Driving to Cancer on a Four-Lane Expressway.

Trends Genet. 2017 Jun 28;:

Authors: Galluzzi L, Vitale I

Abstract
Recent findings from a prospective clinical study involving multiregion whole-exome sequencing suggest that driver mutations in cancer-relevant genes including EGFR and TP53 are often clonal and precede whole-genome duplication events in early lung carcinogenesis. This paves an expressway to extensive subclonal diversification, elevated intratumoral heterogeneity, and dismal disease outcome.

PMID: 28668385 [PubMed - as supplied by publisher]

Exome sequencing reveals DNMT3A and ASXL1 variants associate with progression of chronic myeloid leukemia after tyrosine kinase inhibitor therapy.

Leuk Res. 2017 Jun 16;59:142-148

Authors: Kim T, Tyndel MS, Zhang Z, Ahn J, Choi S, Szardenings M, Lipton JH, Kim HJ, Kim Dong Hwan D

Abstract
OBJECTIVE: The development of tyrosine kinase inhibitors (TKIs) has significantly improved the treatment of chronic myeloid leukemia (CML). However, approximately one third of patients are resistant to TKI and/or progress to advanced disease stages. TKI therapy failure has a well-known association with ABL1 kinase domain (KD) mutations, but only around half of TKI non-responders have detectable ABL1 KD mutations.
METHOD: We attempt to identify genetic markers associated with TKI therapy failure in 13 patients (5 resistant, 8 progressed) without ABL1 KD mutations using whole-exome sequencing.
RESULTS: In 6 patients, we detected mutations in 6 genes commonly mutated in other myeloid neoplasms: ABL1, ASXL1, DNMT3A, IDH1, SETBP1, and TP63. We then used targeted deep sequencing to validate our finding in an independent cohort consisting of 100 CML patients with varying drug responses (74 responsive, 18 resistant, and 8 progressed patients). Mutations in genes associated with epigenetic regulations such as DNMT3A and ASXL1 seem to play an important role in the pathogenesis of CML progression and TKI-resistance independent of ABL1 KD mutations.
CONCLUSION: This study suggests the involvement of other somatic mutations in the development of TKI resistant progression to advanced disease stages in CML, particularly in patients lacking ABL1 KD mutations.

PMID: 28667884 [PubMed - as supplied by publisher]

Untangling Genetic Risk for Alzheimer's Disease.

Biol Psychiatry. 2017 May 22;:

Authors: Pimenova AA, Raj T, Goate AM

Abstract
Alzheimer's disease (AD) is a genetically heterogeneous neurodegenerative disorder caused by fully penetrant single gene mutations in a minority of cases, while the majority of cases are sporadic or show modest familial clustering. These cases are of late onset and likely result from the interaction of many genes and the environment. More than 30 loci have been implicated in AD by a combination of linkage, genome-wide association, and whole genome/exome sequencing. We have learned from these studies that perturbations in endolysosomal, lipid metabolism, and immune response pathways substantially contribute to sporadic AD pathogenesis. We review here current knowledge about functions of AD susceptibility genes, highlighting cells of the myeloid lineage as drivers of at least part of the genetic component in late-onset AD. Although targeted resequencing utilized for the identification of causal variants has discovered coding mutations in some AD-associated genes, a lot of risk variants lie in noncoding regions. Here we discuss the use of functional genomics approaches that integrate transcriptomic, epigenetic, and endophenotype traits with systems biology to annotate genetic variants, and to facilitate discovery of AD risk genes. Further validation in cell culture and mouse models will be necessary to establish causality for these genes. This knowledge will allow mechanism-based design of novel therapeutic interventions in AD and promises coherent implementation of treatment in a personalized manner.

PMID: 28666525 [PubMed - as supplied by publisher]

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Landscape and variation of novel retroduplications in 26 human populations.

PLoS Comput Biol. 2017 Jun 29;13(6):e1005567

Authors: Zhang Y, Li S, Abyzov A, Gerstein MB

Abstract
Retroduplications come from reverse transcription of mRNAs and their insertion back into the genome. Here, we performed comprehensive discovery and analysis of retroduplications in a large cohort of 2,535 individuals from 26 human populations, as part of 1000 Genomes Phase 3. We developed an integrated approach to discover novel retroduplications combining high-coverage exome and low-coverage whole-genome sequencing data, utilizing information from both exon-exon junctions and discordant paired-end reads. We found 503 parent genes having novel retroduplications absent from the reference genome. Based solely on retroduplication variation, we built phylogenetic trees of human populations; these represent superpopulation structure well and indicate that variable retroduplications are effective population markers. We further identified 43 retroduplication parent genes differentiating superpopulations. This group contains several interesting insertion events, including a SLMO2 retroduplication and insertion into CAV3, which has a potential disease association. We also found retroduplications to be associated with a variety of genomic features: (1) Insertion sites were correlated with regular nucleosome positioning. (2) They, predictably, tend to avoid conserved functional regions, such as exons, but, somewhat surprisingly, also avoid introns. (3) Retroduplications tend to be co-inserted with young L1 elements, indicating recent retrotranspositional activity, and (4) they have a weak tendency to originate from highly expressed parent genes. Our investigation provides insight into the functional impact and association with genomic elements of retroduplications. We anticipate our approach and analytical methodology to have application in a more clinical context, where exome sequencing data is abundant and the discovery of retroduplications can potentially improve the accuracy of SNP calling.

PMID: 28662076 [PubMed - as supplied by publisher]

Clinical and genetic diversities of Charcot-Marie-Tooth disease with MFN2 mutations in a large case study.

J Peripher Nerv Syst. 2017 Jun 29;:

Authors: Ando M, Hashiguchi A, Okamoto Y, Yoshimura A, Hiramatsu Y, Yuan J, Higuchi Y, Mitsui J, Ishiura H, Umemura A, Maruyama K, Matsushige T, Morishita S, Nakagawa M, Tsuji S, Takashima H

Abstract
Charcot-Marie-Tooth disease (CMT) constitutes a heterogeneous group affecting motor and sensory neurons in the peripheral nervous system. MFN2 mutations are the most common cause of axonal CMT. We describe the clinical and mutational spectra of CMT patients harboring MFN2 mutations in Japan. We analyzed 1334 unrelated patients with clinically suspected CMT referred by neurological and neuropediatric departments throughout Japan. We conducted mutation screening using a DNA microarray, targeted resequencing, and whole-exome sequencing. We identified pathogenic or likely pathogenic MFN2 variants from 79 CMT patients, comprising 44 heterozygous and 1 compound heterozygous variants. A total of 15 novel variants were detected. An autosomal dominant family history was determined in 43 cases, and the remaining 36 cases were reported as sporadic with no family history. The mean onset age of CMT in these patients was 12 ± 14 (range 0-59) years. We observed neuropathic symptoms in all patients. Some had optic atrophy, vocal cord paralysis, or spasticity. We detected a compound heterozygous MFN2 mutation in a patient with a severe phenotype and the co-occurrence of MFN2 and PMP22 mutations in a patient with an uncommon phenotype. MFN2 is the most frequent causative gene of CMT2 in Japan. We present 15 novel variants and broad clinical and mutational spectra of Japanese MFN2-related CMT patients. Regardless of the onset age and inheritance pattern, MFN2 gene analysis should be performed. Combinations of causative genes should be considered to explain the phenotypic diversity.

PMID: 28660751 [PubMed - as supplied by publisher]

Somatic Mutation Analyses in Studies of the Clonal Evolution and Diagnostic Targets of Prostate Cancer.

Curr Genomics. 2017 Jun;18(3):236-243

Authors: Mikhaylenko DS, Efremov GD, Strelnikov VV, Zaletaev DV, Alekseev BY

Abstract
Prostate cancer (PC) is the most common uro-oncological disease in the global population and still requires a more efficient laboratory diagnosis. Point mutations of oncogenes and tumor sup-pressor genes are the most frequent molecular genetic events in carcinogenesis. The mutations are re-sponsible, to a great extent, for the clonal evolution of cancer and can be considered as primary candi-date molecular markers of PC. Using next-generation sequencing to analyze the mutations in PC, the main molecular PC subtypes were identified, which depended on the presence of fusion genes and FOXA1, CHD1, and SPOP point mutations; other driver mutations responsible for the progression of PC subclones were also characterized. This review summarizes the data on early PC genetic markers (an mtDNA deletion, and TMPRSS2:ERG expression), as well as these somatic mutations at later stages of PC. Emphasis is placed on a switch in AR synthesis to a constitutively active variant and the point muta-tions that facilitate PC transition to a castration-refractory state that is resistant to new AR inhibitors. Based on the current whole-exome sequencing data, the frequencies and localizations of the somatic mu-tations that may provide new genetic diagnostic markers and drug targets are described.

PMID: 28659719 [PubMed - in process]

Identification of EGFLAM, SPATC1L and RNASE13 as novel susceptibility loci for aortic aneurysm in Japanese individuals by exome-wide association studies.

Int J Mol Med. 2017 May;39(5):1091-1100

Authors: Yamada Y, Sakuma J, Takeuchi I, Yasukochi Y, Kato K, Oguri M, Fujimaki T, Horibe H, Muramatsu M, Sawabe M, Fujiwara Y, Taniguchi Y, Obuchi S, Kawai H, Shinkai S, Mori S, Arai T, Tanaka M

Abstract
We performed an exome-wide association study (EWAS) to identify genetic variants - in particular, low‑frequency or rare variants with a moderate to large effect size - that confer susceptibility to aortic aneurysm with 8,782 Japanese subjects (456 patients with aortic aneurysm, 8,326 control individuals) and with the use of Illumina HumanExome-12 DNA Analysis BeadChip or Infinium Exome-24 BeadChip arrays. The correlation of allele frequencies for 41,432 single nucleotide polymorphisms (SNPs) that passed quality control to aortic aneurysm was examined with Fisher's exact test. Based on Bonferroni's correction, a P-value of <1.21x10-6 was considered statistically significant. The EWAS revealed 59 SNPs that were significantly associated with aortic aneurysm. None of these SNPs was significantly (P<2.12x10-4) associated with aortic aneurysm by multivariable logistic regression analysis with adjustment for age, gender and hypertension, although 8 SNPs were related (P<0.05) to this condition. Examination of the correlation of these latter 8 SNPs to true or dissecting aortic aneurysm separately showed that rs1465567 [T/C (W229R)] of the EGF-like, fibronectin type III, and laminin G domains gene (EGFLAM) (dominant model; P=0.0014; odds ratio, 1.63) was significantly (P<0.0016) associated with true aortic aneurysm. We next performed EWASs for true or dissecting aortic aneurysm separately and found that 45 and 19 SNPs were significantly associated with these conditions, respectively. Multivariable logistic regression analysis with adjustment for covariates revealed that rs113710653 [C/T (E231K)] of the spermatogenesis- and centriole associated 1-like gene (SPATC1L) (dominant model; P=0.0002; odds ratio, 5.32) and rs143881017 [C/T (R140H)] of the ribonuclease A family member 13 gene (RNASE13) (dominant model; P=0.0006; odds ratio, 5.77) were significantly (P<2.78x10-4 or P<6.58x10-4, respectively) associated with true or dissecting aortic aneurysm, respectively. EGFLAM and SPATC1L may thus be susceptibility loci for true aortic aneurysm and RNASE13 may be such a locus for dissecting aneurysm in Japanese individuals.

PMID: 28339009 [PubMed - indexed for MEDLINE]

CD55 Deficiency, Early-Onset Protein-Losing Enteropathy, and Thrombosis.

N Engl J Med. 2017 Jun 28;:

Authors: Ozen A, Comrie WA, Ardy RC, Domínguez Conde C, Dalgic B, Beser ÖF, Morawski AR, Karakoc-Aydiner E, Tutar E, Baris S, Ozcay F, Serwas NK, Zhang Y, Matthews HF, Pittaluga S, Folio LR, Unlusoy Aksu A, McElwee JJ, Krolo A, Kiykim A, Baris Z, Gulsan M, Ogulur I, Snapper SB, Houwen RHJ, Leavis HL, Ertem D, Kain R, Sari S, Erkan T, Su HC, Boztug K, Lenardo MJ

Abstract
Background Studies of monogenic gastrointestinal diseases have revealed molecular pathways critical to gut homeostasis and enabled the development of targeted therapies. Methods We studied 11 patients with abdominal pain and diarrhea caused by early-onset protein-losing enteropathy with primary intestinal lymphangiectasia, edema due to hypoproteinemia, malabsorption, and less frequently, bowel inflammation, recurrent infections, and angiopathic thromboembolic disease; the disorder followed an autosomal recessive pattern of inheritance. Whole-exome sequencing was performed to identify gene variants. We evaluated the function of CD55 in patients' cells, which we confirmed by means of exogenous induction of expression of CD55. Results We identified homozygous loss-of-function mutations in the gene encoding CD55 (decay-accelerating factor), which lead to loss of protein expression. Patients' T lymphocytes showed increased complement activation causing surface deposition of complement and the generation of soluble C5a. Costimulatory function and cytokine modulation by CD55 were defective. Genetic reconstitution of CD55 or treatment with a complement-inhibitory therapeutic antibody reversed abnormal complement activation. Conclusions CD55 deficiency with hyperactivation of complement, angiopathic thrombosis, and protein-losing enteropathy (the CHAPLE syndrome) is caused by abnormal complement activation due to biallelic loss-of-function mutations in CD55. (Funded by the National Institute of Allergy and Infectious Diseases and others.).

PMID: 28657829 [PubMed - as supplied by publisher]

India Allele Finder: a web-based annotation tool for identifying common alleles in next-generation sequencing data of Indian origin.

BMC Res Notes. 2017 Jun 27;10(1):233

Authors: Zhang JF, James F, Shukla A, Girisha KM, Paciorkowski AR

Abstract
OBJECTIVE: We built India Allele Finder, an online searchable database and command line tool, that gives researchers access to variant frequencies of Indian Telugu individuals, using publicly available fastq data from the 1000 Genomes Project. Access to appropriate population-based genomic variant annotation can accelerate the interpretation of genomic sequencing data. In particular, exome analysis of individuals of Indian descent will identify population variants not reflected in European exomes, complicating genomic analysis for such individuals.
RESULTS: India Allele Finder offers improved ease-of-use to investigators seeking to identify and annotate sequencing data from Indian populations. We describe the use of India Allele Finder to identify common population variants in a disease quartet whole exome dataset, reducing the number of candidate single nucleotide variants from 84 to 7. India Allele Finder is freely available to investigators to annotate genomic sequencing data from Indian populations. Use of India Allele Finder allows efficient identification of population variants in genomic sequencing data, and is an example of a population-specific annotation tool that simplifies analysis and encourages international collaboration in genomics research.

PMID: 28655339 [PubMed - in process]

A missense variant in FGD6 confers increased risk of polypoidal choroidal vasculopathy.

Nat Genet. 2016 Jun;48(6):640-7

Authors: Huang L, Zhang H, Cheng CY, Wen F, Tam PO, Zhao P, Chen H, Li Z, Chen L, Tai Z, Yamashiro K, Deng S, Zhu X, Chen W, Cai L, Lu F, Li Y, Cheung CM, Shi Y, Miyake M, Lin Y, Gong B, Liu X, Sim KS, Yang J, Mori K, Zhang X, Cackett PD, Tsujikawa M, Nishida K, Hao F, Ma S, Lin H, Cheng J, Fei P, Lai TY, Tang S, Laude A, Inoue S, Yeo IY, Sakurada Y, Zhou Y, Iijima H, Honda S, Lei C, Zhang L, Zheng H, Jiang D, Zhu X, Wong TY, Khor CC, Pang CP, Yoshimura N, Yang Z

Abstract
Polypoidal choroidal vasculopathy (PCV), a subtype of 'wet' age-related macular degeneration (AMD), constitutes up to 55% of cases of wet AMD in Asian patients. In contrast to the choroidal neovascularization (CNV) subtype, the genetic risk factors for PCV are relatively unknown. Exome sequencing analysis of a Han Chinese cohort followed by replication in four independent cohorts identified a rare c.986A>G (p.Lys329Arg) variant in the FGD6 gene as significantly associated with PCV (P = 2.19 × 10(-16), odds ratio (OR) = 2.12) but not with CNV (P = 0.26, OR = 1.13). The intracellular localization of FGD6-Arg329 is distinct from that of FGD6-Lys329. In vitro, FGD6 could regulate proangiogenic activity, and oxidized phospholipids increased expression of FGD6. FGD6-Arg329 promoted more abnormal vessel development in the mouse retina than FGD6-Lys329. Collectively, our data suggest that oxidized phospholipids and FGD6-Arg329 might act synergistically to increase susceptibility to PCV.

PMID: 27089177 [PubMed - indexed for MEDLINE]

Emergence of MET hyper-amplification at progression to MET and BRAF inhibition in colorectal cancer.

Br J Cancer. 2017 Jun 27;:

Authors: Oddo D, Siravegna G, Gloghini A, Vernieri C, Mussolin B, Morano F, Crisafulli G, Berenato R, Corti G, Volpi CC, Buscarino M, Niger M, Dunne PD, Rospo G, Valtorta E, Bartolini A, Fucà G, Lamba S, Martinetti A, Di Bartolomeo M, de Braud F, Bardelli A, Pietrantonio F, Di Nicolantonio F

Abstract
BACKGROUND: Combined MET and BRAF inhibition showed clinical benefit in a patient with rectal cancer carrying BRAF(V600E) and MET amplification. However after 4 months, acquired resistance emerged and the patient deceased shortly after disease progression. The mechanism of resistance to this drug combination is unknown.
METHODS: We analysed plasma circulating tumour DNA obtained at progression by exome sequencing and digital PCR. MET gene and mRNA in situ hybridisation analyses in two bioptic specimens obtained at progression were used to confirm the plasma data.
RESULTS: We identified in plasma MET gene hyper-amplification as a potential mechanism underlying therapy resistance. Increased MET gene copy and transcript levels were detected in liver and lymph node metastatic biopsies. Finally, transduction of MET in BRAF mutant colorectal cancer cells conferred refractoriness to BRAF and MET inhibition.
CONCLUSIONS: We identified in a rectal cancer patient MET gene hyper-amplification as mechanism of resistance to dual BRAF and MET inhibition.British Journal of Cancer advance online publication, 27 June 2017; doi:10.1038/bjc.2017.196 www.bjcancer.com.

PMID: 28654634 [PubMed - as supplied by publisher]

Extension of the phenotype of biallelic loss-of-function mutations in SLC25A46 to the severe form of pontocerebellar hypoplasia type I.

Clin Genet. 2017 Jun 27;:

Authors: Braunisch MC, Gallwitz H, Abicht A, Diebold I, Holinski-Feder E, Van Maldergem L, Lammens M, Kovács-Nagy R, Alhaddad B, Strom TM, Meitinger T, Senderek J, Rudnik-Schöneborn S, Haack TB

Abstract
Biallelic mutations in SLC25A46, encoding a modified solute transporter involved in mitochondrial dynamics, have been identified in a wide range of conditions such as hereditary motor and sensory neuropathy with optic atrophy type VIB (OMIM: *610826) and congenital lethal pontocerebellar hypoplasia (PCH). To date, 18 patients from 13 families have been reported, presenting with the key clinical features of optic atrophy, peripheral neuropathy, and cerebellar atrophy. The course of the disease was highly variable ranging from severe muscular hypotonia at birth and early death to first manifestations in late childhood and survival into the fifties. Here we report on four patients from two families diagnosed with pontocerebellar hypoplasia (PCH) who died within the first month of life from respiratory insufficiency. Patients from one family had pathoanatomically proven spinal motor neuron degeneration (PCH1). Using exome sequencing, we identified biallelic disease-segregating loss-of-function mutations in SLC25A46 in both families. Our study adds to the definition of the SLC25A46-associated phenotypic spectrum that includes neonatal fatalities due to PCH as the severe extreme.

PMID: 28653766 [PubMed - as supplied by publisher]

Development of Kras mutant lung adenocarcinoma in mice with knockout of the airway lineage-specific gene Gprc5a.

Int J Cancer. 2017 Jun 27;:

Authors: Fujimoto J, Nunomura-Nakamura S, Liu Y, Lang W, McDowell T, Jakubek Y, Ezzeddine D, Ochieng JK, Petersen J, Davies G, Fukuoka J, Wistuba II, Ehli E, Fowler J, Scheet P, Kadara H

Abstract
Despite the urgency for prevention and treatment of lung adenocarcinoma (LUAD), we still do not know drivers in pathogenesis of the disease. Earlier work revealed that mice with knockout of the G-protein coupled receptor Gprc5a develop late onset lung tumors including LUADs. Here, we sought to further probe the impact of Gprc5a expression on LUAD pathogenesis. We first surveyed GPRC5A expression in human tissues and found that GPRC5A was markedly elevated in human normal lung relative to other normal tissues and was consistently down-regulated in LUADs. In sharp contrast to wild type littermates, Gprc5a(-/-) mice treated chronically with the nicotine-specific carcinogen NNK developed LUADs by six months following NNK exposure. Immunofluorescence analysis revealed that the LUADs exhibited abundant expression of surfactant protein C and lacked the clara cell marker Ccsp, suggesting that these LUADs originated from alveolar type II cells. Next, we sought to survey genome-wide alterations in the pathogenesis of Gprc5a(-/-) LUADs. Using whole exome sequencing, we found that carcinogen-induced LUADs exhibited markedly higher somatic mutation burdens relative to spontaneous tumors. All LUADs were found to harbor somatic mutations in the Kras oncogene (p. G12D or p. Q61R). In contrast to spontaneous lesions, carcinogen-induced Gprc5a(-/-) LUADs exhibited mutations (variants and copy number gain) in additional drivers (Atm, Kmt2d, Nf1, Trp53, Met, Ezh2). Our study underscores genomic alterations that represent early events in the development of Kras mutant LUAD following Gprc5a loss and tobacco carcinogen exposure and that may constitute targets for prevention and early treatment of this disease. This article is protected by copyright. All rights reserved.

PMID: 28653505 [PubMed - as supplied by publisher]

Newborn Sequencing in Genomic Medicine and Public Health.

Pediatrics. 2017 Feb;139(2):

Authors: Berg JS, Agrawal PB, Bailey DB, Beggs AH, Brenner SE, Brower AM, Cakici JA, Ceyhan-Birsoy O, Chan K, Chen F, Currier RJ, Dukhovny D, Green RC, Harris-Wai J, Holm IA, Iglesias B, Joseph G, Kingsmore SF, Koenig BA, Kwok PY, Lantos J, Leeder SJ, Lewis MA, McGuire AL, Milko LV, Mooney SD, Parad RB, Pereira S, Petrikin J, Powell BC, Powell CM, Puck JM, Rehm HL, Risch N, Roche M, Shieh JT, Veeraraghavan N, Watson MS, Willig L, Yu TW, Urv T, Wise AL

Abstract
The rapid development of genomic sequencing technologies has decreased the cost of genetic analysis to the extent that it seems plausible that genome-scale sequencing could have widespread availability in pediatric care. Genomic sequencing provides a powerful diagnostic modality for patients who manifest symptoms of monogenic disease and an opportunity to detect health conditions before their development. However, many technical, clinical, ethical, and societal challenges should be addressed before such technology is widely deployed in pediatric practice. This article provides an overview of the Newborn Sequencing in Genomic Medicine and Public Health Consortium, which is investigating the application of genome-scale sequencing in newborns for both diagnosis and screening.

PMID: 28096516 [PubMed - indexed for MEDLINE]

Deficiency of WARS2, encoding mitochondrial tryptophanyl tRNA synthetase, causes severe infantile onset leukoencephalopathy.

Am J Med Genet A. 2017 Jun 26;:

Authors: Theisen BE, Rumyantseva A, Cohen JS, Alcaraz WA, Shinde DN, Tang S, Srivastava S, Pevsner J, Trifunovic A, Fatemi A

Abstract
Pathogenic variants in the mitochondrial aminoacyl tRNA synthetases lead to deficiencies in mitochondrial protein synthesis and are associated with a broad range of clinical presentations usually with early onset and inherited in an autosomal recessive manner. Of the 19 mitochondrial aminoacyl tRNA synthetases, WARS2, encoding mitochondrial tryptophanyl tRNA synthetase, was as of late the only one that had not been associated with disease in humans. A case of a family with pathogenic variants in WARS2 that caused mainly intellectual disability, speech impairment, aggressiveness, and athetosis was recently reported. Here we substantially extend and consolidate the symptomatology of WARS2 by presenting a patient with severe infantile-onset leukoencephalopathy, profound intellectual disability, spastic quadriplegia, epilepsy, microcephaly, short stature, failure to thrive, cerebral atrophy, and periventricular white matter abnormalities. He was found by whole-exome sequencing to have compound heterozygous variants in WARS2, c.938A>T (p.K313M) and c.298_300delCTT (p.L100del). De novo synthesis of proteins inside mitochondria was reduced in the patient's fibroblasts, leading to significantly lower steady-state levels of respiratory chain subunits compared to control and resulting in lower oxygen consumption rates.

PMID: 28650581 [PubMed - as supplied by publisher]

The genetics of platelet count and volume in humans.

Platelets. 2017 Jun 26;:1-6

Authors: Eicher JD, Lettre G, Johnson AD

Abstract
The last decade has witnessed an explosion in the depth, variety, and amount of human genetic data that can be generated. This revolution in technical and analytical capacities has enabled the genetic investigation of human traits and disease in thousands to now millions of participants. Investigators have taken advantage of these advancements to gain insight into platelet biology and the platelet's role in human disease. To do so, large human genetics studies have examined the association of genetic variation with two quantitative traits measured in many population and patient based cohorts: platelet count (PLT) and mean platelet volume (MPV). This article will review the many human genetic strategies-ranging from genome-wide association study (GWAS), Exomechip, whole exome sequencing (WES), to whole genome sequencing (WGS)-employed to identify genes and variants that contribute to platelet traits. Additionally, we will discuss how these investigations have examined and interpreted the functional implications of these newly identified genetic factors and whether they also impart risk to human disease. The depth and size of genetic, phenotypic, and other -omic data are primed to continue their growth in the coming years and provide unprecedented opportunities to gain critical insights into platelet biology and how platelets contribute to disease.

PMID: 28649937 [PubMed - as supplied by publisher]

Novel 25 kb Deletion of MERTK Causes Retinitis Pigmentosa With Severe Progression.

Invest Ophthalmol Vis Sci. 2017 Mar 01;58(3):1736-1742

Authors: Evans DR, Green JS, Johnson GJ, Schwartzentruber J, Majewski J, Beaulieu CL, Qin W, Marshall CR, Paton TA, Roslin NM, Paterson AD, Fahiminiya S, French J, Boycott KM, Woods MO, FORGE Canada Consortium

Abstract
Purpose: Retinitis pigmentosa (RP) describes a complex group of inherited retinal dystrophies with almost 300 reported genes and loci. We investigated the genetic etiology of autosomal recessive RP (arRP) in a large kindred with 5 affected family members, who reside on the island of Newfoundland, Canada.
Methods: Genetic linkage analysis was performed on 12 family members (Infinium HumanOmni2.5-8 BeadChip). Whole exome sequencing analysis (Illumina HiSeq) was performed on one affected individual. A custom pipeline was applied to call, annotate, and filter variants. FishingCNV was used to scan the exome for rare copy number variants (CNVs). Candidate CNVs subsequently were visualized from microarray data (CNVPartition v.3.1.6.). MERTK breakpoints were mapped and familial cosegregation was tested using Sanger Sequencing.
Results: We found strong evidence of linkage to a locus on chromosome 2 (logarithm of the odds [LOD] 4.89 [θ = 0]), at an interval encompassing the MERTK gene. Whole exome sequencing did not uncover candidate point mutations in MERTK, or other known RP genes. Subsequently, CNV analysis of the exome data and breakpoint mapping revealed a 25,218 bp deletion of MERTK, encompassing exons 6 to 8, with breakpoints in introns 5 (chr2:112,725,292) and 8 (chr2:112,750,421). A 48 bp insertion sequence was buried within the breakpoint; 18 bps shared homology to MIR4435-2HG and LINC00152, and 30 bp mapped to MERTK. The deletion cosegregated with arRP in the family.
Conclusions: This study describes the molecular and clinical characterization of an arRP family segregating a novel 25 kb deletion of MERTK. These findings may assist clinicians in providing a diagnosis for other unsolved RP cases.

PMID: 28324114 [PubMed - indexed for MEDLINE]

Discovery and characterization of spontaneous mouse models of craniofacial dysmorphology.

Dev Biol. 2016 Jul 15;415(2):216-227

Authors: Palmer K, Fairfield H, Borgeia S, Curtain M, Hassan MG, Dionne L, Yong Karst S, Coombs H, Bronson RT, Reinholdt LG, Bergstrom DE, Donahue LR, Cox TC, Murray SA

Abstract
Craniofacial abnormalities are among the most common features of human genetic syndromes and disorders. The etiology of these conditions is often complex, influenced by both genetic context and the environment. Frequently, craniofacial abnormalities present as part of a syndrome with clear comorbid phenotypes, providing additional insight into mechanisms of the causative gene or pathway. The mouse has been a key tool in our understanding of the genetic mechanisms of craniofacial development and disease, and can provide excellent models for human craniofacial abnormalities. While powerful genetic engineering tools in the mouse have contributed significantly our understanding of craniofacial development and dysmorphology, forward genetic approaches provide an unbiased means to identify new genes and pathways. Moreover, spontaneous mutations can occur on any number of genetic backgrounds, potentially revealing critical genes that require a specific genetic context. Here we report discovery and phenotyping of 43 craniofacial mouse models, derived primarily from a screen for spontaneous mutations in production colonies at the Jackson Laboratory. We identify the causative gene for 33 lines, including novel genes in pathways not previously connected to craniofacial development, and novel alleles of known genes that present with unique phenotypes. Together with our detailed characterization, this work provides a valuable gene discovery resource for the craniofacial community, and a rich source of mouse models for further investigation.

PMID: 26234751 [PubMed - indexed for MEDLINE]

Genotype-phenotype evaluation of MED13L defects in the light of a novel truncating and a recurrent missense mutation.

Eur J Med Genet. 2017 Jun 20;:

Authors: Asadollahi R, Zweier M, Gogoll L, Schiffmann R, Sticht H, Steindl K, Rauch A

Abstract
A decade after the designation of MED13L as a gene and its link to intellectual disability (ID) and dextro-looped transposition of great arteries in 2003, we previously described a recognizable syndrome due to MED13L haploinsufficiency. Subsequent reports of 22 further patients diagnosed by genome-wide testing further delineated the syndrome with expansion of the phenotypic spectrum and showed reduced penetrance for congenital heart defects. We now report two novel patients identified by whole exome sequencing, one with a de novo MED13L truncating mutation and the other with a de novo missense mutation. The first patient indicates some facial resemblance to Kleefstra syndrome as a novel differential diagnosis, and the second patient shows, for the first time, recurrence of a MED13L missense mutation (p.(Asp860Gly)). Notably, our in silico modelling predicted this missense mutation to decrease the stability of an alpha-helix and thereby affecting the MED13L secondary structure, while the majority of published missense mutations remain variants of uncertain significance. Review of the reported patients with MED13L haploinsufficiency indicates moderate to severe ID and facial anomalies in all patients, as well as severe speech delay and muscular hypotonia in the majority. Further common signs include abnormal MRI findings of myelination defects and abnormal corpus callosum, ataxia and coordination problems, autistic features, seizures/abnormal EEG, or congenital heart defects, present in about 20-50% of the patients. With reference to facial anomalies, the majority of patients were reported to show broad/prominent forehead, low set ears, bitemporal narrowing, upslanting palpebral fissures, depressed/flat nasal bridge, bulbous nose, and abnormal chin, but macroglossia and horizontal eyebrows were also observed in ∼30%. The latter are especially important in the differential diagnosis of 1p36 deletion and Kleefstra syndromes, while the more common facial gestalt shows some resemblance to 22q11.2 deletion syndrome. Despite the fact that MED13L was found to be one of the most common ID genes in the Deciphering Developmental Disorders Study, further detailed patient descriptions are needed to explore the full clinical spectrum, potential genotype-phenotype correlations, as well as the role of missense mutations and potential mutational hotspots along the gene.

PMID: 28645799 [PubMed - as supplied by publisher]