03542nas a2200649 4500008004100000022001400041245010900055210006900164260001600233300000700249490000700256520162800263653001601891653001701907653000801924100001901932700002001951700002201971700002501993700002502018700002202043700001702065700002102082700002502103700001902128700002202147700002002169700002102189700001902210700001802229700001802247700002202265700002302287700001802310700002002328700001602348700002602364700001702390700002202407700001702429700002202446700002102468700003202489700002802521700002302549700002902572700002502601700001802626700001902644700002502663700002602688700002302714700001902737700003402756700002402790856007802814 2017 eng d a1474-760X00aWhole exome sequencing coupled with unbiased functional analysis reveals new Hirschsprung disease genes.0 aWhole exome sequencing coupled with unbiased functional analysis c2017 Mar 08 a480 v183 aBACKGROUND: Hirschsprung disease (HSCR), which is congenital obstruction of the bowel, results from a failure of enteric nervous system (ENS) progenitors to migrate, proliferate, differentiate, or survive within the distal intestine. Previous studies that have searched for genes underlying HSCR have focused on ENS-related pathways and genes not fitting the current knowledge have thus often been ignored. We identify and validate novel HSCR genes using whole exome sequencing (WES), burden tests, in silico prediction, unbiased in vivo analyses of the mutated genes in zebrafish, and expression analyses in zebrafish, mouse, and human. RESULTS: We performed de novo mutation (DNM) screening on 24 HSCR trios. We identify 28 DNMs in 21 different genes. Eight of the DNMs we identified occur in RET, the main HSCR gene, and the remaining 20 DNMs reside in genes not reported in the ENS. Knockdown of all 12 genes with missense or loss-of-function DNMs showed that the orthologs of four genes (DENND3, NCLN, NUP98, and TBATA) are indispensable for ENS development in zebrafish, and these results were confirmed by CRISPR knockout. These genes are also expressed in human and mouse gut and/or ENS progenitors. Importantly, the encoded proteins are linked to neuronal processes shared by the central nervous system and the ENS. CONCLUSIONS: Our data open new fields of investigation into HSCR pathology and provide novel insights into the development of the ENS. Moreover, the study demonstrates that functional analyses of genes carrying DNMs are warranted to delineate the full genetic architecture of rare complex diseases.10aHirschprung10aRare Disease10aWES1 aGui, Hongsheng1 aSchriemer, Duco1 aCheng, William, W1 aChauhan, Rajendra, K1 aAntiňolo, Guillermo1 aBerrios, Courtney1 aBleda, Marta1 aBrooks, Alice, S1 aBrouwer, Rutger, W W1 aBurns, Alan, J1 aCherny, Stacey, S1 aDopazo, Joaquin1 aEggen, Bart, J L1 aGriseri, Paola1 aJalloh, Binta1 aLe, Thuy-Linh1 aLui, Vincent, C H1 aLuzón-Toro, Berta1 aMatera, Ivana1 aNgan, Elly, S W1 aPelet, Anna1 aRuiz-Ferrer, Macarena1 aSham, Pak, C1 aShepherd, Iain, T1 aSo, Man-Ting1 aSribudiani, Yunia1 aTang, Clara, S M1 avan den Hout, Mirjam, C G N1 avan der Linde, Herma, C1 avan Ham, Tjakko, J1 avan IJcken, Wilfred, F J1 aVerheij, Joke, B G M1 aAmiel, Jeanne1 aBorrego, Salud1 aCeccherini, Isabella1 aChakravarti, Aravinda1 aLyonnet, Stanislas1 aTam, Paul, K H1 aGarcia-Barceló, Maria-Mercè1 aHofstra, Robert, Mw uhttp://genomebiology.biomedcentral.com/articles/10.1186/s13059-017-1174-601877nas a2200577 4500008004100000245010800041210006900149260001600218490000700234100001900241700002000260700002300280700002600303700002500329700002200354700001700376700002200393700002700415700002000442700002300462700002000485700002300505700001900528700001800547700001800565700002400583700002300607700001800630700002200648700001600670700002600686700001800712700002300730700001700753700002200770700002300792700003500815700002900850700002400879700003100903700002800934700001800962700001900980700002500999700002601024700002301050700002101073700003401094700002701128856014401155 2017 eng d00aWhole exome sequencing coupled with unbiased functional analysis reveals new Hirschsprung disease genes0 aWhole exome sequencing coupled with unbiased functional analysis cJan-12-20170 v181 aGui, Hongsheng1 aSchriemer, Duco1 aCheng, William, W.1 aChauhan, Rajendra, K.1 aAntiňolo, Guillermo1 aBerrios, Courtney1 aBleda, Marta1 aBrooks, Alice, S.1 aBrouwer, Rutger, W. W.1 aBurns, Alan, J.1 aCherny, Stacey, S.1 aDopazo, Joaquin1 aEggen, Bart, J. L.1 aGriseri, Paola1 aJalloh, Binta1 aLe, Thuy-Linh1 aLui, Vincent, C. H.1 aLuzón-Toro, Berta1 aMatera, Ivana1 aNgan, Elly, S. W.1 aPelet, Anna1 aRuiz-Ferrer, Macarena1 aSham, Pak, C.1 aShepherd, Iain, T.1 aSo, Man-Ting1 aSribudiani, Yunia1 aTang, Clara, S. M.1 avan den Hout, Mirjam, C. G. N.1 avan der Linde, Herma, C.1 avan Ham, Tjakko, J.1 avan IJcken, Wilfred, F. J.1 aVerheij, Joke, B. G. M.1 aAmiel, Jeanne1 aBorrego, Salud1 aCeccherini, Isabella1 aChakravarti, Aravinda1 aLyonnet, Stanislas1 aTam, Paul, K. H.1 aGarcia-Barceló, Maria-Mercè1 aHofstra, Robert, M. W. uhttp://genomebiology.biomedcentral.com/articles/10.1186/s13059-017-1174-6http://link.springer.com/content/pdf/10.1186/s13059-017-1174-6.pdf01578nas a2200253 4500008004100000022001400041245006500055210006300120260001500183300001100198490000700209520080700216653002601023653001301049653001301062100002401075700002401099700002101123700002001144700001701164700002001181700002001201856010301221 2016 eng d a1367-481100aWeb-based network analysis and visualization using CellMaps.0 aWebbased network analysis and visualization using CellMaps c2016 10 01 a3041-30 v323 a
UNLABELLED: : CellMaps is an HTML5 open-source web tool that allows displaying, editing, exploring and analyzing biological networks as well as integrating metadata into them. Computations and analyses are remotely executed in high-end servers, and all the functionalities are available through RESTful web services. CellMaps can easily be integrated in any web page by using an available JavaScript API.
AVAILABILITY AND IMPLEMENTATION: The application is available at: http://cellmaps.babelomics.org/ and the code can be found in: https://github.com/opencb/cell-maps The client is implemented in JavaScript and the server in C and Java.
CONTACT: jdopazo@cipf.es
SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
10aBiochemical Phenomena10aInternet10aSoftware1 aSalavert, Francisco1 aGarcía-Alonso, Luz1 aSánchez, Rubén1 aAlonso, Roberto1 aBleda, Marta1 aMedina, Ignacio1 aDopazo, Joaquin uhttps://www.clinbioinfosspa.es/content/web-based-network-analysis-and-visualization-using-cellmaps02967nas a2200529 4500008004100000022001400041245011800055210006900173260001200242300001400254490000800268520135400276653001501630653001001645653001201655653002701667653002101694653002401715653001001739653002101749653002801770653001001798653001101808653003501819653002201854653004201876653001101918653003301929653001301962653002601975653003702001653002502038653001802063100002202081700001902103700001802122700001902140700001502159700001802174700001902192700001902211700002002230700001802250700002202268700002002290856012702310 2016 eng d a1432-120300aWhole exome sequencing of Rett syndrome-like patients reveals the mutational diversity of the clinical phenotype.0 aWhole exome sequencing of Rett syndromelike patients reveals the c2016 12 a1343-13540 v1353 aClassical Rett syndrome (RTT) is a neurodevelopmental disorder where most of cases carry MECP2 mutations. Atypical RTT variants involve mutations in CDKL5 and FOXG1. However, a subset of RTT patients remains that do not carry any mutation in the described genes. Whole exome sequencing was carried out in a cohort of 21 female probands with clinical features overlapping with those of RTT, but without mutations in the customarily studied genes. Candidates were functionally validated by assessing the appearance of a neurological phenotype in Caenorhabditis elegans upon disruption of the corresponding ortholog gene. We detected pathogenic variants that accounted for the RTT-like phenotype in 14 (66.6 %) patients. Five patients were carriers of mutations in genes already known to be associated with other syndromic neurodevelopmental disorders. We determined that the other patients harbored mutations in genes that have not previously been linked to RTT or other neurodevelopmental syndromes, such as the ankyrin repeat containing protein ANKRD31 or the neuronal acetylcholine receptor subunit alpha-5 (CHRNA5). Furthermore, worm assays demonstrated that mutations in the studied candidate genes caused locomotion defects. Our findings indicate that mutations in a variety of genes contribute to the development of RTT-like phenotypes.
10aAdolescent10aAdult10aAnimals10aCaenorhabditis elegans10aCarrier Proteins10aCell Cycle Proteins10aChild10aChild, Preschool10aDNA Mutational Analysis10aExome10aFemale10aForkhead Transcription Factors10aGenetic Variation10aHigh-Throughput Nucleotide Sequencing10aHumans10aMethyl-CpG-Binding Protein 210amutation10aNerve Tissue Proteins10aProtein Serine-Threonine Kinases10aReceptors, Nicotinic10aRett Syndrome1 aLucariello, Mario1 aVidal, Enrique1 aVidal, Silvia1 aSaez, Mauricio1 aRoa, Laura1 aHuertas, Dori1 aPineda, Mercè1 aDalfó, Esther1 aDopazo, Joaquin1 aJurado, Paola1 aArmstrong, Judith1 aEsteller, Manel uhttps://www.clinbioinfosspa.es/content/whole-exome-sequencing-rett-syndrome-patients-reveals-mutational-diversity-clinical02872nas a2200373 4500008004100000022001400041245013900055210006900194260001600263300001400279490000700293520162700300100003001927700002401957700001801981700003201999700002002031700001802051700002802069700002202097700003402119700002602153700003302179700002802212700002702240700001802267700002902285700002002314700002802334700001902362700002002381700001802401856007902419 2015 eng d a1460-208300aWhole Exome Sequencing Reveals ZNF408 as a New Gene Associated With Autosomal Recessive Retinitis Pigmentosa with Vitreal Alterations.0 aWhole Exome Sequencing Reveals ZNF408 as a New Gene Associated W c2015 Apr 16 a4037-40480 v243 aRetinitis Pigmentosa (RP) is a group of progressive inherited retinal dystrophies that cause visual impairment as a result of photoreceptor cell death. RP is heterogeneous, both clinically and genetically making difficult to establish precise genotype-phenotype correlations. In a Spanish family with autosomal recessive RP (arRP), homozygosity mapping and whole exome sequencing led to the identification of a homozygous mutation (c.358_359delGT; p.Ala122Leufs*2) in the ZNF408 gene. A screening performed in 217 additional unrelated families revealed another homozygous mutation (c.1621C>T; p.Arg541Cys) in an isolated RP case. ZNF408 encodes a transcription factor that harbors ten predicted C2H2-type fingers thought to be implicated in DNA binding. To elucidate the ZNF408 role in the retina and the pathogenesis of these mutations we have performed different functional studies. By immunohistochemical analysis in healthy human retina, we identified that ZNF408 is expressed in both cone and rod photoreceptors, in a specific type of amacrine and ganglion cells, and in retinal blood vessels. ZNF408 revealed a cytoplasmic localization and a nuclear distribution in areas corresponding with the euchromatin fraction. Immunolocalization studies showed a partial mislocalization of the p.Arg541Cys mutant protein retaining part of the WT protein in the cytoplasm. Our study demonstrates that ZNF408, previously associated with Familial Exudative Vitreoretinopathy (FEVR), is a new gene causing arRP with vitreous condensations supporting the evidence that this protein plays additional functions into the human retina.1 aAvila-Fernandez, Almudena1 aPerez-Carro, Raquel1 aCorton, Marta1 aLopez-Molina, Maria, Isabel1 aCampello, Laura1 aGaranto, Alex1 aFernadez-Sanchez, Laura1 aDuijkers, Lonneke1 aLopez-Martinez, Miguel, Angel1 aRiveiro-Alvarez, Rosa1 ada Silva, Luciana, Rodrigues1 aSanchez-Alcudia, Rocío1 aMartin-Garrido, Esther1 aReyes, Noelia1 aGarcia-Garcia, Francisco1 aDopazo, Joaquin1 aGarcia-Sandoval, Blanca1 aCollin, Rob, W1 aCuenca, Nicolas1 aAyuso, Carmen uhttp://hmg.oxfordjournals.org/content/early/2015/04/16/hmg.ddv140.abstract03598nas a2200601 4500008004100000022001400041245013900055210006900194260001600263300001200279490000700291520163400298653002401932653001201956653002501968653002301993653001402016653002502030653001002055653003402065653004202099653001502141653001102156653002802167653002002195653001302215653001102228653003702239653003602276653002502312653002602337100003002363700002402393700001802417700003202435700002002467700002302487700002902510700002202539700003402561700002602595700003302621700002802654700002702682700001802709700002902727700002002756700002802776700002102804700002002825700001802845856013302863 2015 eng d a1460-208300aWhole-exome sequencing reveals ZNF408 as a new gene associated with autosomal recessive retinitis pigmentosa with vitreal alterations.0 aWholeexome sequencing reveals ZNF408 as a new gene associated wi c2015 Jul 15 a4037-480 v243 aRetinitis pigmentosa (RP) is a group of progressive inherited retinal dystrophies that cause visual impairment as a result of photoreceptor cell death. RP is heterogeneous, both clinically and genetically making difficult to establish precise genotype-phenotype correlations. In a Spanish family with autosomal recessive RP (arRP), homozygosity mapping and whole-exome sequencing led to the identification of a homozygous mutation (c.358_359delGT; p.Ala122Leufs*2) in the ZNF408 gene. A screening performed in 217 additional unrelated families revealed another homozygous mutation (c.1621C>T; p.Arg541Cys) in an isolated RP case. ZNF408 encodes a transcription factor that harbors 10 predicted C2H2-type fingers thought to be implicated in DNA binding. To elucidate the ZNF408 role in the retina and the pathogenesis of these mutations we have performed different functional studies. By immunohistochemical analysis in healthy human retina, we identified that ZNF408 is expressed in both cone and rod photoreceptors, in a specific type of amacrine and ganglion cells, and in retinal blood vessels. ZNF408 revealed a cytoplasmic localization and a nuclear distribution in areas corresponding with the euchromatin fraction. Immunolocalization studies showed a partial mislocalization of the p.Arg541Cys mutant protein retaining part of the WT protein in the cytoplasm. Our study demonstrates that ZNF408, previously associated with Familial Exudative Vitreoretinopathy (FEVR), is a new gene causing arRP with vitreous condensations supporting the evidence that this protein plays additional functions into the human retina.
10aAmino Acid Sequence10aAnimals10aChlorocebus aethiops10aChromosome Mapping10aCOS Cells10aDNA-Binding Proteins10aExome10aGenome-Wide Association Study10aHigh-Throughput Nucleotide Sequencing10aHomozygote10aHumans10aMolecular Sequence Data10aMutant Proteins10aPedigree10aRetina10aRetinal Cone Photoreceptor Cells10aRetinal Rod Photoreceptor Cells10aRetinitis pigmentosa10aTranscription Factors1 aAvila-Fernandez, Almudena1 aPerez-Carro, Raquel1 aCorton, Marta1 aLopez-Molina, Maria, Isabel1 aCampello, Laura1 aGaranto, Alejandro1 aFernandez-Sanchez, Laura1 aDuijkers, Lonneke1 aLopez-Martinez, Miguel, Angel1 aRiveiro-Alvarez, Rosa1 ada Silva, Luciana, Rodrigues1 aSanchez-Alcudia, Rocío1 aMartin-Garrido, Esther1 aReyes, Noelia1 aGarcia-Garcia, Francisco1 aDopazo, Joaquin1 aGarcia-Sandoval, Blanca1 aCollin, Rob, W J1 aCuenca, Nicolas1 aAyuso, Carmen uhttps://www.clinbioinfosspa.es/content/whole-exome-sequencing-reveals-znf408-new-gene-associated-autosomal-recessive-retinitis-001799nas a2200217 4500008004100000022001400041245013800055210006900193260001600262300001200278490000700290520106000297653001501357653003501372653000801407100002301415700002901438700002001467700002101487856007301508 2014 eng d a1362-496200aA web tool for the design and management of panels of genes for targeted enrichment and massive sequencing for clinical applications.0 aweb tool for the design and management of panels of genes for ta c2014 May 26 aW83-W870 v423 aDisease targeted sequencing is gaining importance as a powerful and cost-effective application of high throughput sequencing technologies to the diagnosis. However, the lack of proper tools to process the data hinders its extensive adoption. Here we present TEAM, an intuitive and easy-to-use web tool that fills the gap between the predicted mutations and the final diagnostic in targeted enrichment sequencing analysis. The tool searches for known diagnostic mutations, corresponding to a disease panel, among the predicted patient’s variants. Diagnostic variants for the disease are taken from four databases of disease-related variants (HGMD-public, HUMSAVAR, ClinVar and COSMIC.) If no primary diagnostic variant is found, then a list of secondary findings that can help to establish a diagnostic is produced. TEAM also provides with an interface for the definition of and customization of panels, by means of which, genes and mutations can be added or discarded to adjust panel definitions. TEAM is freely available at: http://team.babelomics.org.10aDiagnostic10aTargeted enrichment sequencing10aWES1 aAlemán, Alejandro1 aGarcia-Garcia, Francisco1 aMedina, Ignacio1 aDopazo, Joaquín uhttp://nar.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=2486162602033nas a2200205 4500008004100000022001400041245013200055210006900187260001500256300001300271490000700284520134300291653002401634100002301658700002901681700002401710700002001734700002101754856005201775 2014 eng d a1362-496200aA web-based interactive framework to assist in the prioritization of disease candidate genes in whole-exome sequencing studies.0 awebbased interactive framework to assist in the prioritization o c2014 May 6 aW88-W93.0 v423 aWhole-exome sequencing has become a fundamental tool for the discovery of disease-related genes of familial diseases and the identification of somatic driver variants in cancer. However, finding the causal mutation among the enormous background of individual variability in a small number of samples is still a big challenge. Here we describe a web-based tool, BiERapp, which efficiently helps in the identification of causative variants in family and sporadic genetic diseases. The program reads lists of predicted variants (nucleotide substitutions and indels) in affected individuals or tumor samples and controls. In family studies, different modes of inheritance can easily be defined to filter out variants that do not segregate with the disease along the family. Moreover, BiERapp integrates additional information such as allelic frequencies in the general population and the most popular damaging scores to further narrow down the number of putative variants in successive filtering steps. BiERapp provides an interactive and user-friendly interface that implements the filtering strategy used in the context of a large-scale genomic project carried out by the Spanish Network for Research in Rare Diseases (CIBERER) in which more than 800 exomes have been analyzed. BiERapp is freely available at: http://bierapp.babelomics.org/10aNGS. prioritization1 aAlemán, Alejandro1 aGarcia-Garcia, Francisco1 aSalavert, Francisco1 aMedina, Ignacio1 aDopazo, Joaquín uhttp://nar.oxfordjournals.org/content/42/W1/W8803066nas a2200241 4500008004100000022001400041245015200055210006900207260000900276300001200285490000700297520223800304100002802542700003302570700002202603700002702625700003302652700003202685700002002717700001902737700002502756856004302781 2013 eng d a1090-053500aWhole-exome sequencing identifies novel compound heterozygous mutations in USH2A in Spanish patients with autosomal recessive retinitis pigmentosa.0 aWholeexome sequencing identifies novel compound heterozygous mut c2013 a2187-950 v193 aPURPOSE: Retinitis pigmentosa (RP) is an inherited retinal dystrophy characterized by extreme genetic and clinical heterogeneity. Thus, the diagnosis is not always easily performed due to phenotypic and genetic overlap. Current clinical practices have focused on the systematic evaluation of a set of known genes for each phenotype, but this approach may fail in patients with inaccurate diagnosis or infrequent genetic cause. In the present study, we investigated the genetic cause of autosomal recessive RP (arRP) in a Spanish family in which the causal mutation has not yet been identified with primer extension technology and resequencing. METHODS: We designed a whole-exome sequencing (WES)-based approach using NimbleGen SeqCap EZ Exome V3 sample preparation kit and the SOLiD 5500×l next-generation sequencing platform. We sequenced the exomes of both unaffected parents and two affected siblings. Exome analysis resulted in the identification of 43,204 variants in the index patient. All variants passing filter criteria were validated with Sanger sequencing to confirm familial segregation and absence in the control population. In silico prediction tools were used to determine mutational impact on protein function and the structure of the identified variants. RESULTS: Novel Usher syndrome type 2A (USH2A) compound heterozygous mutations, c.4325T>C (p.F1442S) and c.15188T>G (p.L5063R), located in exons 20 and 70, respectively, were identified as probable causative mutations for RP in this family. Family segregation of the variants showed the presence of both mutations in all affected members and in two siblings who were apparently asymptomatic at the time of family ascertainment. Clinical reassessment confirmed the diagnosis of RP in these patients. CONCLUSIONS: Using WES, we identified two heterozygous novel mutations in USH2A as the most likely disease-causing variants in a Spanish family diagnosed with arRP in which the cause of the disease had not yet been identified with commonly used techniques. Our data reinforce the clinical role of WES in the molecular diagnosis of highly heterogeneous genetic diseases where conventional genetic approaches have previously failed in achieving a proper diagnosis.1 aMéndez-Vidal, Cristina1 adel Pozo, María, González-1 aVela-Boza, Alicia1 aSantoyo-López, Javier1 aLópez-Domingo, Francisco, J1 aVázquez-Marouschek, Carmen1 aDopazo, Joaquin1 aBorrego, Salud1 aAntiňolo, Guillermo uhttp://www.molvis.org/molvis/v19/2187/02874nas a2200493 4500008004100000022001400041245007000055210006800125260001600193300001100209490000600220520139500226653001801621653002701639653002101666653004101687653002001728653002401748653000901772653001101781653001801792653004201810653001101852653003701863653001301900653003801913653002701951653001301978100001701991700001902008700001802027700002502045700002102070700002002091700001902111700002602130700002302156700001802179700001602197700002402213700002002237700002002257856010302277 2012 eng d a1559-230800aWhole-genome bisulfite DNA sequencing of a DNMT3B mutant patient.0 aWholegenome bisulfite DNA sequencing of a DNMT3B mutant patient c2012 Jun 01 a542-500 v73 aThe immunodeficiency, centromere instability and facial anomalies (ICF) syndrome is associated to mutations of the DNA methyl-transferase DNMT3B, resulting in a reduction of enzyme activity. Aberrant expression of immune system genes and hypomethylation of pericentromeric regions accompanied by chromosomal instability were determined as alterations driving the disease phenotype. However, so far only technologies capable to analyze single loci were applied to determine epigenetic alterations in ICF patients. In the current study, we performed whole-genome bisulphite sequencing to assess alteration in DNA methylation at base pair resolution. Genome-wide we detected a decrease of methylation level of 42%, with the most profound changes occurring in inactive heterochromatic regions, satellite repeats and transposons. Interestingly, transcriptional active loci and ribosomal RNA repeats escaped global hypomethylation. Despite a genome-wide loss of DNA methylation the epigenetic landscape and crucial regulatory structures were conserved. Remarkably, we revealed a mislocated activity of mutant DNMT3B to H3K4me1 loci resulting in hypermethylation of active promoters. Functionally, we could associate alterations in promoter methylation with the ICF syndrome immunodeficient phenotype by detecting changes in genes related to the B-cell receptor mediated maturation pathway.
10aB-Lymphocytes10aCell Line, Transformed10aChild, Preschool10aDNA (Cytosine-5-)-Methyltransferases10aDNA Methylation10aEpigenesis, Genetic10aFace10aFemale10aGenome, Human10aHigh-Throughput Nucleotide Sequencing10aHumans10aImmunologic Deficiency Syndromes10amutation10aPrimary Immunodeficiency Diseases10aSequence Analysis, DNA10aSulfites1 aHeyn, Holger1 aVidal, Enrique1 aSayols, Sergi1 aSanchez-Mut, Jose, V1 aMoran, Sebastian1 aMedina, Ignacio1 aSandoval, Juan1 aSimó-Riudalbas, Laia1 aSzczesna, Karolina1 aHuertas, Dori1 aGatto, Sole1 aMatarazzo, Maria, R1 aDopazo, Joaquin1 aEsteller, Manel uhttps://www.clinbioinfosspa.es/content/whole-genome-bisulfite-dna-sequencing-dnmt3b-mutant-patient