDS). The four previously reported individuals show ...considerable clinical variability. Unbiased high-throughput sequencing enables the rapid identification of additional cases for such rare entities. We identified the homozygous nonsense variant c.917dup, p.Tyr306* in AEBP1 using clinical exome sequencing in a female individual with previously unsolved CTD. Segregation testing confirmed homozygosity in the clinically affected brother and heterozygous carrier status in the healthy mother. Chromosomal microarray showed that the variant lies in a run of homozygosity, suggesting a common origin of this genomic segment. RT-PCR analysis in the mother revealed a monoallelic expression of the normal transcript supporting a nonsense-mediated mRNA decay and functional nullizygosity as disease mechanism. We describe two individuals from a fourth family with AEBP1-associated CTD. Our results further verify that autosomal-recessive inherited LOF variants in the AEBP1 gene cause clinical features of different EDS subtypes, but also of the marfanoid spectrum. As identification of further individuals is necessary to inform the clinical characterization, we stress the added value of exome sequencing for such rare diseases.
Abstract
Background
BRCA1/2
deleterious variants account for most of the hereditary breast and ovarian cancer cases. Prediction models and guidelines for the assessment of genetic risk rely heavily ...on criteria with high variability such as family cancer history. Here we investigated the efficacy of MRI (magnetic resonance imaging) texture features as a predictor for
BRCA
mutation status.
Methods
A total of 41 female breast cancer individuals at high genetic risk, sixteen with a
BRCA1/2
pathogenic variant and twenty five controls were included. From each MRI 4225 computer-extracted voxels were analyzed. Non-imaging features including clinical, family cancer history variables and triple negative receptor status (TNBC) were complementarily used. Lasso-principal component regression (L-PCR) analysis was implemented to compare the predictive performance, assessed as area under the curve (AUC), when imaging features were used, and lasso logistic regression or conventional logistic regression for the remaining analyses.
Results
Lasso-selected imaging principal components showed the highest predictive value (AUC 0.86), surpassing family cancer history. Clinical variables comprising age at disease onset and bilateral breast cancer yielded a relatively poor AUC (~ 0.56). Combination of imaging with the non-imaging variables led to an improvement of predictive performance in all analyses, with TNBC along with the imaging components yielding the highest AUC (0.94). Replacing family history variables with imaging components yielded an improvement of classification performance of ~ 4%, suggesting that imaging compensates the predictive information arising from family cancer structure.
Conclusions
The L-PCR model uncovered evidence for the utility of MRI texture features in distinguishing between
BRCA1/2
positive and negative high-risk breast cancer individuals, which may suggest value to diagnostic routine. Integration of computer-extracted texture analysis from MRI modalities in prediction models and inclusion criteria might play a role in reducing false positives or missed cases especially when established risk variables such as family history are missing.
The American Association for the Surgery of Trauma (AAST) has proposed a grading system for anatomic severity of 16 Emergency General Surgery conditions, including appendicitis. This is the first ...prospective, multicenter clinical study evaluating the AAST Appendicitis grading scale.
The EAST Appendicitis study utilized data collected prospectively from 27 centers, between January 2017 to June 2018. An overall grade was assigned as the highest grade of the subscales: clinical, radiographic, operative, and pathologic. Grade 1-3 of the clinical subscale was assigned as Grade 1. Patients with a final diagnosis other than appendicitis were excluded. The cohort was divided into two groups: simple appendicitis (Grades 1 and 2), and complicated appendicitis (Grades 3, 4, and 5).Fisher's exact and Kruskal-Wallis tests were used to determine association between the overall AAST grade and the following outcomes: infectious complications, Clavien-Dindo complications, hospital length of stay (LOS), 30-day emergency department visits, readmissions, and secondary interventions.
A total of 2,909 cases were analyzed: 1,656 (57%) were Grade 1; 181 (6%), Grade 2; 399 (14%) Grade 4; and 549 (19%) Grade 5; 94% of patients underwent appendectomy. Index hospitalization LOS increased significantly with increasing grade: 1, 1,1, 1 1,2, 1 1,2, 2 1,3, and 32,5 (p < 0.001). Infectious complications, Clavien-Dindo complications, hospital LOS, and secondary interventions were significantly associated with increasing AAST severity grade during index hospitalization. For 30-day outcomes, similar trends were noted for readmission, 30-day infections complications, 30-day cumulative infectious complications, 30-day Clavien-Dindo complications, 30-day cumulative Clavien-Dindo complications, 30-day secondary interventions, and 30-day cumulative secondary interventions.
The AAST emergency general surgery grade for appendicitis is a valid predictor of clinical outcomes such as infectious complications, overall complications, and the need for secondary intervention.
Prognostic, level III.
CTNND2 encodes δ‐catenin, a component of an adherens junction complex, and plays an important role in neuronal structure and function. To date, only heterozygous loss‐of‐function CTNND2 variants have ...been associated with mild neurodevelopmental delay and behavioral anomalies, a condition, which we named Rauch‐Azzarello syndrome. Here, we report three siblings of a consanguineous family of Syrian descent with a homozygous deletion encompassing the last 19 exons of CTNND2 predicted to disrupt the transcript. All presented with severe neurodevelopmental delay with absent speech, profound motor delay, stereotypic behavior, microcephaly, short stature, muscular hypotonia with lower limb hypertonia, and variable eye anomalies. The parents and the fourth sibling were heterozygous carriers of the deletion and exhibited mild neurodevelopmental impairment resembling that of the previously described heterozygous individuals. The present study unveils a severe manifestation of CTNND2‐associated Rauch‐Azzarello syndrome attributed to biallelic loss‐of‐function aberrations, clinically distinct from the already described mild presentation of heterozygous individuals. Furthermore, we demonstrate novel clinical features in homozygous individuals that have not been reported in heterozygous cases to date.
This is the first report of a severe neurodevelopmental delay disorder attributed to a biallelic loss‐of‐function deletion in CTNND2. Other clinical features included microcephaly, short stature, lower limb hypertonia, and kyphosis. This clinical entity is distinct from the mild condition caused by monoallelic CTNND2 alterations, here named as Rauch‐Azzarello syndrome.
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