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FMR1 premutation carriers (55‐200 CGGs) are at risk of developing Fragile X‐associated primary ovarian insufficiency as well as Fragile X‐associated tremor/ataxia syndrome. FMR1 premutation alleles are also associated with a variety of disorders, including psychiatric, developmental, and neurological problems. However, there is a major concern regarding clinical implications of smaller CGG expansions known as intermediate alleles (IA) or gray zone alleles (45‐54 CGG). Although several studies have hypothesized that IA may be involved in the etiology of FMR1 premutation associated phenotypes, this association still remains unclear. The aim of this study was to provide new data on the clinical implications of IA. We reviewed a total of 17 011 individuals: 1142 with primary ovarian insufficiency, 478 with movement disorders, 14 006 with neurodevelopmental disorders and 1385 controls. Similar IA frequencies were detected in all the cases and controls (cases 1.20% vs controls 1.39%, P = .427). When comparing the allelic frequencies of IA ≥ 50CGGs, a greater, albeit not statistically significant, number of alleles were detected in all the cohorts of patients. Therefore, IA below 50 CGGs should not be considered as risk factors for FMR1 premutation‐associated phenotypes, at least in our population. However, the clinical implication of IA ≥ 50CGGs remains to be further elucidated. [ABSTRACT FROM AUTHOR]

Abstract Background Structural variations such as copy number variants (CNV) influence the expression of different phenotypic traits. Algorithms to identify CNVs through SNP-array platforms are available. The ability to evaluate well-characterized CNVs such as GSTM1 (1p13.3) deletion provides an important opportunity to assess their performance. Results 773 cases and 759 controls from the SBC/EPICURO Study were genotyped in the GSTM1 region using TaqMan, Multiplex Ligation-dependent Probe Amplification (MLPA), and Illumina Infinium 1 M SNP-array platforms. CNV callings provided by TaqMan and MLPA were highly concordant and replicated the association between GSTM1 and bladder cancer. This was not the case when CNVs were called using Illumina 1 M data through available algorithms since no deletion was detected across the study samples. In contrast, when the Log R Ratio (LRR) was used as a continuous measure for the 5 probes contained in this locus, we were able to detect their association with bladder cancer using simple regression models or more sophisticated methods such as the ones implemented in the CNVtools package. Conclusions This study highlights an important limitation in the CNV calling from SNP-array data in regions of common aberrations and suggests that there may be added advantage for using LRR as a continuous measure in association tests rather than relying on calling algorithms.

Abstract Background Mosaicism for copy number and copy neutral chromosomal rearrangements has been recently identified as a relatively common source of genetic variation in the normal population. However its prevalence is poorly defined since it has been only studied systematically in one large-scale study and by using non optimal ad-hoc SNP array data analysis tools, uncovering rather large alterations (> 1 Mb) and affecting a high proportion of cells. Here we propose a novel methodology, Mosaic Alteration Detection-MAD, by providing a software tool that is effective for capturing previously described alterations as wells as new variants that are smaller in size and/or affecting a low percentage of cells. Results The developed method identified all previously known mosaic abnormalities reported in SNP array data obtained from controls, bladder cancer and HapMap individuals. In addition MAD tool was able to detect new mosaic variants not reported before that were smaller in size and with lower percentage of cells affected. The performance of the tool was analysed by studying simulated data for different scenarios. Our method showed high sensitivity and specificity for all assessed scenarios. Conclusions The tool presented here has the ability to identify mosaic abnormalities with high sensitivity and specificity. Our results confirm the lack of sensitivity of former methods by identifying new mosaic variants not reported in previously utilised datasets. Our work suggests that the prevalence of mosaic alterations could be higher than initially thought. The use of appropriate SNP array data analysis methods would help in defining the human genome mosaic map.

Abstract Background Germline genetic variation is associated with the differential expression of many human genes. The phenotypic effects of this type of variation may be important when considering susceptibility to common genetic diseases. Three regions at 8q24 have recently been identified to independently confer risk of prostate cancer. Variation at 8q24 has also recently been associated with risk of breast and colorectal cancer. However, none of the risk variants map at or relatively close to known genes, with c-MYC mapping a few hundred kilobases distally. Results This study identifies cis-regulators of germline c-MYC expression in immortalized lymphocytes of HapMap individuals. Quantitative analysis of c-MYC expression in normal prostate tissues suggests an association between overexpression and variants in Region 1 of prostate cancer risk. Somatic c-MYC overexpression correlates with prostate cancer progression and more aggressive tumor forms, which was also a pathological variable associated with Region 1. Expression profiling analysis and modeling of transcriptional regulatory networks predicts a functional association between MYC and the prostate tumor suppressor KLF6. Analysis of MYC/Myc-driven cell transformation and tumorigenesis substantiates a model in which MYC overexpression promotes transformation by down-regulating KLF6. In this model, a feedback loop through E-cadherin down-regulation causes further transactivation of c-MYC. Conclusion This study proposes that variation at putative 8q24 cis-regulator(s) of transcription can significantly alter germline c-MYC expression levels and, thus, contribute to prostate cancer susceptibility by down-regulating the prostate tumor suppressor KLF6 gene.

The implementation of Next Generation Sequencing, particularly exome sequencing (ES), into clinical practice has revolutionised the genetic diagnosis of rare diseases. However, it is estimated that 50% of patients with neuromuscular diseases remain undiagnosed after ES. Here, we evaluated total RNA sequencing (RNAseq) from muscle biopsies as a diagnostic tool in genetically unsolved patients. Total RNAseq was extracted from muscle biopsies of 54 undiagnosed patients after ES or gene panel sequencing, 3 positive controls (patients with previously identified RNA defects in the DMD gene) and 17 healthy controls. We evaluated the presence of aberrant splicing, outlier gene expression and allelic imbalance in autosomal recessive genes. In addition, variant calling was performed from the RNAseq data. In 7/54 patients (12.9%) we detected pathogenic alterations at the mRNA level, including two exon skipping events (COL6A1), one intronic retention (TTN), one alternative splicing caused by a synonymous variant (RYR1), one pseudoexon (DMD) and two patients with allelic imbalance in an autosomal recessive gene (GNE). In one of these cases, WGS was required to achieve the genetic diagnosis. Three patients (5.55%) remain under investigation due to the detection of alternative splicing events in new candidate genes. In addition, reanalysis of existing ES data allowed the diagnosis of 8/54 individuals (14.8%). In this study, we show that RNAseq analysis improves the diagnostic rate in patients with neuromuscular diseases after inconclusive results in ES. RNAseq not only enables the identification of molecular events that would not have been detected by other methods, but also allows the reclassification of VUS variants identified at the gDNA level. We also highlight the importance of a periodic reanalysis of existing genomic data and the utility of an integrated genomic and transcriptomic analysis. [ABSTRACT FROM AUTHOR]

Background and Objective: Between 5% and 10% of amyotrophic lateral sclerosis (ALS) cases have a family history of the disease, 30% of which do not have an identifiable underlying genetic cause after a comprehensive study of the known ALS-related genes. Based on a significantly increased incidence of ALS in a small geographical region from Spain, the aim of this work was to identify novel ALS-related genes in ALS cases with negative genetic testing., Methods: We detected an increased incidence of both sporadic and, especially, familial ALS cases in a small region from Spain compared with available demographic and epidemiological data. We performed whole genome sequencing in a group of 12 patients with ALS (5 of them familial) from this unique area. We expanded the study to include affected family members and additional cases from a wider surrounding region., Results: We identified a shared missense mutation (c.1586C>T; p.Pro529Leu) in the cyclic AMP regulated phosphoprotein 21 ( ARPP21) gene that encodes an RNA-binding protein, in a total of 10 patients with ALS from 7 unrelated families. No mutations were found in other ALS-causing genes., Conclusions: While previous studies have dismissed a causal role of ARPP21 in ALS, our results strongly support ARPP21 as a novel ALS-causing gene., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Background and Purpose: Pathogenic variants in the RYR1 gene have been associated with a variety of conditions, ranging from congenital myopathy to adult manifestations. Our aim was to characterize the p.Leu2286Val variant in 17 Basque patients, to accurately determine its correlation with clinical features and to explore the possible founder effect of the variant., Methods: Families harbouring the p.Leu2286 RYR1 variant underwent a detailed clinical evaluation, including muscle magnetic resonance imaging, electromyography and muscle biopsy. Haplotypes were analysed in available patients and their relatives., Results: Individuals carrying the p.Leu2286Val shared a common haplotype, suggesting a founder event in the Basque Country population. The most prevalent features were exertional myalgia, high creatine kinase (CK) levels, cramps and muscle hypertrophy. None of the patients carrying only the p.Leu2286Val showed progression to severe muscle weakness and muscle magnetic resonance imaging showed a heterogeneous muscle involvement. Muscle biopsy revealed non-specific findings in two patients and features associated with central core disease in one patient carrying only the p.Leu2286Val and two patients harbouring an additional RYR1 variant. Three individuals carrying an in trans RYR1 variant presented with an earlier onset and more severe phenotype., Conclusion: Here, it is shown that the dominantly inherited p.Leu2286Val RYR1 founder variant is associated with a milder phenotype of exercise intolerance, myalgia and hyperCKemia., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background and Objectives: Immune-mediated necrotizing myopathy (IMNM) caused by antibodies against 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) is an inflammatory myopathy that has been epidemiologically correlated with previous statin exposure. We characterized in detail a series of 11 young statin-naïve patients experiencing a chronic disease course mimicking a limb-girdle muscular dystrophy. With the hypothesis that HMGCR upregulation may increase immunogenicity and trigger the production of autoantibodies, our aim was to expand pathophysiologic knowledge of this distinct phenotype., Methods: Clinical and epidemiologic data, autoantibody titers, creatine kinase (CK) levels, response to treatment, muscle imaging, and muscle biopsies were assessed. HMGCR expression in patients' muscle was assessed by incubating sections of affected patients with purified anti-HMGCR+ serum. Whole-exome sequencing (WES) with a special focus on cholesterol biosynthesis-related genes and high-resolution human leukocyte antigen (HLA) typing were performed., Results: Patients, aged 3-25 years and mostly female (90.9%), presented with subacute proximal weakness progressing over many years and high CK levels (>1,000 U/L). Diagnostic delay ranged from 3 to 27 years. WES did not reveal any pathogenic variants. HLA-DRB1*11:01 carrier frequency was 60%, a significantly higher proportion than in the control population. No upregulation or mislocalization of the enzyme in statin-exposed or statin-naïve anti-HMGCR+ patients was observed, compared with controls., Discussion: WES of a cohort of patients with dystrophy-like anti-HMGCR IMNM did not reveal any common rare variants of any gene, including cholesterol biosynthesis-related genes. HLA analysis showed a strong association with HLA-DRB1*11:01, previously mostly described in statin-exposed adult patients; consequently, a common immunogenic predisposition should be suspected, irrespective of statin exposure. Moreover, we were unable to conclusively demonstrate muscle upregulation/mislocalization of HMGCR in IMNM, whether or not driven by statins.

Objective: COASY, the gene encoding the bifunctional enzyme CoA synthase, which catalyzes the last two reactions of cellular de novo coenzyme A (CoA) biosynthesis, has been linked to two exceedingly rare autosomal recessive disorders, such as COASY protein-associated neurodegeneration (CoPAN), a form of neurodegeneration with brain iron accumulation (NBIA), and pontocerebellar hypoplasia type 12 (PCH12). We aimed to expand the phenotypic spectrum and gain insights into the pathogenesis of COASY-related disorders., Methods: Patients were identified through targeted or exome sequencing. To unravel the molecular mechanisms of disease, RNA sequencing, bioenergetic analysis, and quantification of critical proteins were performed on fibroblasts., Results: We identified five new individuals harboring novel COASY variants. While one case exhibited classical CoPAN features, the others displayed atypical symptoms such as deafness, language and autism spectrum disorders, brain atrophy, and microcephaly. All patients experienced epilepsy, highlighting its potential frequency in COASY-related disorders. Fibroblast transcriptomic profiling unveiled dysregulated expression in genes associated with mitochondrial respiration, responses to oxidative stress, transmembrane transport, various cellular signaling pathways, and protein translation, modification, and trafficking. Bioenergetic analysis revealed impaired mitochondrial oxygen consumption in COASY fibroblasts. Despite comparable total CoA levels to control cells, the amounts of mitochondrial 4'-phosphopantetheinylated proteins were significantly reduced in COASY patients., Interpretation: These results not only extend the clinical phenotype associated with COASY variants but also suggest a continuum between CoPAN and PCH12. The intricate interplay of altered cellular processes and signaling pathways provides valuable insights for further research into the pathogenesis of COASY-associated diseases., (© 2024 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Arterial tortuosity syndrome (ATS) is an autosomal recessive connective tissue disease caused by biallelic variants in the SLC2A10 gene (NG_016284.1) and characterised by tortuosity and elongation of the aorta and medium-sized arteries. It is considered an extremely rare disease; only 106 individuals with genetically confirmed ATS have been identified to date. Four cases of ATS from two families are described, contributing to the clinical delineation of this condition. A patient with microcephaly and a complex uropathy and two cases with diaphragmatic hernia are noticed. Regarding the vascular involvement, a predominant supra-aortic involvement stands out and only 1 patient with significant arterial stenoses was described. All presented severe tortuosity of the intracranial arteries. To reduce hemodynamic stress on the arterial wall, beta-adrenergic blocking treatment was prescribed. A not previously described variant (NM_030777.4:c.899T>G (p.Leu300Trp)) was detected in a proband; it has an allegedly deleterious effect in compound heterozygous state with the pathogenic variant c.417T>A (p.Tyr139Ter). The other 3 patients, siblings born to healthy consanguineous parents, had a variant in homozygous state: c.510G>A (p.Trp170Ter)., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

We report a 6-year-old female with linear skin hyperpigmentation on the axillae and groin, intellectual disability, dysplastic teeth and nails, and facial dysmorphism who was diagnosed with a novel PHF6 pathogenic splicing variant. Males with PHF6 mutations have been associated with the X-linked recessive disorder Börjeson-Forssman-Lehmann, but females have a distinct phenotype which is likely modulated by X-inactivation., (© 2021 Wiley Periodicals LLC.)

Cancer is a complex disease resulting from the accumulation of genetic dysfunctions. Tumor heterogeneity causes the molecular variety that divergently controls responses to chemotherapy, leading to the recurrent problem of cancer reappearance. For many decades, efforts have focused on identifying essential tumoral genes and cancer driver mutations. More recently, prompted by the clinical success of the synthetic lethality (SL)-based therapy of the PARP inhibitors in homologous recombinant deficient tumors, scientists have centered their novel research on SL interactions (SLI). The state of the art to find new genetic interactions are currently large-scale forward genetic CRISPR screens. CRISPR technology has rapidly evolved to be a common tool in the vast majority of laboratories, as tools to implement CRISPR screen protocols are available to all researchers. Taking advantage of SLI, combinatorial therapies have become the ultimate model to treat cancer with lower toxicity, and therefore better efficiency. This review explores the CRISPR screen methodology, integrates the up-to-date published findings on CRISPR screens in the cancer field and proposes future directions to uncover cancer regulation and individual responses to chemotherapy.

Early-onset Alzheimer's disease (EOAD) and frontotemporal dementia (FTD) have a high proportion of genetically determined cases. Next-generation sequencing technologies have triggered the discovery of new mutations and genetic variants in dementia-causal genes. We performed whole-exome sequencing and selective analysis of known genes causative of EOAD and FTD in a well-characterized Spanish cohort of 103 patients (60 EOAD, 43 FTD) to find genetic variants associated to patients' phenotype. In EOAD patients, a new likely pathogenic variant in PSEN1 gene (p.G378R) was found. In FTD patients, 2 likely pathogenic variants were found, one in MAPT gene (p.P397S) and one in VCP gene (p.R159H). In our series, 2% of early-onset dementia without criteria for clinical genetic testing according to current guidelines presented a likely pathogenic mutation. We have also detected 13 additional variants of uncertain significance in causal genes, as well as rare variants in risk genes for dementia (ABCA7, SORL1, SQSTM1, and TREM2). Next-generation technologies in neurodegenerative diseases constitute a powerful tool that significantly contributes to patients' diagnosis., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: About 40% of RAS/BRAF wild-type metastatic colorectal cancer (mCRC) patients undergoing anti-EGFR-based therapy have poor outcomes. Treatment failure is not only associated with poorer prognosis but higher healthcare costs. Our aim was to identify novel somatic genetic variants in the primary tumor and assess their effect on anti-EGFR response., Patients and Methods: Tumor (somatic) and blood (germline) DNA samples were obtained from two well-defined cohorts of mCRC patients, those sensitive and those resistant to EGFR blockade. Genetic variant screening of 43 EGFR-related genes was performed using targeted next-generation sequencing (NGS). Relevant clinical data were collected through chart review to assess genetic results., Results: Among 61 patients, 38 were sensitive and 23 were resistant to treatment. We identified eight somatic variants that predicted non-response. Three were located in insulin-related genes (I668N and E1218K in IGF1R , T1156M in IRS2 ) and three in genes belonging to the LRIG family (T152T in LRIG1 , S697L in LRIG2 and V812M in LRIG3 ). The remaining two variants were found in NRAS (G115Efs*46) and PDGFRA (T301T). We did not identify any somatic variants related to good response., Conclusions: This study provides evidence that novel somatic genetic variants along the EGFR-triggered pathway could modulate the response to anti-EGFR drugs in mCRC patients. It also highlights the influence of insulin-related genes and LRIG genes on anti-EGFR efficacy. Our findings could help characterize patients who are resistant to anti-EGFR blockade despite harboring RAS/BRAF wild-type tumors.

PRMT7 encodes for an arginine methyltransferase that methylates arginine residues on various protein substrates and has been shown to play a role in various developmental processes. Mutations in PRMT7 have been recently shown to be implicated in a phenotype with intellectual disability, short stature and brachydactyly, and considered to be a phenocopy of pseudohypoparathyroidism. We report a patient with short stature, psychomotor delay, hearing loss and brachydactyly, for whom whole exome sequencing detected two mutations in PRMT7 and parental segregation studies detected biallelic mutation inheritance. Few patients with biallelic PRMT7 mutations have been reported so far in the literature. We report a new patient and review all reported cases to date to delineate the clinical manifestations that may help in diagnosis this disorder, known as Short Stature, Brachydactyly, Intellectual Developmental Disability, and Seizures syndrome, allowing appropriate management and genetic counselling., (Copyright © 2018. Published by Elsevier Masson SAS.)

Obesity is a multifactorial disorder with high heritability (50-75%), which is probably higher in early-onset and severe cases. Although rare monogenic forms and several genes and regions of susceptibility, including copy number variants (CNVs), have been described, the genetic causes underlying the disease still remain largely unknown. We searched for rare CNVs (>100kb in size, altering genes and present in <1/2000 population controls) in 157 Spanish children with non-syndromic early-onset obesity (EOO: body mass index >3 standard deviations above the mean at <3 years of age) using SNP array molecular karyotypes. We then performed case control studies (480 EOO cases/480 non-obese controls) with the validated CNVs and rare sequence variants (RSVs) detected by targeted resequencing of selected CNV genes (n = 14), and also studied the inheritance patterns in available first-degree relatives. A higher burden of gain-type CNVs was detected in EOO cases versus controls (OR = 1.71, p-value = 0.0358). In addition to a gain of the NPY gene in a familial case with EOO and attention deficit hyperactivity disorder, likely pathogenic CNVs included gains of glutamate receptors (GRIK1, GRM7) and the X-linked gastrin-peptide receptor (GRPR), all inherited from obese parents. Putatively functional RSVs absent in controls were also identified in EOO cases at NPY, GRIK1 and GRPR. A patient with a heterozygous deletion disrupting two contiguous and related genes, SLCO4C1 and SLCO6A1, also had a missense RSV at SLCO4C1 on the other allele, suggestive of a recessive model. The genes identified showed a clear enrichment of shared co-expression partners with known genes strongly related to obesity, reinforcing their role in the pathophysiology of the disease. Our data reveal a higher burden of rare CNVs and RSVs in several related genes in patients with EOO compared to controls, and implicate NPY, GRPR, two glutamate receptors and SLCO4C1 in highly penetrant forms of familial obesity.

Detectable clonal mosaicism for large chromosomal events has been associated with aging and an increased risk of hematological and some solid cancers. We hypothesized that genetic cancer predisposition disorders, such as Fanconi anemia (FA), could manifest a high rate of chromosomal mosaic events (CMEs) in peripheral blood, which could be used as early biomarkers of cancer risk. We studied the prevalence of CMEs by single-nucleotide polymorphism (SNP) array in 130 FA patients' blood DNA and their impact on cancer risk. We detected 51 CMEs (4.4-159 Mb in size) in 16 out of 130 patients (12.3%), of which 9 had multiple CMEs. The most frequent events were gains at 3q (n = 6) and 1q (n = 5), both previously associated with leukemia, as well as rearrangements with breakpoint clustering within the major histocompatibility complex locus ( P = 7.3 × 10 -9 ). Compared with 15 743 age-matched population controls, FA patients had a 126 to 140 times higher risk of detectable CMEs in blood ( P < 2.2 × 10 -16 ). Prevalent and incident hematologic and solid cancers were more common in CME carriers (odds ratio [OR] = 11.6, 95% confidence interval [CI] = 3.4-39.3, P = 2.8 × 10 -5 ), leading to poorer prognosis. The age-adjusted hazard risk (HR) of having cancer was almost 5 times higher in FA individuals with CMEs than in those without CMEs. Regarding survival, the HR of dying was 4 times higher in FA individuals having CMEs (HR = 4.0, 95% CI = 2.0-7.9, P = 5.7 × 10 -5 ). Therefore, our data suggest that molecular karyotyping with SNP arrays in easy-to-obtain blood samples could be used for better monitoring of bone marrow clonal events, cancer risk, and overall survival of FA patients., Competing Interests: Conflict-of-interest disclosure: B.R.-S. is an employee of, and L.A.P.-J. is a scientific advisor for, qGenomics, SL. The remaining authors declare no competing financial interests.

Next-generation sequencing (NGS) has the capacity of carrier screening in gamete donation (GD) programs. We have developed and validated an NGS carrier-screening test (qCarrier test) that includes 200 genes associated with 368 disorders (277 autosomal recessive and 37 X-linked). Carrier screening is performed on oocyte donation candidates and the male partner of oocyte recipient. Carriers of X-linked conditions are excluded from the GD program, whereas donors are chosen who do not carry mutations for the same gene/disease as the recipients. The validation phase showed a high sensitivity (>99% sensitivity) detecting all single-nucleotide variants, 13 indels, and 25 copy-number variants included in the validation set. A total of 1,301 individuals were analysed with the qCarrier test, including 483 candidate oocyte donors and 635 receptor couples, 105 females receiving sperm donation, and 39 couples seeking pregnancy. We identified 56% of individuals who are carriers for at least one genetic condition and 1.7% of female donors who were excluded from the program due to a carrier state of X-linked conditions. Globally, 3% of a priori assigned donations had a high reproductive risk that could be minimized after testing. Genetic counselling at different stages is essential for helping to facilitate a successful and healthy pregnancy., (© 2016 WILEY PERIODICALS, INC.)

Background: Urothelial bladder cancer is a highly heterogeneous disease. Cancer cell lines are useful tools for its study. This is a comprehensive genomic characterization of 40 urothelial bladder carcinoma (UBC) cell lines including information on origin, mutation status of genes implicated in bladder cancer (FGFR3, PIK3CA, TP53, and RAS), copy number alterations assessed using high density SNP arrays, uniparental disomy (UPD) events, and gene expression., Results: Based on gene mutation patterns and genomic changes we identify lines representative of the FGFR3-driven tumor pathway and of the TP53/RB tumor suppressor-driven pathway. High-density array copy number analysis identified significant focal gains (1q32, 5p13.1-12, 7q11, and 7q33) and losses (i.e. 6p22.1) in regions altered in tumors but not previously described as affected in bladder cell lines. We also identify new evidence for frequent regions of UPD, often coinciding with regions reported to be lost in tumors. Previously undescribed chromosome X losses found in UBC lines also point to potential tumor suppressor genes. Cell lines representative of the FGFR3-driven pathway showed a lower number of UPD events., Conclusions: Overall, there is a predominance of more aggressive tumor subtypes among the cell lines. We provide a cell line classification that establishes their relatedness to the major molecularly-defined bladder tumor subtypes. The compiled information should serve as a useful reference to the bladder cancer research community and should help to select cell lines appropriate for the functional analysis of bladder cancer genes, for example those being identified through massive parallel sequencing.

Background: Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders with high heritability. Recent findings support a highly heterogeneous and complex genetic etiology including rare de novo and inherited mutations or chromosomal rearrangements as well as double or multiple hits., Methods: We performed whole-exome sequencing (WES) and blood cell transcriptome by RNAseq in a subset of male patients with idiopathic ASD (n = 36) in order to identify causative genes, transcriptomic alterations, and susceptibility variants., Results: We detected likely monogenic causes in seven cases: five de novo (SCN2A, MED13L, KCNV1, CUL3, and PTEN) and two inherited X-linked variants (MAOA and CDKL5). Transcriptomic analyses allowed the identification of intronic causative mutations missed by the usual filtering of WES and revealed functional consequences of some rare mutations. These included aberrant transcripts (PTEN, POLR3C), deregulated expression in 1.7% of mutated genes (that is, SEMA6B, MECP2, ANK3, CREBBP), allele-specific expression (FUS, MTOR, TAF1C), and non-sense-mediated decay (RIT1, ALG9). The analysis of rare inherited variants showed enrichment in relevant pathways such as the PI3K-Akt signaling and the axon guidance., Conclusions: Integrative analysis of WES and blood RNAseq data has proven to be an efficient strategy to identify likely monogenic forms of ASD (19% in our cohort), as well as additional rare inherited mutations that can contribute to ASD risk in a multifactorial manner. Blood transcriptomic data, besides validating 88% of expressed variants, allowed the identification of missed intronic mutations and revealed functional correlations of genetic variants, including changes in splicing, expression levels, and allelic expression.

Analyses of genome-wide association study (GWAS) data have revealed that detectable genetic mosaicism involving large (>2 Mb) structural autosomal alterations occurs in a fraction of individuals. We present results for a set of 24,849 genotyped individuals (total GWAS set II [TGSII]) in whom 341 large autosomal abnormalities were observed in 168 (0.68%) individuals. Merging data from the new TGSII set with data from two prior reports (the Gene-Environment Association Studies and the total GWAS set I) generated a large dataset of 127,179 individuals; we then conducted a meta-analysis to investigate the patterns of detectable autosomal mosaicism (n = 1,315 events in 925 [0.73%] individuals). Restricting to events >2 Mb in size, we observed an increase in event frequency as event size decreased. The combined results underscore that the rate of detectable mosaicism increases with age (p value = 5.5 × 10(-31)) and is higher in men (p value = 0.002) but lower in participants of African ancestry (p value = 0.003). In a subset of 47 individuals from whom serial samples were collected up to 6 years apart, complex changes were noted over time and showed an overall increase in the proportion of mosaic cells as age increased. Our large combined sample allowed for a unique ability to characterize detectable genetic mosaicism involving large structural events and strengthens the emerging evidence of non-random erosion of the genome in the aging population., (Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)