Fernando Santos-Simarro
Hospital Universitario La Paz
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Publication
Featured researches published by Fernando Santos-Simarro.
Cell | 2015
Darío G. Lupiáñez; Katerina Kraft; Verena Heinrich; Peter Krawitz; Francesco Brancati; Eva Klopocki; Denise Horn; Hülya Kayserili; John M. Opitz; Renata Laxova; Fernando Santos-Simarro; Brigitte Gilbert-Dussardier; Lars Wittler; Marina Borschiwer; Stefan A. Haas; Marco Osterwalder; Martin Franke; Bernd Timmermann; Jochen Hecht; Malte Spielmann; Axel Visel; Stefan Mundlos
Mammalian genomes are organized into megabase-scale topologically associated domains (TADs). We demonstrate that disruption of TADs can rewire long-range regulatory architecture and result in pathogenic phenotypes. We show that distinct human limb malformations are caused by deletions, inversions, or duplications altering the structure of the TAD-spanning WNT6/IHH/EPHA4/PAX3 locus. Using CRISPR/Cas genome editing, we generated mice with corresponding rearrangements. Both in mouse limb tissue and patient-derived fibroblasts, disease-relevant structural changes cause ectopic interactions between promoters and non-coding DNA, and a cluster of limb enhancers normally associated with Epha4 is misplaced relative to TAD boundaries and drives ectopic limb expression of another gene in the locus. This rewiring occurred only if the variant disrupted a CTCF-associated boundary domain. Our results demonstrate the functional importance of TADs for orchestrating gene expression via genome architecture and indicate criteria for predicting the pathogenicity of human structural variants, particularly in non-coding regions of the human genome.
Clinical Genetics | 2016
Alireza Haghighi; Z. Kavehmanesh; F. Salehzadeh; Fernando Santos-Simarro; L. Van Maldergem; L. Cimbalistiene; Felicity Collins; M. Chopra; S. Al-Sinani; S. Dastmalchian; Deepthi De Silva; H. Bakhti; Abhimanyu Garg; P Hilbert
Congenital generalized lipodystrophy (CGL) is an autosomal recessive disorder with two major subtypes. Variants in AGPAT2 result in CGL type 1 with milder manifestations, whereas BSCL2 variants cause CGL type 2 with more severe features. Muscle hypertrophy caused by lack of adipose tissue is present early in life in CGL patients. Our aim was to investigate 10 CGL patients from 7 different countries and report genotype–phenotype relationships. Genetic analysis identified disease‐causing variants in AGPAT2 (five patients) and in BSCL2 (five patients), including three novel variants; c.134C>A (p.Ser45*), c.216C>G (p.Tyr72*) in AGPAT2 and c.458C>A (p.Ser153*) in BSCL2. We also report possible novel clinical features such as anemia, breast enlargement, steatorrhea, intraventricular hemorrhage and nephrolithiasis in CGL patients. Generalized lipodystrophy and muscular hypertrophy were the only features in all of our patients. Hepatomegaly was the second common feature. Some manifestations were exclusively noticed in our CGL2 patients; hypertrichosis, high‐pitched voice and umbilical hernia. Bone cysts and history of seizures were noticed only in CGL1 patients. The findings of this study expand our knowledge of genotype–phenotype correlations in CGL patients. These results have important clinical applications in diagnosis and management of the CGL patients as well as in genetic counseling in families at‐risk.
Human Mutation | 2014
Jair Tenorio; Alicia Mansilla; María Valencia; Victor Martinez-Glez; Valeria Romanelli; Pedro Arias; Nerea Castrejón; Fernando A. Poletta; Encarna Guillén-Navarro; Gema Gordo; Elena Mansilla; Fe Amalia García-Santiago; Isabel González-Casado; Elena Vallespín; María Palomares; María Ángeles Mori; Fernando Santos-Simarro; Sixto García-Miñaúr; Luis Fernández; Rocío Mena; Sara Benito-Sanz; Angela del Pozo; J.C. Silla; Kristina Ibanez; Eduardo López-Granados; Alex Martin-Trujillo; David Montaner; Karen E. Heath; Angel Campos-Barros; Joaquín Dopazo
Overgrowth syndromes (OGS) are a group of disorders in which all parameters of growth and physical development are above the mean for age and sex. We evaluated a series of 270 families from the Spanish Overgrowth Syndrome Registry with no known OGS. We identified one de novo deletion and three missense mutations in RNF125 in six patients from four families with overgrowth, macrocephaly, intellectual disability, mild hydrocephaly, hypoglycemia, and inflammatory diseases resembling Sjögren syndrome. RNF125 encodes an E3 ubiquitin ligase and is a novel gene of OGS. Our studies of the RNF125 pathway point to upregulation of RIG‐I‐IPS1‐MDA5 and/or disruption of the PI3K‐AKT and interferon signaling pathways as the putative final effectors.
American Journal of Medical Genetics Part A | 2016
Jair Tenorio; Valeria Romanelli; Alex Martin-Trujillo; García‐Moya Fernández; Mabel Segovia; Claudia Perandones; Luis A. Pérez Jurado; Manel Esteller; Mario F. Fraga; Pedro Arias; Gema Gordo; Irene Dapía; Rocío Mena; María Palomares; Guiomar Perez de Nanclares; Julián Nevado; Sixto García-Miñaúr; Fernando Santos-Simarro; Victor Martinez-Glez; Elena Vallespín; David Monk; Pablo Lapunzina
Beckwith–Wiedemann syndrome (BWS) is an overgrowth syndrome characterized by an excessive prenatal and postnatal growth, macrosomia, macroglossia, and hemihyperplasia. The molecular basis of this syndrome is complex and heterogeneous, involving genes located at 11p15.5. BWS is correlated with assisted reproductive techniques. BWS in individuals born following assisted reproductive techniques has been found to occur four to nine times higher compared to children with to BWS born after spontaneous conception. Here, we report a series of 187 patients with to BWS born either after assisted reproductive techniques or conceived naturally. Eighty‐eight percent of BWS patients born via assisted reproductive techniques had hypomethylation of KCNQ1OT1:TSS‐DMR in comparison with 49% for patients with BWS conceived naturally. None of the patients with BWS born via assisted reproductive techniques had hypermethylation of H19/IGF2:IG‐DMR, neither CDKN1 C mutations nor patUPD11. We did not find differences in the frequency of multi‐locus imprinting disturbances between groups. Patients with BWS born via assisted reproductive techniques had an increased frequency of advanced bone age, congenital heart disease, and decreased frequency of earlobe anomalies but these differences may be explained by the different molecular background compared to those with BWS and spontaneous fertilization. We conclude there is a correlation of the molecular etiology of BWS with the type of conception.
European Journal of Human Genetics | 2015
Julián Nevado; Jill A. Rosenfeld; Rocío Mena; María Palomares-Bralo; Elena Vallespín; María Ángeles Mori; Jair Tenorio; Karen W. Gripp; Elizabeth Denenberg; Miguel del Campo; Alberto Plaja; Rubén Martín-Arenas; Fernando Santos-Simarro; Lluís Armengol; Gordon C. Gowans; María Orera; M Carmen Sanchez-Hombre; Esther Corbacho-Fernández; Alberto Fernández-Jaén; Chad R. Haldeman-Englert; Sulagna C. Saitta; Holly Dubbs; Duban B Bénédicte; Xia Li; Lani Devaney; Mary Beth Dinulos; Stephanie E. Vallee; M. Carmen Crespo; Blanca Sanchez Fernandez; Victoria E. Fernandez-Montano
Array comparative genomic hybridization (aCGH) is a powerful genetic tool that has enabled the identification of novel imbalances in individuals with intellectual disability (ID), autistic disorders and congenital malformations. Here we report a ‘genotype first’ approach using aCGH on 13 unrelated patients with 19p13.3 submicroscopic rearrangement (11 deletions and 2 duplications) and review cases in the literature and in public databases. Shared phenotypic features suggest that these patients represent an interstitial microdeletion/microduplication syndrome at 19p13.3. Common features consist of abnormal head circumference in most patients (macrocephaly with the deletions and microcephaly with the duplications), ID with developmental delay (DD), hypotonia, speech delay and common dysmorphic features. The phenotype is associated with at least a ~0.113 Mb critical region harboring three strong candidate genes probably associated with DD, ID, speech delay and other dysmorphic features: MAP2K2, ZBTB7A and PIAS4, an E3 ubiquitin ligase involved in the ubiquitin signaling pathways, which we hypothesize for the first time to be associated with head size in humans.
International Journal of Molecular Sciences | 2014
María Esperanza Teresa-Rodrigo; Juliane Eckhold; Beatriz Puisac; Andreas Dalski; María Concepción Gil-Rodríguez; Diana Braunholz; Carolina Baquero; María Hernández-Marcos; Juan Carlos de Karam; Milagros Ciero; Fernando Santos-Simarro; Pablo Lapunzina; Jolanta Wierzba; Cesar H. Casale; Feliciano J. Ramos; Gabriele Gillessen-Kaesbach; Frank J. Kaiser; Juan Pié
Cornelia de Lange syndrome (CdLS) is a congenital developmental disorder characterized by distinctive craniofacial features, growth retardation, cognitive impairment, limb defects, hirsutism, and multisystem involvement. Mutations in five genes encoding structural components (SMC1A, SMC3, RAD21) or functionally associated factors (NIPBL, HDAC8) of the cohesin complex have been found in patients with CdLS. In about 60% of the patients, mutations in NIPBL could be identified. Interestingly, 17% of them are predicted to change normal splicing, however, detailed molecular investigations are often missing. Here, we report the first systematic study of the physiological splicing of the NIPBL gene, that would reveal the identification of four new splicing isoforms ΔE10, ΔE12, ΔE33,34, and B’. Furthermore, we have investigated nine mutations affecting splice-sites in the NIPBL gene identified in twelve CdLS patients. All mutations have been examined on the DNA and RNA level, as well as by in silico analyses. Although patients with mutations affecting NIPBL splicing show a broad clinical variability, the more severe phenotypes seem to be associated with aberrant transcripts resulting in a shift of the reading frame.
American Journal of Medical Genetics Part A | 2016
Jimena Barraza-García; Carlos I. Rivera-Pedroza; Luis Salamanca; Alberta Belinchón; Vanesa López-González; Lucía Sentchordi-Montané; Angela del Pozo; Fernando Santos-Simarro; Angel Campos-Barros; Pablo Lapunzina; Encarna Guillén-Navarro; Isabel González-Casado; Sixto García-Miñaúr; Karen E. Heath
Primordial dwarfism encompasses rare conditions characterized by severe intrauterine growth retardation and growth deficiency throughout life. Recently, three POC1A mutations have been reported in six families with the primordial dwarfism, SOFT syndrome (Short stature, Onychodysplasia, Facial dysmorphism, and hypoTrichosis). Using a custom‐designed Next‐generation sequencing skeletal dysplasia panel, we have identified two novel homozygous POC1A mutations in two individuals with primordial dwarfism. The severe growth retardation and the facial profiles are strikingly similar between our patients and those described previously. However, one of our patients was diagnosed with severe foramen magnum stenosis and subglottic tracheal stenosis, malformations not previously associated with this syndrome. Our findings confirm that POC1A mutations cause SOFT syndrome and that mutations in this gene should be considered in patients with severe pre‐ and postnatal short stature, symmetric shortening of long bones, triangular facies, sparse hair and short, thickened distal phalanges.
Genetics in Medicine | 2017
María Palomares-Bralo; Elena Vallespín; Angela del Pozo; Kristina Ibanez; J.C. Silla; Enrique Galán; Gema Gordo; Víctor Martínez-Glez; Lázaro I Alba-Valdivia; Karen E. Heath; Sixto García-Miñaúr; Pablo Lapunzina; Fernando Santos-Simarro
Pitfalls of trio-based exome sequencing: imprinted genes and parental mosaicism— MAGEL2 as an example
Clinical Genetics | 2017
Fernando Santos-Simarro; Elena Vallespín; A. del Pozo; Kristina Ibanez; J.C. Silla; Luis Fernández; Julián Nevado; H. González-Pecellín; V.E.F. Montaño; R. Martin; L.I. Alba Valdivia; Sixto García-Miñaúr; Pablo Lapunzina; María Palomares-Bralo
To the Editor: Recently, heterozygous variants in PUF60 (Poly-U Binding Splicing Factor 60KDa) have been identified to be responsible for Verheij syndrome (MIM 615583) in 13 individuals harboring protein truncating, missense and splice-site variants enabling the delineation of a recognizable phenotype characterized by global intellectual disability (ID), growth restriction, microcephaly, distinctive dysmorphic features and frequently associated congenital malformations (CM) affecting the skeleton, eyes, kidneys and heart. We report on 3 further patients with de novo pathogenic variants in PUF60. Patient 1 is a female, first and only child of a healthy non-consanguineous couple. Gestation was uneventful and delivery was normal at term with growth parameters within normal limits. On neonatal examination, she showed bilateral talipes and during the second week of life, she was diagnosed with bilateral iris coloboma and unilateral left chorioretinal coloboma. She was initially evaluated in our clinical genetics clinic at the age of 4 months. On follow-up, she showed a progressive delay both in her psychomotor
European Journal of Human Genetics | 2018
Anneke Kievit; Federico Tessadori; Hannie Douben; Ingrid Jordens; Madelon M. Maurice; Jeannette Hoogeboom; Raoul C. M. Hennekam; Sheela Nampoothiri; Hülya Kayserili; Marco Castori; Margo Whiteford; Connie S. Motter; Catherine Ward Melver; Michael L. Cunningham; Anne V. Hing; Nancy Mizue Kokitsu-Nakata; Siulan Vendramini-Pittoli; Antonio Richieri-Costa; Annette F. Baas; Corstiaan C. Breugem; Karen Duran; Maarten P. G. Massink; Patrick W. B. Derksen; Wilfred van IJcken; Leontine van Unen; Fernando Santos-Simarro; Pablo Lapunzina; Vera L.G.S. Lopes; Elaine Lustosa-Mendes; Max Krall
Blepharocheilodontic syndrome (BCDS) consists of lagophthalmia, ectropion of the lower eyelids, distichiasis, euryblepharon, cleft lip/palate and dental anomalies and has autosomal dominant inheritance with variable expression. We identified heterozygous variants in two genes of the cadherin–catenin complex, CDH1, encoding E-cadherin, and CTNND1, encoding p120 catenin delta1 in 15 of 17 BCDS index patients, as was recently described in a different publication. CDH1 plays an essential role in epithelial cell adherence; CTNND1 binds to CDH1 and controls the stability of the complex. Functional experiments in zebrafish and human cells showed that the CDH1 variants impair the cell adhesion function of the cadherin–catenin complex in a dominant-negative manner. Variants in CDH1 have been linked to familial hereditary diffuse gastric cancer and invasive lobular breast cancer; however, no cases of gastric or breast cancer have been reported in our BCDS cases. Functional experiments reported here indicated the BCDS variants comprise a distinct class of CDH1 variants. Altogether, we identified the genetic cause of BCDS enabling DNA diagnostics and counseling, in addition we describe a novel class of dominant negative CDH1 variants.