Impact of genetic variation on three dimensional structure and function of proteins.

PLoS One. 2017;12(3):e0171355

Authors: Bhattacharya R, Rose PW, Burley SK, Prlić A

Abstract
The Protein Data Bank (PDB; http://wwpdb.org) was established in 1971 as the first open access digital data resource in biology with seven protein structures as its initial holdings. The global PDB archive now contains more than 126,000 experimentally determined atomic level three-dimensional (3D) structures of biological macromolecules (proteins, DNA, RNA), all of which are freely accessible via the Internet. Knowledge of the 3D structure of the gene product can help in understanding its function and role in disease. Of particular interest in the PDB archive are proteins for which 3D structures of genetic variant proteins have been determined, thus revealing atomic-level structural differences caused by the variation at the DNA level. Herein, we present a systematic and qualitative analysis of such cases. We observe a wide range of structural and functional changes caused by single amino acid differences, including changes in enzyme activity, aggregation propensity, structural stability, binding, and dissociation, some in the context of large assemblies. Structural comparison of wild type and mutated proteins, when both are available, provide insights into atomic-level structural differences caused by the genetic variation.

PMID: 28296894 [PubMed - indexed for MEDLINE]

M-CAP eliminates a majority of variants of uncertain significance in clinical exomes at high sensitivity.

Nat Genet. 2016 Dec;48(12):1581-1586

Authors: Jagadeesh KA, Wenger AM, Berger MJ, Guturu H, Stenson PD, Cooper DN, Bernstein JA, Bejerano G

Abstract
Variant pathogenicity classifiers such as SIFT, PolyPhen-2, CADD, and MetaLR assist in interpretation of the hundreds of rare, missense variants in the typical patient genome by deprioritizing some variants as likely benign. These widely used methods misclassify 26 to 38% of known pathogenic mutations, which could lead to missed diagnoses if the classifiers are trusted as definitive in a clinical setting. We developed M-CAP, a clinical pathogenicity classifier that outperforms existing methods at all thresholds and correctly dismisses 60% of rare, missense variants of uncertain significance in a typical genome at 95% sensitivity.

PMID: 27776117 [PubMed - indexed for MEDLINE]

Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing.

Nat Genet. 2016 Sep;48(9):1060-5

Authors: Sifrim A, Hitz MP, Wilsdon A, Breckpot J, Turki SH, Thienpont B, McRae J, Fitzgerald TW, Singh T, Swaminathan GJ, Prigmore E, Rajan D, Abdul-Khaliq H, Banka S, Bauer UM, Bentham J, Berger F, Bhattacharya S, Bu'Lock F, Canham N, Colgiu IG, Cosgrove C, Cox H, Daehnert I, Daly A, Danesh J, Fryer A, Gewillig M, Hobson E, Hoff K, Homfray T, INTERVAL Study, Kahlert AK, Ketley A, Kramer HH, Lachlan K, Lampe AK, Louw JJ, Manickara AK, Manase D, McCarthy KP, Metcalfe K, Moore C, Newbury-Ecob R, Omer SO, Ouwehand WH, Park SM, Parker MJ, Pickardt T, Pollard MO, Robert L, Roberts DJ, Sambrook J, Setchfield K, Stiller B, Thornborough C, Toka O, Watkins H, Williams D, Wright M, Mital S, Daubeney PE, Keavney B, Goodship J, UK10K Consortium, Abu-Sulaiman RM, Klaassen S, Wright CF, Firth HV, Barrett JC, Devriendt K, FitzPatrick DR, Brook JD, Deciphering Developmental Disorders Study, Hurles ME

Abstract
Congenital heart defects (CHDs) have a neonatal incidence of 0.8-1% (refs. 1,2). Despite abundant examples of monogenic CHD in humans and mice, CHD has a low absolute sibling recurrence risk (∼2.7%), suggesting a considerable role for de novo mutations (DNMs) and/or incomplete penetrance. De novo protein-truncating variants (PTVs) have been shown to be enriched among the 10% of 'syndromic' patients with extra-cardiac manifestations. We exome sequenced 1,891 probands, including both syndromic CHD (S-CHD, n = 610) and nonsyndromic CHD (NS-CHD, n = 1,281). In S-CHD, we confirmed a significant enrichment of de novo PTVs but not inherited PTVs in known CHD-associated genes, consistent with recent findings. Conversely, in NS-CHD we observed significant enrichment of PTVs inherited from unaffected parents in CHD-associated genes. We identified three genome-wide significant S-CHD disorders caused by DNMs in CHD4, CDK13 and PRKD1. Our study finds evidence for distinct genetic architectures underlying the low sibling recurrence risk in S-CHD and NS-CHD.

PMID: 27479907 [PubMed - indexed for MEDLINE]

The genomic landscape and evolution of endometrial carcinoma progression and abdominopelvic metastasis.

Nat Genet. 2016 Aug;48(8):848-55

Authors: Gibson WJ, Hoivik EA, Halle MK, Taylor-Weiner A, Cherniack AD, Berg A, Holst F, Zack TI, Werner HM, Staby KM, Rosenberg M, Stefansson IM, Kusonmano K, Chevalier A, Mauland KK, Trovik J, Krakstad C, Giannakis M, Hodis E, Woie K, Bjorge L, Vintermyr OK, Wala JA, Lawrence MS, Getz G, Carter SL, Beroukhim R, Salvesen HB

Abstract
Recent studies have detailed the genomic landscape of primary endometrial cancers, but the evolution of these cancers into metastases has not been characterized. We performed whole-exome sequencing of 98 tumor biopsies including complex atypical hyperplasias, primary tumors and paired abdominopelvic metastases to survey the evolutionary landscape of endometrial cancer. We expanded and reanalyzed The Cancer Genome Atlas (TCGA) data, identifying new recurrent alterations in primary tumors, including mutations in the estrogen receptor cofactor gene NRIP1 in 12% of patients. We found that likely driver events were present in both primary and metastatic tissue samples, with notable exceptions such as ARID1A mutations. Phylogenetic analyses indicated that the sampled metastases typically arose from a common ancestral subclone that was not detected in the primary tumor biopsy. These data demonstrate extensive genetic heterogeneity in endometrial cancers and relative homogeneity across metastatic sites.

PMID: 27348297 [PubMed - indexed for MEDLINE]

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Use of targeted sequence capture and high-throughput sequencing identifies a novel PKD1 mutation involved in adult polycystic kidney disease.

Gene. 2017 Sep 01;:

Authors: Sha YK, Sha YW, Mei LB, Huang XJ, Wang X, Lin SB, Li L, Li P

Abstract
Polycystic kidney disease (PKD) is a common inherited disease that is characterized by a progressive development of renal cysts. Approximately 85% of PKD cases are due to mutations in the polycystin 1 (PKD1) gene. Here, we report a pedigree containing nine patients with autosomal dominant PKD (ADPKD). Using targeted exome sequencing of PKD1 and PKD2 genes, we identified a novel heterozygous frameshift mutation c.3976_3977insCT (p.F1326Sfs*21) in the PKD1 gene that segregated between affected and unaffected family members. This mutation is currently not present in the 1000 Genomes Project nor ExAC databases and is therefore a novel PKD1 mutation involved in ADPKD. These results provide a novel sequence variant for the genetic analysis of this disease.

PMID: 28870863 [PubMed - as supplied by publisher]

Identification of new susceptibility loci for type 2 diabetes and shared etiological pathways with coronary heart disease.

Nat Genet. 2017 Sep 04;:

Authors: Zhao W, Rasheed A, Tikkanen E, Lee JJ, Butterworth AS, Howson JMM, Assimes TL, Chowdhury R, Orho-Melander M, Damrauer S, Small A, Asma S, Imamura M, Yamauch T, Chambers JC, Chen P, Sapkota BR, Shah N, Jabeen S, Surendran P, Lu Y, Zhang W, Imran A, Abbas S, Majeed F, Trindade K, Qamar N, Mallick NH, Yaqoob Z, Saghir T, Rizvi SNH, Memon A, Rasheed SZ, Memon FU, Mehmood K, Ahmed N, Qureshi IH, Tanveer-Us-Salam, Iqbal W, Malik U, Mehra N, Kuo JZ, Sheu WH, Guo X, Hsiung CA, Juang JJ, Taylor KD, Hung YJ, Lee WJ, Quertermous T, Lee IT, Hsu CC, Bottinger EP, Ralhan S, Teo YY, Wang TD, Alam DS, Di Angelantonio E, Epstein S, Nielsen SF, Nordestgaard BG, Tybjaerg-Hansen A, Young R, CHD Exome+ Consortium, Benn M, Frikke-Schmidt R, Kamstrup PR, EPIC-CVD Consortium, EPIC-Interact Consortium, Michigan Biobank, Jukema JW, Sattar N, Smit R, Chung RH, Liang KW, Anand S, Sanghera DK, Ripatti S, Loos RJF, Kooner JS, Tai ES, Rotter JI, Chen YI, Frossard P, Maeda S, Kadowaki T, Reilly M, Pare G, Melander O, Salomaa V, Rader DJ, Danesh J, Voight BF, Saleheen D

Abstract
To evaluate the shared genetic etiology of type 2 diabetes (T2D) and coronary heart disease (CHD), we conducted a genome-wide, multi-ancestry study of genetic variation for both diseases in up to 265,678 subjects for T2D and 260,365 subjects for CHD. We identify 16 previously unreported loci for T2D and 1 locus for CHD, including a new T2D association at a missense variant in HLA-DRB5 (odds ratio (OR) = 1.29). We show that genetically mediated increase in T2D risk also confers higher CHD risk. Joint T2D-CHD analysis identified eight variants-two of which are coding-where T2D and CHD associations appear to colocalize, including a new joint T2D-CHD association at the CCDC92 locus that also replicated for T2D. The variants associated with both outcomes implicate new pathways as well as targets of existing drugs, including icosapent ethyl and adipocyte fatty-acid-binding protein.

PMID: 28869590 [PubMed - as supplied by publisher]

[A report of atypical hypomyelinating leukodystrophy with atrophy of the basal ganglia and cerebellum caused by a de novo mutation in tubulin beta 4A (TUBB4A) gene and literature review].

Zhonghua Nei Ke Za Zhi. 2017 Jun 01;56(6):433-437

Authors: Du Y, Li C, Guo J, Guo P, Li ZY, Zhang W

Abstract
Objective: To explore the clinical symptoms and neuroimaging features of a patient with atypical hypomyelinating leukodystrophy with atrophy of the basal ganglia and cerebellum (H-ABC) caused by a novel TUBB4A mutation. Methods: We analyzed the clinical data, imaging features and the result of genetic testing of a case diagnosed as atypical H-ABC. Results: The initial symptoms were progressive spasticity, mild cerebellar ataxia and mild cognitive impairment. MRI showed regional blurring of slight high signal on T(2)-weight and FLAIR image in white matter of the bilateral midbrain ventral, internal capsule, posteior horn of lateral ventricle and centrum semiovale, with normal bilateral cerebellar and caudoputamen nucleus. Compared with normal subjects of the same age and gender, hypometabolism was found by (18)F-FDG-PET in brainstem, cerebellar and caudoputamen nucleus in the patient. Genetic testing revealed a de novo pathogenic exome missense heterozygous mutations c. 70G>A in TUBB4A, which was not reported in the human gene mutation database (HGMDpro) and was assessed to be a pathogenic mutation by pathogenic mutation prediction software. Conclusions: The diversity of TUBB4A gene mutations may cause different functional and/or structural impairment in subcortical white matter, cerebellar and caudoputamen nucleus, leading to atypical symptoms and neuroimaging features. Genetic testing for pathogenic mutation in TUBB4A gene is a key for the diagnosis of H-ABC.

PMID: 28592043 [PubMed - indexed for MEDLINE]

A homozygous CEP135 mutation is associated with multiple morphological abnormalities of the sperm flagella (MMAF).

Gene. 2017 Aug 30;:

Authors: Sha YW, Xu X, Mei LB, Li P, Su ZY, He XQ, Li L

Abstract
Multiple morphological abnormalities of the sperm flagella (MMAF) is a rare disease associated with primary infertility; however, ~50% of the genetic alterations associated with MMAF remain unclear. Here, we reported the case of a 30-year-old infertile male from a consanguineous family. Whole-exome sequencing identified a homozygous mutation in the CEP135 gene (c.A1364T:p.D455V), with CEP135 previously reported to play a role in centriole biogenesis and specifically central pair assembly. D455V-mutated proteins formed protein aggregates in the centrosome and the flagella, which might potentially affect the function of centriole assembly. Moreover, intracytoplasmic sperm injection was performed using sperm from this patient; however, pregnancy failed following embryo transfer. This represents the first report of a homozygous mutation of CEP135 associated with MMAF. These results provide researchers and clinicians with a deeper understanding of the gene involved with MMAF and will help predict and assess pregnancy outcomes associated with in vitro fertilization.

PMID: 28866084 [PubMed - as supplied by publisher]

A Dutch MYH7 founder mutation, p.(Asn1918Lys), is associated with early onset cardiomyopathy and congenital heart defects.

Neth Heart J. 2017 Sep 01;:

Authors: van der Linde IHM, Hiemstra YL, Bökenkamp R, van Mil AM, Breuning MH, Ruivenkamp C, Ten Broeke SW, Veldkamp RF, van Waning JI, van Slegtenhorst MA, van Spaendonck-Zwarts KY, Lekanne Deprez RH, Herkert JC, Boven L, van der Zwaag PA, Jongbloed JDH, Bootsma M, Barge-Schaapveld DQCM

Abstract
BACKGROUND: Mutations in the myosin heavy chain 7 (MYH7) gene commonly cause cardiomyopathy but are less frequently associated with congenital heart defects.
METHODS: In this study, we describe a mutation in the MYH7 gene, c. 5754C > G; p. (Asn1918Lys), present in 15 probands and 65 family members.
RESULTS: Of the 80 carriers (age range 0-88 years), 46 (57.5%) had cardiomyopathy (mainly dilated cardiomyopathy (DCM)) and seven (8.8%) had a congenital heart defect. Childhood onset of cardiomyopathy was present in almost 10% of carriers. However, in only a slight majority (53.7%) was the left ventricular ejection fraction reduced and almost no arrhythmias or conduction disorders were noted. Moreover, only one carrier required heart transplantation and nine (11.3%) an implantable cardioverter defibrillator. In addition, the standardised mortality ratio for MYH7 carriers was not significantly increased. Whole exome sequencing in several cases with paediatric onset of DCM and one with isolated congenital heart defects did not reveal additional known disease-causing variants. Haplotype analysis suggests that the MYH7 variant is a founder mutation, and is therefore the first Dutch founder mutation identified in the MYH7 gene. The mutation appears to have originated in the western region of the province of South Holland between 500 and 900 years ago.
CONCLUSION: Clinically, the p. (Asn1918Lys) mutation is associated with congenital heart defects and/or cardiomyopathy at young age but with a relatively benign course.

PMID: 28864942 [PubMed - as supplied by publisher]

Optimizing genomic medicine in epilepsy through a gene-customized approach to missense variant interpretation.

Genome Res. 2017 Sep 01;:

Authors: Traynelis J, Silk M, Wang Q, Berkovic SF, Liu L, Ascher DB, Balding DJ, Petrovski S

Abstract
Gene panel and exome sequencing have revealed a high rate of molecular diagnoses among diseases where the genetic architecture has proven suitable for sequencing approaches, with a large number of distinct and highly penetrant causal variants identified among a growing list of disease genes. The challenge is, given the DNA sequence of a new patient, to distinguish disease-causing from benign variants. Large samples of human standing variation data highlight regional variation in the tolerance to missense variation within the protein-coding sequence of genes. This information is not well captured by existing bioinformatic tools, but is effective in improving variant interpretation. To address this limitation in existing tools, we introduce the missense tolerance ratio (MTR), which summarizes available human standing variation data within genes to encapsulate population level genetic variation. We find that patient-ascertained pathogenic variants preferentially cluster in low MTR regions (P < 0.005) of well-informed genes. By evaluating 20 publicly available predictive tools across genes linked to epilepsy, we also highlight the importance of understanding the empirical null distribution of existing prediction tools, as these vary across genes. Subsequently integrating the MTR with the empirically selected bioinformatic tools in a gene-specific approach demonstrates a clear improvement in the ability to predict pathogenic missense variants from background missense variation in disease genes. Among an independent test sample of case and control missense variants, case variants (0.83 median score) consistently achieve higher pathogenicity prediction probabilities than control variants (0.02 median score; Mann-Whitney U test, P < 1 × 10(-16)). We focus on the application to epilepsy genes; however, the framework is applicable to disease genes beyond epilepsy.

PMID: 28864458 [PubMed - as supplied by publisher]

New MCM8 mutation associated with premature ovarian insufficiency and chromosomal instability in a highly consanguineous Tunisian family.

Fertil Steril. 2017 Aug 29;:

Authors: Bouali N, Francou B, Bouligand J, Imanci D, Dimassi S, Tosca L, Zaouali M, Mougou S, Young J, Saad A, Guiochon-Mantel A

Abstract
OBJECTIVE: To identify the gene(s) involved in the etiology of premature ovarian insufficiency in a highly consanguineous Tunisian family.
DESIGN: Genetic analysis of a large consanguineous family with several affected siblings.
SETTING: University hospital-based cytogenetics and molecular genetics laboratories.
PATIENT(S): A highly consanguineous Tunisian family with several affected siblings born to healthy second-degree cousins.
INTERVENTION(S): None.
MAIN OUTCOME MEASURE(S): Targeted exome sequencing was performed by next-generation sequencing for affected family members. Mutations were validated by Sanger sequencing. Functional experiments were performed to explore the deleterious effects of the identified mutation. DNA damage was induced by increasing mitomycin C (MMC) concentrations on cultured peripheral lymphocytes.
RESULT(S): Analysis of the next-generation sequencing data revealed a new homozygous missense mutation in the minichromosome maintenance 8 gene (MCM8).This homozygous mutation (c. 482A>C; p.His161Pro) was predicted to be deleterious and segregated with the disease in the family. MCM8 participates in homologous recombination during meiosis and DNA double-stranded break repair by dimerizing with MCM9. Mcm8 knock out results in an early block in follicle development and small gonads. Given this, we tested the chromosomal breakage repair capacity of homozygous and heterozygous MCM8 p.His161Pro mutation on cultured peripheral lymphocytes exposed to increasing MMC concentrations. We found that chromosomal breakage after MMC exposure was significantly higher in cells from homozygously affected individuals than in those from a healthy control.
CONCLUSION(S): Our findings provide additional support to the view that MCM8 mutations are involved in the primary ovarian insufficiency phenotype.

PMID: 28863940 [PubMed - as supplied by publisher]

Exome sequencing identifies a novel mutation of the GDI1 gene in a Chinese non-syndromic X-linked intellectual disability family.

Genet Mol Biol. 2017 Aug 31;:0

Authors: Duan Y, Lin S, Xie L, Zheng K, Chen S, Song H, Zeng X, Gu X, Wang H, Zhang L, Shao H, Hong W, Zhang L, Duan S

Abstract
X-linked intellectual disability (XLID) has been associated with various genes. Diagnosis of XLID, especially for non-syndromic ones (NS-XLID), is often hampered by the heterogeneity of this disease. Here we report the case of a Chinese family in which three males suffer from intellectual disability (ID). The three patients shared the same phenotype: no typical clinical manifestation other than IQ score ≤ 70. For a genetic diagnosis for this family we carried out whole exome sequencing on the proband, and validated 16 variants of interest in the genomic DNA of all the family members. A missense mutation (c.710G > T), which mapped to exon 6 of the Rab GDP-Dissociation Inhibitor 1 (GDI1) gene, was found segregating with the ID phenotype, and this mutation changes the 237th position in the guanosine diphosphate dissociation inhibitor (GDI) protein from glycine to valine (p. Gly237Val). Through molecular dynamics simulations we found that this substitution results in a conformational change of GDI, possibly affecting the Rab-binding capacity of this protein. In conclusion, our study identified a novel GDI1 mutation that is possibly NS-XLID causative, and showed that whole exome sequencing provides advantages for detecting novel ID-associated variants and can greatly facilitate the genetic diagnosis of the disease.

PMID: 28863211 [PubMed - as supplied by publisher]

Diagnostic exome sequencing in early-onset Parkinson's disease confirms VPS13C as a rare cause of autosomal-recessive Parkinson's disease.

Clin Genet. 2017 Sep 01;:

Authors: Schormair B, Kemlink D, Mollenhauer B, Fiala O, Machetanz G, Roth J, Berutti R, Strom TM, Haslinger B, Trenkwalder C, Zahorakova D, Martasek P, Ruzicka E, Winkelmann J

Abstract
Parkinson's disease (PD) is a genetically heterogeneous disorder and new putative disease genes are discovered constantly. Therefore, whole exome sequencing could be an efficient approach to genetic testing in PD. To evaluate its performance in early-onset sporadic PD, we performed diagnostic exome sequencing in 80 individuals with manifestation of PD symptoms at age 40 or earlier and a negative family history of PD. Variants in validated and candidate disease genes and risk factors for PD and atypical Parkinson syndromes were annotated, followed by further analysis for selected variants. We detected pathogenic variants in Mendelian genes in 6.25% of cases and high-impact risk factor variants in GBA in 5% of cases, resulting in overall maximum diagnostic yield of 11.25%. One individual was compound heterozygous for variants affecting canonical splice sites in VPS13C, confirming the causal role of protein-truncating variants in this gene linked to autosomal-recessive early-onset PD. Despite the low diagnostic yield of exome sequencing in sporadic early-onset Parkinson's disease, the confirmation of the recently discovered VPS13C gene highlights its advantage over using predefined gene panels.

PMID: 28862745 [PubMed - as supplied by publisher]

Lost in translation: returning germline genetic results in genome-scale cancer research.

Genome Med. 2017 Apr 28;9(1):41

Authors: Johns AL, McKay SH, Humphris JL, Pinese M, Chantrill LA, Mead RS, Tucker K, Andrews L, Goodwin A, Leonard C, High HA, Nones K, Patch AM, Merrett ND, Pavlakis N, Kassahn KS, Samra JS, Miller DK, Chang DK, Pajic M, Australian Pancreatic Cancer Genome Initiative, Pearson JV, Grimmond SM, Waddell N, Zeps N, Gill AJ, Biankin AV

Abstract
BACKGROUND: The return of research results (RoR) remains a complex and well-debated issue. Despite the debate, actual data related to the experience of giving individual results back, and the impact these results may have on clinical care and health outcomes, is sorely lacking. Through the work of the Australian Pancreatic Cancer Genome Initiative (APGI) we: (1) delineate the pathway back to the patient where actionable research data were identified; and (2) report the clinical utilisation of individual results returned. Using this experience, we discuss barriers and opportunities associated with a comprehensive process of RoR in large-scale genomic research that may be useful for others developing their own policies.
METHODS: We performed whole-genome (n = 184) and exome (n = 208) sequencing of matched tumour-normal DNA pairs from 392 patients with sporadic pancreatic cancer (PC) as part of the APGI. We identified pathogenic germline mutations in candidate genes (n = 130) with established predisposition to PC or medium-high penetrance genes with well-defined cancer associated syndromes or phenotypes. Variants from candidate genes were annotated and classified according to international guidelines. Variants were considered actionable if clinical utility was established, with regard to prevention, diagnosis, prognostication and/or therapy.
RESULTS: A total of 48,904 germline variants were identified, with 2356 unique variants undergoing annotation and in silico classification. Twenty cases were deemed actionable and were returned via previously described RoR framework, representing an actionable finding rate of 5.1%. Overall, 1.78% of our cohort experienced clinical benefit from RoR.
CONCLUSION: Returning research results within the context of large-scale genomics research is a labour-intensive, highly variable, complex operation. Results that warrant action are not infrequent, but the prevalence of those who experience a clinical difference as a result of returning individual results is currently low.

PMID: 28454591 [PubMed - indexed for MEDLINE]

Spontaneous preterm birth and single nucleotide gene polymorphisms: a recent update.

BMC Genomics. 2016 Oct 17;17(Suppl 9):759

Authors: Sheikh IA, Ahmad E, Jamal MS, Rehan M, Assidi M, Tayubi IA, AlBasri SF, Bajouh OS, Turki RF, Abuzenadah AM, Damanhouri GA, Beg MA, Al-Qahtani M

Abstract
BACKGROUND: Preterm birth (PTB), birth at <37 weeks of gestation, is a significant global public health problem. World-wide, about 15 million babies are born preterm each year resulting in more than a million deaths of children. Preterm neonates are more prone to problems and need intensive care hospitalization. Health issues may persist through early adulthood and even be carried on to the next generation. Majority (70 %) of PTBs are spontaneous with about a half without any apparent cause and the other half associated with a number of risk factors. Genetic factors are one of the significant risks for PTB. The focus of this review is on single nucleotide gene polymorphisms (SNPs) that are reported to be associated with PTB.
RESULTS: A comprehensive evaluation of studies on SNPs known to confer potential risk of PTB was done by performing a targeted PubMed search for the years 2007-2015 and systematically reviewing all relevant studies. Evaluation of 92 studies identified 119 candidate genes with SNPs that had potential association with PTB. The genes were associated with functions of a wide spectrum of tissue and cell types such as endocrine, tissue remodeling, vascular, metabolic, and immune and inflammatory systems.
CONCLUSIONS: A number of potential functional candidate gene variants have been reported that predispose women for PTB. Understanding the complex genomic landscape of PTB needs high-throughput genome sequencing methods such as whole-exome sequencing and whole-genome sequencing approaches that will significantly enhance the understanding of PTB. Identification of high risk women, avoidance of possible risk factors, and provision of personalized health care are important to manage PTB.

PMID: 27766960 [PubMed - indexed for MEDLINE]

Low-frequency nonsynonymous variants in FKBPL and ARPC1B genes are associated with breast cancer risk in Chinese women.

Mol Carcinog. 2017 Feb;56(2):774-780

Authors: Zhou W, Jiang Y, Zhu M, Hang D, Chen J, Zhou J, Dai J, Ma H, Hu Z, Jin G, Sha J, Shen H

Abstract
Genome-wide association studies have reported more than 100 independent common loci associated with breast cancer risk. The contribution of low-frequency or rare variants to breast cancer susceptibility has not been well explored. Thus, we applied exome chip to genotype >200 000 low-frequency and rare variants in 1064 breast cancer cases and 1125 cancer-free controls and subsequently validated promising associations in another 1040 breast cancer cases and 1240 controls. We identified two low-frequency nonsynonymous variants at FKBPL (rs200847762, OR = 0.34, 95% CI = 0.20-0.57, P = 4.31 × 10(-5) ) and ARPC1B (rs1045012, OR = 0.56, 95% CI = 0.43-0.74, P = 4.30 × 10(-5) ) associated with breast cancer risk. In stratification analyses, we found that the protective effect of rs200847762 was stronger in ER-positive breast cancer (OR = 0.18, 95% CI = 0.06-0.42) than that in ER-negative one (OR = 0.59, 95% CI = 0.31-1.05). Our findings indicate that low-frequency variants may also contribute to breast cancer susceptibility and genetic variants in 6p21.33 and 7q22.1 are important in breast carcinogenesis. © 2016 Wiley Periodicals, Inc.

PMID: 27479355 [PubMed - indexed for MEDLINE]

The stepwise evolution of the exome during acquisition of docetaxel resistance in breast cancer cells.

BMC Genomics. 2016 Jun 09;17:442

Authors: Hansen SN, Ehlers NS, Zhu S, Thomsen MB, Nielsen RL, Liu D, Wang G, Hou Y, Zhang X, Xu X, Bolund L, Yang H, Wang J, Moreira J, Ditzel HJ, Brünner N, Schrohl AS, Stenvang J, Gupta R

Abstract
BACKGROUND: Resistance to taxane-based therapy in breast cancer patients is a major clinical problem that may be addressed through insight of the genomic alterations leading to taxane resistance in breast cancer cells. In the current study we used whole exome sequencing to discover somatic genomic alterations, evolving across evolutionary stages during the acquisition of docetaxel resistance in breast cancer cell lines.
RESULTS: Two human breast cancer in vitro models (MCF-7 and MDA-MB-231) of the step-wise acquisition of docetaxel resistance were developed by exposing cells to 18 gradually increasing concentrations of docetaxel. Whole exome sequencing performed at five successive stages during this process was used to identify single point mutational events, insertions/deletions and copy number alterations associated with the acquisition of docetaxel resistance. Acquired coding variation undergoing positive selection and harboring characteristics likely to be functional were further prioritized using network-based approaches. A number of genomic changes were found to be undergoing evolutionary selection, some of which were likely to be functional. Of the five stages of progression toward resistance, most resistance relevant genomic variation appeared to arise midway towards fully resistant cells corresponding to passage 31 (5 nM docetaxel) for MDA-MB-231 and passage 16 (1.2 nM docetaxel) for MCF-7, and where the cells also exhibited a period of reduced growth rate or arrest, respectively. MCF-7 cell acquired several copy number gains on chromosome 7, including ABC transporter genes, including ABCB1 and ABCB4, as well as DMTF1, CLDN12, CROT, and SRI. For MDA-MB-231 numerous copy number losses on chromosome X involving more than 30 genes was observed. Of these genes, CASK, POLA1, PRDX4, MED14 and PIGA were highly prioritized by the applied network-based gene ranking approach. At higher docetaxel concentration MCF-7 subclones exhibited a copy number loss in E2F4, and the gene encoding this important transcription factor was down-regulated in MCF-7 resistant cells.
CONCLUSIONS: Our study of the evolution of acquired docetaxel resistance identified several genomic changes that might explain development of docetaxel resistance. Interestingly, the most relevant resistance-associated changes appeared to originate midway through the evolution towards fully resistant cell lines. Our data suggest that no single genomic event sufficiently predicts resistance to docetaxel, but require genomic alterations affecting multiple pathways that in concert establish the final resistance stage.

PMID: 27277198 [PubMed - indexed for MEDLINE]

MYT1L mutations cause intellectual disability and variable obesity by dysregulating gene expression and development of the neuroendocrine hypothalamus.

PLoS Genet. 2017 Aug 31;13(8):e1006957

Authors: Blanchet P, Bebin M, Bruet S, Cooper GM, Thompson ML, Duban-Bedu B, Gerard B, Piton A, Suckno S, Deshpande C, Clowes V, Vogt J, Turnpenny P, Williamson MP, Alembik Y, Clinical Sequencing Exploratory Research Study Consortium, Deciphering Developmental Disorders Consortium, Glasgow E, McNeill A

Abstract
Deletions at chromosome 2p25.3 are associated with a syndrome consisting of intellectual disability and obesity. The smallest region of overlap for deletions at 2p25.3 contains PXDN and MYT1L. MYT1L is expressed only within the brain in humans. We hypothesized that single nucleotide variants (SNVs) in MYT1L would cause a phenotype resembling deletion at 2p25.3. To examine this we sought MYT1L SNVs in exome sequencing data from 4, 296 parent-child trios. Further variants were identified through a genematcher-facilitated collaboration. We report 9 patients with MYT1L SNVs (4 loss of function and 5 missense). The phenotype of SNV carriers overlapped with that of 2p25.3 deletion carriers. To identify the transcriptomic consequences of MYT1L loss of function we used CRISPR-Cas9 to create a knockout cell line. Gene Ontology analysis in knockout cells demonstrated altered expression of genes that regulate gene expression and that are localized to the nucleus. These differentially expressed genes were enriched for OMIM disease ontology terms "mental retardation". To study the developmental effects of MYT1L loss of function we created a zebrafish knockdown using morpholinos. Knockdown zebrafish manifested loss of oxytocin expression in the preoptic neuroendocrine area. This study demonstrates that MYT1L variants are associated with syndromic obesity in humans. The mechanism is related to dysregulated expression of neurodevelopmental genes and altered development of the neuroendocrine hypothalamus.

PMID: 28859103 [PubMed - as supplied by publisher]

Novel Molecular Targets for Chemoprevention in Malignancies of the Head and Neck.

Cancers (Basel). 2017 Aug 31;9(9):

Authors: Bhatia A, Burtness B

Abstract
Cancers of the head and neck region are among the leading causes of cancer-related mortalities worldwide. Oral leukoplakia and erythroplakia are identified as precursor lesions to malignancy. Patients cured of an initial primary head and neck cancer are also susceptible to developing second primary tumors due to cancerization of their mucosal field. Multi-step acquisition of genetic mutations leading to tumorigenesis and development of invasive cancer has been previously described. Recently, whole exome sequencing of tumor specimens has helped to identify driver mutations in this disease. For these reasons, chemoprevention or the use of systemic or biologic agents to prevent carcinogenesis is an attractive concept in head and neck cancers. Nonetheless, despite extensive clinical research in this field over the past couple decades, no standard of care option has emerged. This review article reports on targeted interventions that have been attempted in clinical trials to date, and focuses on novel molecular pathways and drugs in development that are worthy of being tested for this indication as part of future endeavors.

PMID: 28858212 [PubMed]