Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma.

Cancer Cell. 2017 Sep 26;:

Authors: Mackay A, Burford A, Carvalho D, Izquierdo E, Fazal-Salom J, Taylor KR, Bjerke L, Clarke M, Vinci M, Nandhabalan M, Temelso S, Popov S, Molinari V, Raman P, Waanders AJ, Han HJ, Gupta S, Marshall L, Zacharoulis S, Vaidya S, Mandeville HC, Bridges LR, Martin AJ, Al-Sarraj S, Chandler C, Ng HK, Li X, Mu K, Trabelsi S, Brahim DH, Kisljakov AN, Konovalov DM, Moore AS, Carcaboso AM, Sunol M, de Torres C, Cruz O, Mora J, Shats LI, Stavale JN, Bidinotto LT, Reis RM, Entz-Werle N, Farrell M, Cryan J, Crimmins D, Caird J, Pears J, Monje M, Debily MA, Castel D, Grill J, Hawkins C, Nikbakht H, Jabado N, Baker SJ, Pfister SM, Jones DTW, Fouladi M, von Bueren AO, Baudis M, Resnick A, Jones C

Abstract
We collated data from 157 unpublished cases of pediatric high-grade glioma and diffuse intrinsic pontine glioma and 20 publicly available datasets in an integrated analysis of >1,000 cases. We identified co-segregating mutations in histone-mutant subgroups including loss of FBXW7 in H3.3G34R/V, TOP3A rearrangements in H3.3K27M, and BCOR mutations in H3.1K27M. Histone wild-type subgroups are refined by the presence of key oncogenic events or methylation profiles more closely resembling lower-grade tumors. Genomic aberrations increase with age, highlighting the infant population as biologically and clinically distinct. Uncommon pathway dysregulation is seen in small subsets of tumors, further defining the molecular diversity of the disease, opening up avenues for biological study and providing a basis for functionally defined future treatment stratification.

PMID: 28966033 [PubMed - as supplied by publisher]

The study of familial hypercholesterolemia in Italy: A narrative review.

Atheroscler Suppl. 2017 Oct;29:1-10

Authors: Bertolini S, Pisciotta L, Fasano T, Rabacchi C, Calandra S

Abstract
In this review we outline our experience in the clinical and molecular diagnosis of familial hypercholesterolemia (FH), built up over more than three decades. We started our work by selecting FH patients on the basis of stringent clinical criteria, including extensive family studies. In most patients we confirmed the clinical diagnosis by showing a reduced LDLR activity in skin fibroblasts. After the isolation of LDLR cDNA and the characterization of the corresponding gene by the Dallas group, we started a systematic molecular investigation of our patients first using Southern blotting, and, subsequently Sanger sequencing. Up to now we have been able to identify 260 mutations of LDLR gene in more than 1000 genotyped FH patients, including 68 homozygotes. During this survey we identified 13 mutation clusters located in different geographical districts, which gave us the chance to compare the phenotype of patients carrying the most common mutations. We also found that mutations in APOB and PCSK9 genes were a rare cause of FH in our cohort. Despite our efforts, we failed to identify mutations in candidate genes in ∼20% of cases of definite FH. An exome-wide study, conducted within the context of an international collaboration, excluded the presence of other major genes in our unexplained FH cases. Recently, we have adopted sequencing technology of the next generation (NGS) with the parallel sequencing of a panel of FH targeted genes as a way of obtaining a more comprehensive picture of the gene variants potentially involved in the disease.

PMID: 28965614 [PubMed - in process]

Differential analysis between somatic mutation and germline variation profiles reveals cancer-related genes.

Genome Med. 2017 Aug 25;9(1):79

Authors: Przytycki PF, Singh M

Abstract
A major aim of cancer genomics is to pinpoint which somatically mutated genes are involved in tumor initiation and progression. We introduce a new framework for uncovering cancer genes, differential mutation analysis, which compares the mutational profiles of genes across cancer genomes with their natural germline variation across healthy individuals. We present DiffMut, a fast and simple approach for differential mutational analysis, and demonstrate that it is more effective in discovering cancer genes than considerably more sophisticated approaches. We conclude that germline variation across healthy human genomes provides a powerful means for characterizing somatic mutation frequency and identifying cancer driver genes. DiffMut is available at https://github.com/Singh-Lab/Differential-Mutation-Analysis .

PMID: 28841835 [PubMed - indexed for MEDLINE]

Contribution of exome sequencing for genetic diagnostic in arrhythmogenic right ventricular cardiomyopathy/dysplasia.

PLoS One. 2017;12(8):e0181840

Authors: Fedida J, Fressart V, Charron P, Surget E, Hery T, Richard P, Donal E, Keren B, Duthoit G, Hidden-Lucet F, Villard E, Gandjbakhch E

Abstract
BACKGROUND: Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia (ARVC/D) is an inherited cardiomyopathy mainly caused by heterozygous desmosomal gene mutations, the major gene being PKP2. The genetic cause remains unknown in ~50% of probands with routine desmosomal gene screening. The aim of this study was to assess the diagnostic accuracy of whole exome sequencing (WES) in ARVC/D with negative genetic testing.
METHODS: WES was performed in 22 patients, all without a mutation identified in desmosomal genes. Putative pathogenic variants were screened in 96 candidate genes associated with other cardiomyopathies/channelopathies. The sequencing coverage depth of PKP2, DSP, DSG2, DSC2, JUP and TMEM43 exons was compared to the mean coverage distribution to detect large insertions/deletions. All suspected deletions were verified by real-time qPCR, Multiplex-Ligation-dependent-Probe-Amplification (MLPA) and cGH-Array. MLPA was performed in 50 additional gene-negative probands.
RESULTS: Coverage-depth analysis from the 22 WES data identified two large heterozygous PKP2 deletions: one from exon 1 to 14 and one restricted to exon 4, confirmed by qPCR and MLPA. MLPA identified 2 additional PKP2 deletions (exon 1-7 and exon 1-14) in 50 additional probands confirming a significant frequency of large PKP2 deletions (5.7%) in gene-negative ARVC/D. Putative pathogenic heterozygous variants in EYA4, RBM20, PSEN1, and COX15 were identified in 4 unrelated probands.
CONCLUSION: A rather high frequency (5.7%) of large PKP2 deletions, undetectable by Sanger sequencing, was detected as the cause of ARVC/D. Coverage-depth analysis through next-generation sequencing appears accurate to detect large deletions at the same time than conventional putative mutations in desmosomal and cardiomyopathy-associated genes.

PMID: 28767663 [PubMed - indexed for MEDLINE]

Candidate Genes for Nonsyndromic Cleft Palate Detected by Exome Sequencing.

J Dent Res. 2017 Oct;96(11):1314-1321

Authors: Hoebel AK, Drichel D, van de Vorst M, Böhmer AC, Sivalingam S, Ishorst N, Klamt J, Gölz L, Alblas M, Maaser A, Keppler K, Zink AM, Dixon MJ, Dixon J, Hemprich A, Kruse T, Graf I, Dunsche A, Schmidt G, Daratsianos N, Nowak S, Aldhorae KA, Nöthen MM, Knapp M, Thiele H, Gilissen C, Reutter H, Hoischen A, Mangold E, Ludwig KU

Abstract
Nonsyndromic cleft palate only (nsCPO) is a facial malformation that has a livebirth prevalence of 1 in 2,500. Research suggests that the etiology of nsCPO is multifactorial, with a clear genetic component. To date, genome-wide association studies have identified only 1 conclusive common variant for nsCPO, that is, a missense variant in the gene grainyhead-like-3 ( GRHL3). Thus, the underlying genetic causes of nsCPO remain largely unknown. The present study aimed at identifying rare variants that might contribute to nsCPO risk, via whole-exome sequencing (WES), in multiply affected Central European nsCPO pedigrees. WES was performed in 2 affected first-degree relatives from each family. Variants shared between both individuals were analyzed for their potential deleterious nature and a low frequency in the general population. Genes carrying promising variants were annotated for 1) reported associations with facial development, 2) multiple occurrence of variants, and 3) expression in mouse embryonic palatal shelves. This strategy resulted in the identification of a set of 26 candidate genes that were resequenced in 132 independent nsCPO cases and 623 independent controls of 2 different ethnicities, using molecular inversion probes. No rare loss-of-function mutation was identified in either WES or resequencing step. However, we identified 2 or more missense variants predicted to be deleterious in each of 3 genes ( ACACB, PTPRS, MIB1) in individuals from independent families. In addition, the analyses identified a novel variant in GRHL3 in 1 patient and a variant in CREBBP in 2 siblings. Both genes underlie different syndromic forms of CPO. A plausible hypothesis is that the apparently nonsyndromic clefts in these 3 patients might represent hypomorphic forms of the respective syndromes. In summary, the present study identified rare variants that might contribute to nsCPO risk and suggests candidate genes for further investigation.

PMID: 28767323 [PubMed - indexed for MEDLINE]

ENPP1 Mutation Causes Recessive Cole Disease by Altering Melanogenesis.

J Invest Dermatol. 2017 Sep 27;:

Authors: Chourabi M, Liew MS, Lim S, H'mida-Ben Brahim D, Boussofara L, Dai L, Wong PM, Foo JN, Sriha B, Robinson KS, Denil S, Common JE, Mamaï O, Ben Khalifa Y, Bollen M, Liu J, Denguezli M, Bonnard C, Saad A, Reversade B

Abstract
Cole disease is a genodermatosis of pigmentation following a strict dominant mode of inheritance. In this study we investigated eight patients affected with an overlapping genodermatosis following recessive inheritance. The patients presented with hypo- and hyper-pigmented macules over the body, resembling dyschromatosis universalis hereditaria in addition to punctuate palmoplantar keratosis. By homozygosity mapping and whole-exome sequencing, a biallelic p.Cys120Arg mutation in Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) was identified in all patients. We found that this mutation, like those causing dominant Cole disease, impairs homo-dimerization of the ENPP1 enzyme which is mediated by its two somatomedin-B-like domains. Histological analysis revealed structural and molecular changes in affected skin which were likely to originate from defective melanocytes since keratinocytes do not express ENPP1. Consistently, RNA-seq analysis of patient-derived primary melanocytes revealed alterations in melanocyte development and in pigmentation signaling pathways. We therefore conclude that germline ENPP1 cysteine-specific mutations, primarily affecting the melanocyte lineage, cause a clinical spectrum of dyschromatosis, in which the p.Cys120Arg allele represents a recessive and more severe form of Cole disease.

PMID: 28964717 [PubMed - as supplied by publisher]

A phase II study of temsirolimus added to low-dose weekly carboplatin and paclitaxel for patients with recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC).

Ann Oncol. 2017 Oct 01;28(10):2533-2538

Authors: Dunn LA, Fury MG, Xiao H, Baxi SS, Sherman EJ, Korte S, Pfister C, Haque S, Katabi N, Ho AL, Pfister DG

Abstract
Background: Activating events along the PI3K/mTOR pathway are common in head and neck squamous cell carcinomas (HNSCC), and preclinical studies suggest additive or synergistic effects when combining mTORC1 inhibitors with carboplatin and paclitaxel chemotherapy.
Patients and methods: In this single-institution phase II study, the combination of temsirolimus 25 mg, carboplatin AUC 1.5, and paclitaxel 80 mg/m2 administered on days 1 and 8 of a 21-day cycle was evaluated in 36 patients with recurrent and/or metastatic (R/M) HNSCC. The primary end point was objective response rate after two cycles of treatment. Secondary end points include the safety and tolerability profile and overall survival. Correlative studies with exome mutational analysis were performed in pre-treatment biopsy samples from 21 patients.
Results: Fifteen (41.7%) patients had an objective response, which were all partial responses, and 19 (52.3%) patients had stable disease as best response. The two patients who were designated as 'non-responders' were removed from study prior to two cycles of treatment, but are included in the efficacy and safety analyses. The median duration on study was 5.3 months and the median progression-free survival and overall survival were 5.9 months (95% confidence interval, 4.8-7.1) and 12.8 months (95% confidence interval, 9.8-15.8), respectively. The most common grade 3 and 4 adverse events were hematologic toxicities. Three (3.8%) patients developed neutropenic fever on study. Three of four patients with PIK3CA mutations experienced tumor regressions, and responses were also seen in patients with other genetic alterations in the PI3K/mTOR pathway.
Conclusion: The combination of temsirolimus with low-dose weekly carboplatin and paclitaxel appears to have meaningful clinical efficacy in the treatment of R/M HNSCC. This regimen has a relatively high response rate compared to other treatments evaluated in R/M HNSCC, and potential associations with genetic alterations in the PI3K/mTOR pathway should be further explored.

PMID: 28961834 [PubMed - in process]

Utility and limitations of exome sequencing in the molecular diagnosis of pediatric inherited platelet disorders.

Am J Hematol. 2017 Sep 27;:

Authors: Romasko EJ, Devkota B, Biswas S, Jayaraman V, Rajagopalan R, Dulik MC, Thom CS, Choi J, Jairam S, Scarano MI, Krantz ID, Spinner NB, Conlin LK, Lambert MP

Abstract
Inherited platelet disorders (IPD) are a heterogeneous group of rare disorders that affect platelet number and function and often predispose to other significant medical complications. In spite of the identification of over 50 IPD disease-associated genes, a molecular diagnosis is only identified in a minority (10%) of affected patients without a clinically suspected etiology. We studied a cohort of 21 pediatric patients with suspected IPDs by exome sequencing (ES) to: 1) examine the performance of the exome test for IPD genes, 2) determine if this exome-wide diagnostic test provided a higher diagnostic yield than has been previously reported, 3) to evaluate the frequency of variants of uncertain significance identified, and 4) to identify candidate variants for functional evaluation in patients with an uncertain or negative diagnosis. We established a high priority gene list of 53 genes, evaluated exome capture kit performance, and determined the coverage for these genes and disease-related variants. We identified likely disease causing variants in 5 of the 21 probands (23.8%) and variants of uncertain significance in 52% of patients studied. In conclusion, ES has the potential to molecularly diagnose causes of IPD, and to identify candidate genes for functional evaluation. Robust exome sequencing also requires that coverage of genes known to be associated with clinical findings of interest need to be carefully examined and supplemented if necessary. Clinicians who undertake ES should understand the limitations of the test and the full significance of results that may be returned. This article is protected by copyright. All rights reserved.

PMID: 28960434 [PubMed - as supplied by publisher]

Monitoring Treatment Response and Metastatic Relapse in Advanced Bladder Cancer by Liquid Biopsy Analysis.

Eur Urol. 2017 Sep 25;:

Authors: Birkenkamp-Demtröder K, Christensen E, Nordentoft I, Knudsen M, Taber A, Høyer S, Lamy P, Agerbæk M, Jensen JB, Dyrskjøt L

Abstract
Of the patients undergoing radical cystectomy, 20-80% experience relapse. Minimally invasive methods for early detection of metastatic relapse after cystectomy and for monitoring ongoing therapy are urgently needed to improve individualised follow-up and treatment. Therefore, we evaluated the use of circulating tumour DNA (ctDNA) in plasma and urine to detect metastatic relapse after cystectomy and measure treatment efficacy. We exome sequenced tumour and germline DNA from patients with muscle-invasive bladder cancer and monitored ctDNA in 370 liquid biopsies throughout the disease courses by 84 personalised digital droplet polymerase chain reaction assays targeting 61 genes. Patients were prospectively recruited between 2013 and 2017. Patients with metastatic relapse had significantly higher ctDNA levels compared with disease-free patients (p<0.001). The median positive lead time between ctDNA detection in plasma and diagnosis of relapse was 101 d after cystectomy (range 0-932 d). Early detection of metastatic relapse and treatment response using liquid biopsies represents a novel, highly sensitive tool for monitoring patients, supporting clinicians, and guiding treatment decisions.
PATIENT SUMMARY: Measurement of tumour-specific mutations in plasma and urine may be a powerful tool to monitor response during treatment and identify early signs of metastatic disease.

PMID: 28958829 [PubMed - as supplied by publisher]

Unpaired Extracellular Cysteine Mutations of CSF3R Mediate Gain or Loss of Function.

Cancer Res. 2017 Aug 15;77(16):4258-4267

Authors: Zhang H, Means S, Schultz AR, Watanabe-Smith K, Medeiros BC, Bottomly D, Wilmot B, McWeeney SK, Kükenshöner T, Hantschel O, Tyner JW

Abstract
Exclusive of membrane-proximal mutations seen commonly in chronic neutrophilic leukemia (e.g., T618I), functionally defective mutations in the extracellular domain of the G-CSF receptor (CSF3R) have been reported only in severe congenital and idiopathic neutropenia patients. Here, we describe the first activating mutation in the fibronectin-like type III domain of the extracellular region of CSF3R (W341C) in a leukemia patient. This mutation transformed cells via cysteine-mediated intermolecular disulfide bonds, leading to receptor dimerization. Interestingly, a CSF3R cytoplasmic truncation mutation (W791X) found on the same allele as the extracellular mutation and the expansion of the compound mutation was associated with increased leukocytosis and disease progression of the patient. Notably, the primary patient sample and cells transformed by W341C and W341C/W791X exhibited sensitivity to JAK inhibitors. We further showed that disruption of original cysteine pairs in the CSF3R extracellular domain resulted in either gain- or loss-of-function changes, part of which was attributable to cysteine-mediated dimer formation. This, therefore, represents the first characterization of unpaired cysteines that mediate both gain- and loss-of-function phenotypes. Overall, our results show the structural and functional importance of conserved extracellular cysteine pairs in CSF3R and suggest the necessity for broader screening of CSF3R extracellular domain in leukemia patients. Cancer Res; 77(16); 4258-67. ©2017 AACR.

PMID: 28652245 [PubMed - indexed for MEDLINE]

Gene selection tool (GST): A R-based tool for genetic disorders based on the sliding-window proportion test using whole-exome sequencing data.

PLoS One. 2017;12(9):e0185514

Authors: Lee S, Jung M, Jung J, Park K, Ryu JW, Kim J, Kim DS

Abstract
Whole-exome sequencing (WES) can identify causative mutations in hereditary diseases. However, WES data might have a large candidate variant list, including false positives. Moreover, in families, it is more difficult to select disease-associated variants because many variants are shared among members. To reduce false positives and extract accurate candidates, we used a multilocus variant instead of a single-locus variant (SNV). We set up a specific window to analyze the multilocus variant and devised a sliding-window approach to observe all variants. We developed the gene selection tool (GST) based on proportion tests for linkage analysis using WES data. This tool is R program coded and has high sensitivity. We tested our code to find the gene for hereditary spastic paraplegia using SNVs from a specific family and identified the gene known to cause the disease in a significant gene list. The list identified other genes that might be associated with the disease.

PMID: 28957403 [PubMed - in process]

De novo CTBP1 variant is associated with decreased mitochondrial respiratory chain activities.

Neurol Genet. 2017 Oct;3(5):e187

Authors: Sommerville EW, Alston CL, Pyle A, He L, Falkous G, Naismith K, Chinnery PF, McFarland R, Taylor RW

Abstract
OBJECTIVE: To determine the genetic etiology of a young woman presenting an early-onset, progressive neurodegenerative disorder with evidence of decreased mitochondrial complex I and IV activities in skeletal muscle suggestive of a mitochondrial disorder.
METHODS: A case report including diagnostic workup, whole-exome sequencing of the affected patient, filtering, and prioritization of candidate variants assuming a suspected autosomal recessive mitochondrial disorder and segregation studies.
RESULTS: After excluding candidate variants for an autosomal recessive mitochondrial disorder, re-evaluation of rare and novel heterozygous variants identified a recently reported, recurrent pathogenic heterozygous CTBP1 missense change (c.991C>T, p.Arg331Trp), which was confirmed to have arisen de novo.
CONCLUSIONS: We report the fifth known patient harboring a recurrent pathogenic de novo c.991C>T p.(Arg331Trp) CTBP1 variant, who was initially suspected to have an autosomal recessive mitochondrial disorder. Inheritance of suspected early-onset mitochondrial disease could wrongly be assumed to be autosomal recessive. Hence, this warrants continued re-evaluation of rare and novel heterozygous variants in patients with apparently unsolved suspected mitochondrial disease investigated using next-generation sequencing.

PMID: 28955726 [PubMed]

Tongxinluo Inhibits Renal Fibrosis in Diabetic Nephropathy: Involvement of the Suppression of Intercellular Transfer of TGF-[Formula: see text]1-Containing Exosomes from GECs to GMCs.

Am J Chin Med. 2017;45(5):1075-1092

Authors: Wu XM, Gao YB, Xu LP, Zou DW, Zhu ZY, Wang XL, Yao WJ, Luo LT, Tong Y, Tian NX, Han ZJ, Dang WY

Abstract
Glomerular mesangial cells (GMCs) activation is implicated in the pathogenesis of diabetic nephropathy (DN). Our previous study revealed that high glucose (HG)-treated glomerular endothelial cells (GECs) produce an increased number of TGF-[Formula: see text]1-containing exosomes to activate GMCs through the TGF-[Formula: see text]1/Smad3 signaling pathway. We also identified that Tongxinluo (TXL), a traditional Chinese medicine, has beneficial effects on the treatment of DN in DN patients and type 2 diabetic mice. However, it remained elusive whether TXL could ameliorate renal structure and function through suppression of intercellular transfer of TGF-[Formula: see text]1-containing exosomes from GECs to GMCs. In this study, we demonstrate that TXL can inhibit the secretion of TGF-[Formula: see text]1-containing exosomes from HG-treated GECs. Furthermore, exosomes produced by HG induced-GECs treated with TXL cannot trigger GMC activation, proliferation and extracellular matrix (ECM) overproduction both in vitro and in vivo. These results suggest that TXL can prevent the transfer of TGF-[Formula: see text]1 from GECs to GMCs via exosomes, which may be one of the mechanisms of TXL in the treatment of DN.

PMID: 28659030 [PubMed - indexed for MEDLINE]

Gene-set analysis shows association between FMRP targets and autism spectrum disorder.

Eur J Hum Genet. 2017 Jun;25(7):863-868

Authors: Jansen A, Dieleman GC, Smit AB, Verhage M, Verhulst FC, Polderman TJC, Posthuma D

Abstract
Autism spectrum disorder (ASD) is a heterogeneous group of disorders characterized by problems with social interaction, communication, and repetitive and restricted behavior. Despite its high heritability and the substantial progress made in elucidating genetic associations, the corresponding biological mechanisms are largely unknown. Our objective is to investigate the contribution of common genetic variation to biological pathways functionally involved in ASD. We conducted gene-set analyses to identify ASD-associated functional biological pathways using the statistical tools MAGMA and INRICH. Gene-set selection was based on previously reported associations with psychiatric disorders and resulted in testing of specific synaptic and glial sets, a glutamate pathway gene-set, mitochondrial gene-sets and gene-sets consisting of fragile X mental retardation protein (FMRP) targets. In total 32 gene-sets were tested. We used Psychiatric Genomics Consortium genome-wide association studies summary statistics of ASD. The study is based on the largest ASD sample to date (N=5305). We found one significantly associated gene-set consisting of FMRP-targeting transcripts (MAGMA: p corr.=0.014, INRICH: p corr.=0.031; all competitive P-values). The results indicate the involvement of FMRP-targeted transcripts in ASD in common genetic variation. This novel finding is in line with the literature as FMRP has been linked to fragile X syndrome, ASD and cognitive development in whole-exome sequencing and copy number variant studies. This gene-set has also been linked to Schizophrenia suggesting that FMRP-targeted transcripts might be involved in a general mechanism with shared genetic etiology between psychiatric disorders.

PMID: 28422133 [PubMed - indexed for MEDLINE]

Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID.

Eur J Hum Genet. 2017 Jun;25(7):889-893

Authors: Redler S, Strom TM, Wieland T, Cremer K, Engels H, Distelmaier F, Schaper J, Küchler A, Lemke JR, Jeschke S, Schreyer N, Sticht H, Koch M, Lüdecke HJ, Wieczorek D

Abstract
For a large number of individuals with intellectual disability (ID), the molecular basis of the disorder is still unknown. However, whole-exome sequencing (WES) is providing more and more insights into the genetic landscape of ID. In the present study, we performed trio-based WES in 311 patients with unsolved ID and additional clinical features, and identified homozygous CPLX1 variants in three patients with ID from two unrelated families. All displayed marked developmental delay and migrating myoclonic epilepsy, and one showed a cerebellar cleft in addition. The encoded protein, complexin 1, is crucially involved in neuronal synaptic regulation, and homozygous Cplx1 knockout mice have the earliest known onset of ataxia seen in a mouse model. Recently, a homozygous truncating variant in CPLX1 was suggested to be causative for migrating epilepsy and structural brain abnormalities. ID was not reported although it cannot be completely ruled out. However, the currently limited knowledge on CPLX1 suggests that loss of complexin 1 function may lead to a complex but variable clinical phenotype, and our findings encourage further investigations of CPLX1 in patients with ID, developmental delay and myoclonic epilepsy to unravel the phenotypic spectrum of carriers of CPLX1 variants.

PMID: 28422131 [PubMed - indexed for MEDLINE]

Associations Between Cancer Predisposition Testing Panel Genes and Breast Cancer.

JAMA Oncol. 2017 Sep 01;3(9):1190-1196

Authors: Couch FJ, Shimelis H, Hu C, Hart SN, Polley EC, Na J, Hallberg E, Moore R, Thomas A, Lilyquist J, Feng B, McFarland R, Pesaran T, Huether R, LaDuca H, Chao EC, Goldgar DE, Dolinsky JS

Abstract
Importance: Germline pathogenic variants in BRCA1 and BRCA2 predispose to an increased lifetime risk of breast cancer. However, the relevance of germline variants in other genes from multigene hereditary cancer testing panels is not well defined.
Objective: To determine the risks of breast cancer associated with germline variants in cancer predisposition genes.
Design, Setting, and Participants: A study population of 65 057 patients with breast cancer receiving germline genetic testing of cancer predisposition genes with hereditary cancer multigene panels. Associations between pathogenic variants in non-BRCA1 and non-BRCA2 predisposition genes and breast cancer risk were estimated in a case-control analysis of patients with breast cancer and Exome Aggregation Consortium reference controls. The women underwent testing between March 15, 2012, and June 30, 2016.
Main Outcomes and Measures: Breast cancer risk conferred by pathogenic variants in non-BRCA1 and non-BRCA2 predisposition genes.
Results: The mean (SD) age at diagnosis for the 65 057 women included in the analysis was 48.5 (11.1) years. The frequency of pathogenic variants in 21 panel genes identified in 41 611 consecutively tested white women with breast cancer was estimated at 10.2%. After exclusion of BRCA1, BRCA2, and syndromic breast cancer genes (CDH1, PTEN, and TP53), observed pathogenic variants in 5 of 16 genes were associated with high or moderately increased risks of breast cancer: ATM (OR, 2.78; 95% CI, 2.22-3.62), BARD1 (OR, 2.16; 95% CI, 1.31-3.63), CHEK2 (OR, 1.48; 95% CI, 1.31-1.67), PALB2 (OR, 7.46; 95% CI, 5.12-11.19), and RAD51D (OR, 3.07; 95% CI, 1.21-7.88). Conversely, variants in the BRIP1 and RAD51C ovarian cancer risk genes; the MRE11A, RAD50, and NBN MRN complex genes; the MLH1 and PMS2 mismatch repair genes; and NF1 were not associated with increased risks of breast cancer.
Conclusions and Relevance: This study establishes several panel genes as high- and moderate-risk breast cancer genes and provides estimates of breast cancer risk associated with pathogenic variants in these genes among individuals qualifying for clinical genetic testing.

PMID: 28418444 [PubMed - indexed for MEDLINE]

Two females with mutations in USP9X highlight the variable expressivity of the intellectual disability syndrome.

Eur J Med Genet. 2017 Jul;60(7):359-364

Authors: Au PYB, Huang L, Broley S, Gallagher L, Creede E, Lahey D, Ordorica S, Mina K, Boycott KM, Baynam G, Dyment DA

Abstract
The genetic causes of intellectual disability (ID) are heterogeneous and include both chromosomal and monogenic etiologies. The X-chromosome is known to contain many ID-related genes and males show a marked predominance for intellectual disability. Here we report two females with syndromic intellectual disability. The first individual was relatively mild in her presentation with mild-moderate intellectual disability, hydronephrosis and altered pigmentation along the lines of Blaschko without additional congenital anomalies. A second female presented shortly after birth with dysmorphic facial features, post-axial polydactyly and, on follow-up assessment, demonstrated moderate intellectual disability. Chromosomal studies for Individual 1 identified an X-chromosome deletion due to a de novo pericentric inversion; the inversion breakpoint was associated with deletion of the 5'UTR of the USP9X, a gene which has been implicated in a syndromic intellectual disability affecting females. The second individual had a de novo frameshift mutation detected by whole-exome sequencing that was predicted to be deleterious, NM_001039590.2 (USP9X): c.4104_4105del (p.(Arg1368Serfs*2)). Haploinsufficiency of USP9X in females has been associated with ID and congenital malformations that include heart defects, scoliosis, dental abnormalities, anal atresia, polydactyly, Dandy Walker malformation and hypoplastic corpus callosum. The extent of the congenital malformations observed in Individual 1 was less striking than Individual 2 and other individuals previously reported in the literature, and suggests that USP9X mutations in females can have a wider spectrum of presentation than previously appreciated.

PMID: 28377321 [PubMed - indexed for MEDLINE]

Tocilizumab Promotes Regulatory T-cell Alleviation in STAT3 Gain-of-function-associated Multi-organ Autoimmune Syndrome.

Clin Ther. 2017 Feb;39(2):444-449

Authors: Khoury T, Molho-Pessach V, Ramot Y, Ayman AR, Elpeleg O, Berkman N, Zlotogorski A, Ilan Y

Abstract
PURPOSE: Signal transducer and activator of transcription 3 is a member of a family of proteins involved in the regulation of inflammation, differentiation, proliferation, and survival of cells. Here we describe a 38-year-old male who has experienced gastrointestinal, dermatologic, pulmonary, and malignant manifestations.
METHODS: Whole-exome sequencing, validated by Sanger sequencing, was performed after extensive investigations.
FINDINGS: Whole-exome sequencing revealed a heterozygous missense mutation in the signal transducer and activator of transcription 3 gene, c.1261G>A (p.G421R). Fluorescence-activated cell sorting analysis of peripheral T lymphocytes revealed low levels of CD4(+)CD25(+)FoxP3 and CD8(+)CD25(+)FoxP3 regulatory T cells. After treatment with 2 cycles of tocilizumab, an interleukin-6 receptor antibody, a significant increase in the level of regulatory T cells was observed, accompanied by clinical improvement.
IMPLICATIONS: This case sheds light on the emerging role of signal transducer and activator of transcription 3 gain-of-function mutation in the pathogenesis of autoimmune diseases, and further addresses the therapeutic role of interleukin-6 blocker treatment in this syndrome.

PMID: 28153428 [PubMed - indexed for MEDLINE]

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Analysis of sequence data to identify potential risk variants for oral clefts in multiplex families.

Mol Genet Genomic Med. 2017 Sep;5(5):570-579

Authors: Holzinger ER, Li Q, Parker MM, Hetmanski JB, Marazita ML, Mangold E, Ludwig KU, Taub MA, Begum F, Murray JC, Albacha-Hejazi H, Alqosayer K, Al-Souki G, Albasha Hejazi A, Scott AF, Beaty TH, Bailey-Wilson JE

Abstract
BACKGROUND: Nonsyndromic oral clefts are craniofacial malformations, which include cleft lip with or without cleft palate. The etiology for oral clefts is complex with both genetic and environmental factors contributing to risk. Previous genome-wide association (GWAS) studies have identified multiple loci with small effects; however, many causal variants remain elusive.
METHODS: In this study, we address this by specifically looking for rare, potentially damaging variants in family-based data. We analyzed both whole exome sequence (WES) data and whole genome sequence (WGS) data in multiplex cleft families to identify variants shared by affected individuals.
RESULTS: Here we present the results from these analyses. Our most interesting finding was from a single Syrian family, which showed enrichment of nonsynonymous and potentially damaging rare variants in two genes: CASP9 and FAT4.
CONCLUSION: Neither of these candidate genes has previously been associated with oral clefts and, if confirmed as contributing to disease risk, may indicate novel biological pathways in the genetic etiology for oral clefts.

PMID: 28944239 [PubMed]