Tumor heterogeneity predicts metastatic potential in colorectal cancer.

Clin Cancer Res. 2017 Sep 22;:

Authors: Joung JG, Oh BY, Hong HK, AlKhalidi H, Al-Alem F, Lee HO, Bae JS, Kim J, Cha HU, Alotaibi M, Cho YB, Hassanain M, Lee WY, Park WY

Abstract
PURPOSE: Tumors continuously evolve to maintain growth; secondary mutations facilitate this process, resulting in high tumor heterogeneity. In this study, we compared mutations in paired primary and metastatic colorectal cancer (CRC) tumor samples to determine whether tumor heterogeneity can predict tumor metastasis.
EXPERIMENTAL DESIGN: Somatic variations in 46 pairs of matched primary-liver metastatic tumors and 42 primary tumors without metastasis were analyzed by whole exome sequencing. Tumor clonality was estimated from single nucleotide and copy number variations. The correlation between clinical parameters of patients and clonal heterogeneity in liver metastasis was evaluated.
RESULTS: Tumor heterogeneity across CRC samples was highly variable; however, a high degree of tumor heterogeneity was associated with a worse disease free survival. Highly heterogeneous primary CRC was correlated with a higher rate of liver metastasis. Recurrent somatic mutations in APC, TP53, and KRAS were frequently detected in highly heterogeneous CRC. The variant allele frequency of these mutations was high, while somatic mutations in other genes such as PIK3CA and NOTCH1 were low. The number and distribution of primary CRC sub-clones were preserved in metastatic tumors.
CONCLUSIONS: Heterogeneity of primary CRC tumors can predict the potential for liver metastasis and thus, clinical outcome of patients.

PMID: 28939741 [PubMed - as supplied by publisher]

A targeted next-generation sequencing panel reveals novel mutations in Japanese patients with primary ciliary dyskinesia.

Auris Nasus Larynx. 2017 Sep 19;:

Authors: Takeuchi K, Kitano M, Kiyotoshi H, Ikegami K, Ogawa S, Ikejiri M, Nagao M, Fujisawa T, Nakatani K

Abstract
OBJECTIVE: Primary ciliary dyskinesia (PCD) is a rare genetic disorder caused by functional impairment of cilia throughout the body. The early diagnosis of PCD is important for the prevention of long-term sequelae; however, this is often challenging because of the phenotypic heterogeneity of PCD and difficulty in genetic analysis. The majority of PCD patients in Japan are not diagnosed properly. To diagnose PCD more accurately, we developed a targeted next-generation sequencing (NGS) panel.
METHODS: We examined 46 patients (age range, 1-64 years; 23 male and 23 female) who were clinically suspected of PCD. First, mutation hotspots in DNAH5 and DNAI1 were sequenced by the Sanger method. Next, exome sequencing was performed in 32 known PCD genes using our novel NGS panel with the Ion Torrent PGM system. Variant annotation was generated by Ion Reporter Version 5.0 (Life Technologies). Mutations found in the panel were validated by Sanger sequencing.
RESULTS: Disease-causing gene mutations were found in 10 patients from 7 families: DNAH5 in 4 families, and DNAI1, CCDC40, and RSPH4A in 1 family each. Heterozygous mutations were found in 1 patient. The majority of the mutations found in the present analysis were novel.
CONCLUSION: Japanese PCD patients have novel mutations in cilia-related genes. This targeted NGS panel can identify disease-causing mutations in patients with PCD.

PMID: 28939216 [PubMed - as supplied by publisher]

Whole exome sequencing in inborn errors of immunity: use the power but mind the limits.

Curr Opin Allergy Clin Immunol. 2017 Sep 21;:

Authors: Bucciol G, Van Nieuwenhove E, Moens L, Itan Y, Meyts I

Abstract
PURPOSE OF REVIEW: Next-generation sequencing, especially whole exome sequencing (WES), has revolutionized the molecular diagnosis of inborn errors of immunity. This review summarizes the generation and analysis of next-generation sequencing data.
RECENT FINDINGS: The focus is on prioritizing strategies for unveiling the potential disease-causing variant. We also highlighted oversights and imperfections of WES and targeted panel sequencing, as well as the need for functional validation.
SUMMARY: The information is crucial for a judicious use of WES by researchers, but even more so by the clinical immunologist.

PMID: 28938278 [PubMed - as supplied by publisher]

Severe Neonatal Cholestasis in Cerebrotendinous Xanthomatosis: Genetics, Immunostaining, Mass Spectrometry.

J Pediatr Gastroenterol Nutr. 2017 Sep 20;:

Authors: Gong JY, Setchell KDR, Zhao J, Zhang W, Wolfe B, Lu Y, Lackner K, Knisely AS, Wang NL, Hao CZ, Zhang MH, Wang JS

Abstract
OBJECTIVES: Cerebrotendinous xanthomatosis (CTX) is caused by defects in sterol 27-hydroxylase (CYP27A1, encoded by CYP27A1), a key enzyme in the bile acid synthesis pathway. CTX usually presents as neurologic disease in adults or older children. The very rare reports of CTX manifest as neonatal cholestasis assess the cholestasis as transient, with patient survival. Our experience differs.
METHODS: Homozygous or compound heterozygous CYP27A1 mutations were detected in 8 neonatal cholestasis patients by whole exome sequencing, panel sequencing, or Sanger sequencing. Their clinical and biochemical data were retrospectively reviewed. Immunostaining for CYP27A1 was conducted in liver of 4 patients. Mass spectrometry was used to analyze patients' urine samples.
RESULTS: All 8 infants had severe cholestasis. Five died from, or were transplanted for, liver failure; 3 cleared their jaundice eventually. Marking for CYP27A1 was weak or absent in 3 of the 4 patient specimens. Mass spectrometry of urine revealed a predominance of sulfated and doubly conjugated (sulfated-glucuronidated) bile alcohols. No patient harbored a putatively pathogenic mutation in genes other than CYP27A1 that have been implicated in cholestatic liver disease.
CONCLUSION: CTX manifest as neonatal cholestasis has a bile acid profile different from CTX manifest in later life, and thus may be overlooked. Immunostaining, mass spectrometry of urine, and genetic studies can support one another in making the diagnosis. A substantial proportion of CTX patients with severe neonatal cholestasis may die or need liver transplantation. CTX manifest in infancy as severe cholestasis warrants further investigation of biochemical diagnostic criteria and best management.

PMID: 28937538 [PubMed - as supplied by publisher]

Effective Immunological Guidance of Genetic Analyses Including Exome Sequencing in Patients Evaluated for Hemophagocytic Lymphohistiocytosis.

J Clin Immunol. 2017 Sep 21;:

Authors: Ammann S, Lehmberg K, Zur Stadt U, Klemann C, Bode SFN, Speckmann C, Janka G, Wustrau K, Rakhmanov M, Fuchs I, Hennies HC, Ehl S, HLH study of the GPOH

Abstract
We report our experience in using flow cytometry-based immunological screening prospectively as a decision tool for the use of genetic studies in the diagnostic approach to patients with hemophagocytic lymphohistiocytosis (HLH). We restricted genetic analysis largely to patients with abnormal immunological screening, but included whole exome sequencing (WES) for those with normal findings upon Sanger sequencing. Among 290 children with suspected HLH analyzed between 2010 and 2014 (including 17 affected, but asymptomatic siblings), 87/162 patients with "full" HLH and 79/111 patients with "incomplete/atypical" HLH had normal immunological screening results. In 10 patients, degranulation could not be tested. Among the 166 patients with normal screening, genetic analysis was not performed in 107 (all with uneventful follow-up), while 154 single gene tests by Sanger sequencing in the remaining 59 patients only identified a single atypical CHS patient. Flow cytometry correctly predicted all 29 patients with FHL-2, XLP1 or 2. Among 85 patients with defective NK degranulation (including 13 asymptomatic siblings), 70 were Sanger sequenced resulting in a genetic diagnosis in 55 (79%). Eight patients underwent WES, revealing mutations in two known and one unknown cytotoxicity genes and one metabolic disease. FHL3 was the most frequent genetic diagnosis. Immunological screening provided an excellent decision tool for the need and depth of genetic analysis of HLH patients and provided functionally relevant information for rapid patient classification, contributing to a significant reduction in the time from diagnosis to transplantation in recent years.

PMID: 28936583 [PubMed - as supplied by publisher]

Identification of novel candidate disease genes from de novo exonic copy number variants.

Genome Med. 2017 Sep 21;9(1):83

Authors: Gambin T, Yuan B, Bi W, Liu P, Rosenfeld JA, Coban-Akdemir Z, Pursley AN, Nagamani SCS, Marom R, Golla S, Dengle L, Petrie HG, Matalon R, Emrick L, Proud MB, Treadwell-Deering D, Chao HT, Koillinen H, Brown C, Urraca N, Mostafavi R, Bernes S, Roeder ER, Nugent KM, Bader PI, Bellus G, Cummings M, Northrup H, Ashfaq M, Westman R, Wildin R, Beck AE, Immken L, Elton L, Varghese S, Buchanan E, Faivre L, Lefebvre M, Schaaf CP, Walkiewicz M, Yang Y, Kang SL, Lalani SR, Bacino CA, Beaudet AL, Breman AM, Smith JL, Cheung SW, Lupski JR, Patel A, Shaw CA, Stankiewicz P

Abstract
BACKGROUND: Exon-targeted microarrays can detect small (<1000 bp) intragenic copy number variants (CNVs), including those that affect only a single exon. This genome-wide high-sensitivity approach increases the molecular diagnosis for conditions with known disease-associated genes, enables better genotype-phenotype correlations, and facilitates variant allele detection allowing novel disease gene discovery.
METHODS: We retrospectively analyzed data from 63,127 patients referred for clinical chromosomal microarray analysis (CMA) at Baylor Genetics laboratories, including 46,755 individuals tested using exon-targeted arrays, from 2007 to 2017. Small CNVs harboring a single gene or two to five non-disease-associated genes were identified; the genes involved were evaluated for a potential disease association.
RESULTS: In this clinical population, among rare CNVs involving any single gene reported in 7200 patients (11%), we identified 145 de novo autosomal CNVs (117 losses and 28 intragenic gains), 257 X-linked deletion CNVs in males, and 1049 inherited autosomal CNVs (878 losses and 171 intragenic gains); 111 known disease genes were potentially disrupted by de novo autosomal or X-linked (in males) single-gene CNVs. Ninety-one genes, either recently proposed as candidate disease genes or not yet associated with diseases, were disrupted by 147 single-gene CNVs, including 37 de novo deletions and ten de novo intragenic duplications on autosomes and 100 X-linked CNVs in males. Clinical features in individuals with de novo or X-linked CNVs encompassing at most five genes (224 bp to 1.6 Mb in size) were compared to those in individuals with larger-sized deletions (up to 5 Mb in size) in the internal CMA database or loss-of-function single nucleotide variants (SNVs) detected by clinical or research whole-exome sequencing (WES). This enabled the identification of recently published genes (BPTF, NONO, PSMD12, TANGO2, and TRIP12), novel candidate disease genes (ARGLU1 and STK3), and further confirmation of disease association for two recently proposed disease genes (MEIS2 and PTCHD1). Notably, exon-targeted CMA detected several pathogenic single-exon CNVs missed by clinical WES analyses.
CONCLUSIONS: Together, these data document the efficacy of exon-targeted CMA for detection of genic and exonic CNVs, complementing and extending WES in clinical diagnostics, and the potential for discovery of novel disease genes by genome-wide assay.

PMID: 28934986 [PubMed - in process]

TECRL, a new life-threatening inherited arrhythmia gene associated with overlapping clinical features of both LQTS and CPVT.

EMBO Mol Med. 2016 12;8(12):1390-1408

Authors: Devalla HD, Gélinas R, Aburawi EH, Beqqali A, Goyette P, Freund C, Chaix MA, Tadros R, Jiang H, Le Béchec A, Monshouwer-Kloots JJ, Zwetsloot T, Kosmidis G, Latour F, Alikashani A, Hoekstra M, Schlaepfer J, Mummery CL, Stevenson B, Kutalik Z, de Vries AA, Rivard L, Wilde AA, Talajic M, Verkerk AO, Al-Gazali L, Rioux JD, Bhuiyan ZA, Passier R

Abstract
Genetic causes of many familial arrhythmia syndromes remain elusive. In this study, whole-exome sequencing (WES) was carried out on patients from three different families that presented with life-threatening arrhythmias and high risk of sudden cardiac death (SCD). Two French Canadian probands carried identical homozygous rare variant in TECRL gene (p.Arg196Gln), which encodes the trans-2,3-enoyl-CoA reductase-like protein. Both patients had cardiac arrest, stress-induced atrial and ventricular tachycardia, and QT prolongation on adrenergic stimulation. A third patient from a consanguineous Sudanese family diagnosed with catecholaminergic polymorphic ventricular tachycardia (CPVT) had a homozygous splice site mutation (c.331+1G>A) in TECRL Analysis of intracellular calcium ([Ca(2+)]i) dynamics in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) generated from this individual (TECRLHom-hiPSCs), his heterozygous but clinically asymptomatic father (TECRLHet-hiPSCs), and a healthy individual (CTRL-hiPSCs) from the same Sudanese family, revealed smaller [Ca(2+)]i transient amplitudes as well as elevated diastolic [Ca(2+)]i in TECRLHom-hiPSC-CMs compared with CTRL-hiPSC-CMs. The [Ca(2+)]i transient also rose markedly slower and contained lower sarcoplasmic reticulum (SR) calcium stores, evidenced by the decreased magnitude of caffeine-induced [Ca(2+)]i transients. In addition, the decay phase of the [Ca(2+)]i transient was slower in TECRLHom-hiPSC-CMs due to decreased SERCA and NCX activities. Furthermore, TECRLHom-hiPSC-CMs showed prolonged action potentials (APs) compared with CTRL-hiPSC-CMs. TECRL knockdown in control human embryonic stem cell-derived CMs (hESC-CMs) also resulted in significantly longer APs. Moreover, stimulation by noradrenaline (NA) significantly increased the propensity for triggered activity based on delayed afterdepolarizations (DADs) in TECRLHom-hiPSC-CMs and treatment with flecainide, a class Ic antiarrhythmic drug, significantly reduced the triggered activity in these cells. In summary, we report that mutations in TECRL are associated with inherited arrhythmias characterized by clinical features of both LQTS and CPVT Patient-specific hiPSC-CMs recapitulated salient features of the clinical phenotype and provide a platform for drug screening evidenced by initial identification of flecainide as a potential therapeutic. These findings have implications for diagnosis and treatment of inherited cardiac arrhythmias.

PMID: 27861123 [PubMed - indexed for MEDLINE]

Genetic analysis of hereditary gingival fibromatosis using whole exome sequencing and bioinformatics.

Oral Dis. 2017 Jan;23(1):102-109

Authors: Hwang J, Kim YL, Kang S, Kim S, Kim SO, Lee JH, Han DH

Abstract
OBJECTIVES: Our study aims to identify genetic variants associated with hereditary gingival fibromatosis (HGF) by applying whole-exome sequencing (WES) and bioinformatics analyses such as gene set enrichment analysis (GSEA) and protein functional network study.
SUBJECTS AND METHODS: Two affected siblings whose grandparents and parents have normal gingiva were chosen for our investigation. Saliva collected from the patients and their parents were used for WES. GSEA and protein functional network study were performed to find gene groups in a biological coordination which are associated with HGF.
RESULTS: Genetic variants for homozygotes and compound heterozygotes were analyzed and translated into 845 genes. The result from protein functional network study showed that these genetic variants were mainly observed in genes affecting fibronectin as well as the immune and autoimmune system. Additionally, three mutated genes in our HGF patients, TMCO1, RIN2, and INSR, were found through human phenotype ontology (HPO) to have potential to contribute to gingival hyperplasia.
CONCLUSIONS: Genetic analysis of HGF in this study implicated mutations in fibronectin and the immune system as triggering abnormal gingival fibromatosis.

PMID: 27614106 [PubMed - indexed for MEDLINE]

HESX1 mutations in patients with congenital hypopituitarism: variable phenotypes with the same genotype.

Clin Endocrinol (Oxf). 2016 Sep;85(3):408-14

Authors: Fang Q, Benedetti AF, Ma Q, Gregory L, Li JZ, Dattani M, Sadeghi-Nejad A, Arnhold IJ, Mendonca BB, Camper SA, Carvalho LR

Abstract
INTRODUCTION: Mutations in the transcription factor HESX1 can cause isolated growth hormone deficiency (IGHD) or combined pituitary hormone deficiency (CPHD) with or without septo-optic dysplasia (SOD). So far there is no clear genotype-phenotype correlation.
PATIENTS AND RESULTS: We report four different recessive loss-of-function mutations in three unrelated families with CPHD and no midline defects or SOD. A homozygous p.R160C mutation was found by Sanger sequencing in two siblings from a consanguineous family. These patients presented with ACTH, TSH and GH deficiencies, severe anterior pituitary hypoplasia (APH) or pituitary aplasia (PA) and normal posterior pituitary. The p.R160C mutation was previously reported in a case with SOD, CPHD and ectopic posterior pituitary (EPP). Using exome sequencing, a homozygous p.I26T mutation was found in a Brazilian patient born to consanguineous parents. This patient had evolving CPHD, normal ACTH, APH and normal posterior pituitary (NPP). A previously reported patient homozygous for p.I26T had evolving CPHD and EPP. Finally, we identified compound heterozygous mutations in HESX1, p.[R159W];[R160H], in a patient with PA and CPHD. We showed that both of these mutations abrogate the ability of HESX1 to repress PROP1-mediated transcriptional activation. A patient homozygous for p.R160H was previously reported in a patient with CPHD, EPP, APH.
CONCLUSION: These three examples demonstrate that HESX1 mutations cause variable clinical features in patients, which suggests an influence of modifier genes or environmental factors on the phenotype.

PMID: 27000987 [PubMed - indexed for MEDLINE]

Whole exome sequencing identified a novel missense mutation in EPM2A underlying Lafora disease in a Pakistani family.

Seizure. 2017 Sep 01;51:200-203

Authors: Aslam Z, Lee E, Badshah M, Naeem M, Kang C

PMID: 28934672 [PubMed - as supplied by publisher]

The HNF1A mutant Ala180Val: Clinical challenges in determining causality of a rare HNF1A variant in familial diabetes.

Diabetes Res Clin Pract. 2017 Sep 01;133:142-149

Authors: Sagen JV, Bjørkhaug L, Haukanes BI, Grevle L, Molnes J, Nedrebø BG, Søvik O, Njølstad PR, Johansson S, Molven A

Abstract
AIMS: Heterozygous mutations in hepatocyte nuclear factor-1A (HNF1A) cause maturity-onset diabetes of the young type 3 (MODY3). Our aim was to compare two families with suspected dominantly inherited diabetes and a new HNF1A variant of unknown clinical significance.
METHODS: The HNF1A gene was sequenced in two independently recruited families from the Norwegian MODY Registry. Both familes were phenotyped clinically and biochemically. Microsatellite markers around and within the HNF1A locus were used for haplotyping. Chromosomal linkage analysis was performed in one family, and whole-exome sequencing was undertaken in two affected family members from each family. Transactivation activity, DNA binding and nuclear localization of wild type and mutant HNF-1A were assessed.
RESULTS: The novel HNF1A variant c.539C>T (p.Ala180Val) was found in both families. The variant fully co-segregated with diabetes in one family. In the other family, two subjects with diabetes mellitus and one with normal glucose levels were homozygous variant carriers. Chromosomal linkage of diabetes to the HNF1A locus or to other genomic regions could not be established. The protein functional studies did not reveal significant differences between wild type and variant HNF-1A. In each family, whole-exome sequencing failed to identify any other variant that could explain the disease.
CONCLUSIONS: The HNF1A variant p.Ala180Val does not seem to cause MODY3, although it may confer risk for type 2 diabetes mellitus. Our data demonstrate challenges in causality evaluation of rare variants detected in known diabetes genes.

PMID: 28934671 [PubMed - as supplied by publisher]

UFM1 founder mutation in the Roma population causes recessive variant of H-ABC.

Neurology. 2017 Sep 20;:

Authors: Hamilton EMC, Bertini E, Kalaydjieva L, Morar B, Dojčáková D, Liu J, Vanderver A, Curiel J, Persoon CM, Diodato D, Pinelli L, van der Meij NL, Plecko B, Blaser S, Wolf NI, Waisfisz Q, Abbink TEM, van der Knaap MS, Recessive H-ABC Research Group

Abstract
OBJECTIVE: To identify the gene defect in patients with hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) who are negative for TUBB4A mutations.
METHODS: We performed homozygosity mapping and whole exome sequencing (WES) to detect the disease-causing variant. We used a Taqman assay for population screening. We developed a luciferase reporter construct to investigate the effect of the promoter mutation on expression.
RESULTS: Sixteen patients from 14 families from different countries fulfilling the MRI criteria for H-ABC exhibited a similar, severe clinical phenotype, including lack of development and a severe epileptic encephalopathy. The majority of patients had a known Roma ethnic background. Single nucleotide polymorphism array analysis in 5 patients identified one large overlapping homozygous region on chromosome 13. WES in 2 patients revealed a homozygous deletion in the promoter region of UFM1. Sanger sequencing confirmed homozygosity for this variant in all 16 patients. All patients shared a common haplotype, indicative of a founder effect. Screening of 1,000 controls from different European Roma panels demonstrated an overall carrier rate of the mutation of 3%-25%. Transfection assays showed that the deletion significantly reduced expression in specific CNS cell lines.
CONCLUSIONS: UFM1 encodes ubiquitin-fold modifier 1 (UFM1), a member of the ubiquitin-like family involved in posttranslational modification of proteins. Its exact biological role is unclear. This study associates a UFM1 gene defect with a disease and sheds new light on possible UFM1 functional networks.

PMID: 28931644 [PubMed - as supplied by publisher]

Variation in AKT Protein Kinases in Human Populations.

Am J Physiol Regul Integr Comp Physiol. 2017 Sep 20;:ajpregu.00295.2017

Authors: Rotwein P

Abstract
The three AKT kinases are related proteins that are essential for normal growth and metabolic regulation, and are implicated as key signaling mediators in many physiological and patho-physiological processes. Each AKT is activated by common biochemical signals that act downstream of growth factor and hormone receptors via phosphatidylinositol-3 kinase, and each controls several downstream pathways. The importance of AKT actions in human physiology is strengthened by the rarity of modifying mutations in their genes, and by the devastating impact caused by these mutations on growth and development, and in disorders such as cancer. Recent advances in genomics present unique opportunities for enhancing our understanding of human physiology and disease predisposition through the lens of population genetics, and the availability of DNA sequence data from 60,706 people in the Exome Aggregation Consortium has prompted this analysis. Results reveal a cohort of potential missense and other alterations in the coding regions of each AKT gene, but with nearly all changes being uncommon. The total number of different alleles per gene varied over an ~3-fold range, from 52 for AKT3 to 158 for AKT2, with variants distributed throughout all AKT protein domains. Previously characterized disease-causing mutations were found rarely in the general population. In contrast, a fairly prevalent amino acid substitution in AKT2 appears linked to increased predisposition for type-2 diabetes. Further analysis of variant AKT molecules as identified here will provide opportunities to understand the intricacies of AKT signaling and actions at a population level in human physiology and pathology.

PMID: 28931550 [PubMed - as supplied by publisher]

Molecular investigation by whole exome sequencing revealed a high proportion of pathogenic variants among Thai victims of sudden unexpected death syndrome.

PLoS One. 2017;12(7):e0180056

Authors: Suktitipat B, Sathirareuangchai S, Roothumnong E, Thongnoppakhun W, Wangkiratikant P, Vorasan N, Krittayaphong R, Pithukpakorn M, Boonyapisit W

Abstract
INTRODUCTION: Sudden unexpected death syndrome (SUDS) is an important cause of death in young healthy adults with a high incident rate in Southeast Asia; however, there are no molecular autopsy reports about these victims. We performed a combination of both a detailed autopsy and a molecular autopsy by whole exome sequencing (WES) to investigate the cause of SUDS in Thai sudden death victims.
MATERIALS AND METHODS: A detailed forensic autopsy was performed to identify the cause of death, followed by a molecular autopsy, in 42 sudden death victims who died between January 2015 and August 2015. The coding sequences of 98 SUDS-related genes were sequenced using WES. Potentially causative variants were filtered based on the variant functions annotated in the dbNSFP database. Variants with inconclusive clinical significance evidence in ClinVar were resolved with a variant prediction algorithm, metaSVM, and the frequency data of the variants found in public databases, such as the 1000 Genome Project, ESP6500 project, and the Exome Aggregation Consortium (ExAc) project.
RESULTS: Combining both autopsy and molecular autopsy enabled the potential identification of cause of death in 81% of the cases. Among the 25 victims with WES data, 72% (18/25) were found to have potentially causative SUDS mutations. The majority of the victims had at a mutation in the TTN gene (8/18 = 44%), and only one victim had an SCN5A mutation.
CONCLUSIONS: WES can help to identify the genetic causes in victims of SUDS and may help to further guide investigations into their relatives to prevent additional SUDS victims.

PMID: 28704380 [PubMed - indexed for MEDLINE]

The contribution of rare variants to risk of schizophrenia in individuals with and without intellectual disability.

Nat Genet. 2017 Aug;49(8):1167-1173

Authors: Singh T, Walters JTR, Johnstone M, Curtis D, Suvisaari J, Torniainen M, Rees E, Iyegbe C, Blackwood D, McIntosh AM, Kirov G, Geschwind D, Murray RM, Di Forti M, Bramon E, Gandal M, Hultman CM, Sklar P, INTERVAL Study, UK10K Consortium, Palotie A, Sullivan PF, O'Donovan MC, Owen MJ, Barrett JC

Abstract
By performing a meta-analysis of rare coding variants in whole-exome sequences from 4,133 schizophrenia cases and 9,274 controls, de novo mutations in 1,077 family trios, and copy number variants from 6,882 cases and 11,255 controls, we show that individuals with schizophrenia carry a significant burden of rare, damaging variants in 3,488 genes previously identified as having a near-complete depletion of loss-of-function variants. In patients with schizophrenia who also have intellectual disability, this burden is concentrated in risk genes associated with neurodevelopmental disorders. After excluding known risk genes for neurodevelopmental disorders, a significant rare variant burden persists in other genes intolerant of loss-of-function variants; although this effect is notably stronger in patients with both schizophrenia and intellectual disability, it is also seen in patients with schizophrenia who do not have intellectual disability. Together, our results show that rare, damaging variants contribute to the risk of schizophrenia both with and without intellectual disability and support an overlap of genetic risk between schizophrenia and other neurodevelopmental disorders.

PMID: 28650482 [PubMed - indexed for MEDLINE]

Whole-exome sequencing implicates DGKH as a risk gene for panic disorder in the Faroese population.

Am J Med Genet B Neuropsychiatr Genet. 2016 Dec;171(8):1013-1022

Authors: Gregersen NO, Lescai F, Liang J, Li Q, Als T, Buttenschøn HN, Hedemand A, Biskopstø M, Wang J, Wang AG, Børglum AD, Mors O, Demontis D

Abstract
The demographic history of the isolated population of the Faroe Islands may have induced enrichment of variants rarely seen in outbred European populations, including enrichment of risk variants for panic disorder (PD). PD is a common mental disorder, characterized by recurring and unprovoked panic attacks, and genetic factors have been estimated to explain around 40% of the risk. In this study the potential enrichment of PD risk variants was explored based on whole-exome sequencing of 54 patients with PD and 211 control individuals from the Faroese population. No genome-wide significant associations were found, however several single variants and genes showed strong association with PD, where DGKH was found to be the strongest PD associated gene. Interestingly DGKH has previously demonstrated genome-wide significant association with bipolar disorder as well as evidence of association to other mental disorders. Additionally, we found an enrichment of PD risk variants in the Faroese population; variants with otherwise low frequency in more outbreed European populations. © 2016 Wiley Periodicals, Inc.

PMID: 27255576 [PubMed - indexed for MEDLINE]

Whole-genome sequencing in multiplex families with psychoses reveals mutations in the SHANK2 and SMARCA1 genes segregating with illness.

Mol Psychiatry. 2016 Dec;21(12):1690-1695

Authors: Homann OR, Misura K, Lamas E, Sandrock RW, Nelson P, McDonough SI, DeLisi LE

Abstract
A current focus in psychiatric genetics is detection of multiple common risk alleles through very large genome-wide association study analyses. Yet families do exist, albeit rare, that have multiple affected members who are presumed to have a similar inherited cause to their illnesses. We hypothesized that within some of these families there may be rare highly penetrant mutations that segregate with illness. In this exploratory study, the genomes of 90 individuals across nine families were sequenced. Each family included a minimum of three available relatives affected with a psychotic illness and three available unaffected relatives. Twenty-six variants were identified that are private to a family, alter protein sequence, and are transmitted to all sequenced affected individuals within the family. In one family, seven siblings with schizophrenia spectrum disorders each carry a novel private missense variant within the SHANK2 gene. This variant lies within the consensus SH3 protein-binding motif by which SHANK2 may interact with post-synaptic glutamate receptors. In another family, four affected siblings and their unaffected mother each carry a novel private missense variant in the SMARCA1 gene on the X chromosome. Both variants represent candidates that may be causal for psychotic disorders when considered in the context of their transmission pattern and known gene and disease biology.

PMID: 27001614 [PubMed - indexed for MEDLINE]

Genomic characterization of primary central nervous system lymphoma.

Acta Neuropathol. 2016 Jun;131(6):865-75

Authors: Fukumura K, Kawazu M, Kojima S, Ueno T, Sai E, Soda M, Ueda H, Yasuda T, Yamaguchi H, Lee J, Shishido-Hara Y, Sasaki A, Shirahata M, Mishima K, Ichimura K, Mukasa A, Narita Y, Saito N, Aburatani H, Nishikawa R, Nagane M, Mano H

Abstract
Primary central nervous system lymphoma (PCNSL) is a rare malignancy confined to the central nervous system (CNS), and majority of PCNSL is pathologically classified as diffuse large B-cell lymphoma (DLBCL). We have now performed whole-exome sequencing for 41 tumor tissues of DLBCL-type PCNSL and paired normal specimens and also RNA-sequencing for 30 tumors, revealing a very high frequency of nonsynonymous somatic mutations in PIM1 (100 %), BTG2 (92.7 %), and MYD88 (85.4 %). Many genes in the NF-κB pathway are concurrently mutated within the same tumors. Further, focal deletion or somatic mutations in the HLA genes are associated with poor prognosis. Copy number amplification and overexpression of genes at chromosome 7q35 were both found to predict short progression-free survival as well. Oncogenic mutations in GRB2 were also detected, the effects of which in cultured cells were attenuated by inhibitors of the downstream kinases MAP2K1 and MAP2K2. Individuals with tumors positive for MYD88 mutations also harbored the same mutations at a low frequency in peripheral blood mononuclear cells, suggesting that MYD88 mutation-positive precancerous cells originate outside of the CNS and develop into lymphoma after additional genetic hits that confer adaptation to the CNS environment.

PMID: 26757737 [PubMed - indexed for MEDLINE]

Targeted Gene Panel Sequencing for Early-onset Inflammatory Bowel Disease and Chronic Diarrhea.

Inflamm Bowel Dis. 2017 Sep 19;:

Authors: Petersen BS, August D, Abt R, Alddafari M, Atarod L, Baris S, Bhavsar H, Brinkert F, Buchta M, Bulashevska A, Chee R, Cordeiro AI, Dara N, Dückers G, Elmarsafy A, Frede N, Galal N, Gerner P, Glocker EO, Goldacker S, Hammermann J, Hasselblatt P, Havlicekova Z, Hübscher K, Jesenak M, Karaca NE, Karakoc-Aydiner E, Kharaghani MM, Kilic SS, Kiykim A, Klein C, Klemann C, Kobbe R, Kotlarz D, Laass MW, Leahy TR, Mesdaghi M, Mitton S, Neves JF, Öztürk B, Pereira LF, Rohr J, Restrepo JLR, Ruzaike G, Saleh N, Seneviratne S, Senol E, Speckmann C, Tegtmeyer D, Thankam P, van der Werff Ten Bosch J, von Bernuth H, Zeissig S, Zeissig Y, Franke A, Grimbacher B

Abstract
BACKGROUND: In contrast to adult-onset inflammatory bowel disease (IBD), where many genetic loci have been shown to be involved in complex disease etiology, early-onset IBD (eoIBD) and associated syndromes can sometimes present as monogenic conditions. As a result, the clinical phenotype and ideal disease management in these patients often differ from those in adult-onset IBD. However, due to high costs and the complexity of data analysis, high-throughput screening for genetic causes has not yet become a standard part of the diagnostic work-up of eoIBD patients.
METHODS: We selected 28 genes of interest associated with monogenic IBD and performed targeted panel sequencing in 71 patients diagnosed with eoIBD or early-onset chronic diarrhea to detect causative variants. We compared these results to whole-exome sequencing (WES) data available for 25 of these patients.
RESULTS: Target coverage was significantly higher in the targeted gene panel approach compared with WES, whereas the cost of the panel was considerably lower (approximately 25% of WES). Disease-causing variants affecting protein function were identified in 5 patients (7%), located in genes of the IL10 signaling pathway (3), WAS (1), and DKC1 (1). The functional effects of 8 candidate variants in 5 additional patients (7%) are under further investigation. WES did not identify additional causative mutations in 25 patients.
CONCLUSIONS: Targeted gene panel sequencing is a fast and effective screening method for monogenic causes of eoIBD that should be routinely established in national referral centers.

PMID: 28930861 [PubMed - as supplied by publisher]

[Pathogenesis and genetics of osteosarcoma : Current concepts and developments].

Pathologe. 2017 Sep 19;:

Authors: Baumhoer D

Abstract
Osteosarcomas are genetically complex tumours for which the cell of origin and the molecular pathogenesis are still poorly understood. Despite intensive multimodal treatment protocols only two thirds of patients currently survive the disease which is at least partly due to the early occurring chromosomal instability resulting in marked inter- and intratumoral heterogeneity. This review article outlines the current state of osteosarcoma research with a particular focus on exome- and genome-wide sequencing analyses and potential impacts on new therapeutic opportunities.

PMID: 28929220 [PubMed - as supplied by publisher]