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Item A comprehensive molecular study on Coffin-Siris and Nicolaides-Baraitser syndromes identifies a broad molecular and clinical spectrum converging on altered chromatin remodeling(OXFORD UNIV PRESS, 2013-01-01) Wieczorek, Dagmar; Boegershausen, Nina; Beleggia, Filippo; Steiner-Haldenstaett, Sabine; Pohl, Esther; Li, Yun; Milz, Esther; Martin, Marcel; Thiele, Holger; Altmueller, Janine; Alanay, Yasemin; Kayserili, Hulya; Klein-Hitpass, Ludger; Bohringer, Stefan; Wollstein, Andreas; Albrecht, Beate; Boduroglu, Koray; Caliebe, Almuth; Chrzanowska, Krystyna; Cogulu, Ozgur; Cristofoli, Francesca; Czeschik, Johanna Christina; Devriendt, Koenraad; Dotti, Maria Teresa; Elcioglu, Nursel; Gener, Blanca; Goecke, Timm O.; Krajewska-Walasek, Malgorzata; Guillen-Navarro, Encarnacion; Hayek, Joussef; Houge, Gunnar; Kilic, Esra; Simsek-Kiper, Pelin Ozlem; Lopez-Gonzalez, Vanesa; Kuechler, Alma; Lyonnet, Stanislas; Mari, Francesca; Marozza, Annabella; Dramard, Michele Mathieu; Mikat, Barbara; Morin, Gilles; Morice-Picard, Fanny; Ozkinay, Ferda; Rauch, Anita; Renieri, Alessandra; Tinschert, Sigrid; Utine, G. Eda; Vilain, Catheline; Vivarelli, Rossella; Zweier, Christiane; Nuernberg, Peter; Rahmann, Sven; Vermeesch, Joris; Luedecke, Hermann-Josef; Zeschnigk, Michael; Wollnik, BerndChromatin remodeling complexes are known to modify chemical marks on histones or to induce conformational changes in the chromatin in order to regulate transcription. Denovodominant mutations in different members of the SWI/SNF chromatin remodeling complex have recently been described in individuals with Coffin-Siris (CSS) and Nicolaides-Baraitser (NCBRS) syndromes. Using a combination of whole-exome sequencing, NGS-based sequencing of 23 SWI/SNF complex genes, and molecular karyotyping in 46 previously undescribed individuals with CSS and NCBRS, we identified a de novo 1-bp deletion (c.677delG, p.Gly226Glufs{*}53) and a de novo missense mutation (c.914G>T, p.Cys305Phe) in PHF6 in two individuals diagnosed with CSS. PHF6 interacts with the nucleosome remodeling and deacetylation ( NuRD) complex implicating dysfunction of a second chromatin remodeling complex in the pathogenesis of CSS-like phenotypes. Altogether, we identified mutations in 60\% of the studied individuals (28/46), located in the genes ARID1A, ARID1B, SMARCB1, SMARCE1, SMARCA2, and PHF6. We show that mutations in ARID1B are the main cause of CSS, accounting for 76\% of identified mutations. ARID1B and SMARCB1 mutations were also found in individuals with the initial diagnosis of NCBRS. These individuals apparently belong to a small subset who display an intermediate CSS/NCBRS phenotype. Our proposed genotype-phenotype correlations are important for molecular screening strategies.Item RAP1-mediated MEK/ERK pathway defects in Kabuki syndrome(AMER SOC CLINICAL INVESTIGATION INC, 2015-01-01) Boegershausen, Nina; Tsai, I.-Chun; Pohl, Esther; Kiper, Pelin Ozlem Simsek; Beleggia, Filippo; Percin, E. Ferda; Keupp, Katharina; Matchan, Angela; Milz, Esther; Alanay, Yasemin; Kayserili, Hulya; Liu, Yicheng; Banka, Siddharth; Kranz, Andrea; Zenker, Martin; Wieczorek, Dagmar; Elcioglu, Nursel; Prontera, Paolo; Lyonnet, Stanislas; Meitinger, Thomas; Stewart, A. Francis; Donnai, Dian; Strom, Tim M.; Boduroglu, Koray; Yigit, Goekhan; Li, Yun; Katsanis, Nicholas; Wollnik, BerndThe genetic disorder Kabuki syndrome (KS) is characterized by developmental delay and congenital anomalies. Dominant mutations in the chromatin regulators lysine (K)-specific methyltransferase 2D (KMT2D) (also known as MLL2) and lysine (K)-specific demethylase 6A (KDM6A) underlie the majority of cases. Although the functions of these chromatin-modifying proteins have been studied extensively, the physiological systems regulated by them are largely unknown. Using whole-exome sequencing, we identified a mutation in RAP1A that was converted to homozygosity as the result of uniparental isodisomy (UPD) in a patient with KS and a de novo, dominant mutation in RAP1B in a second individual with a KS-like phenotype. We elucidated a genetic and functional interaction between the respective KS-associated genes and their products in zebrafish models and patient cell lines. Specifically, we determined that dysfunction of known KS genes and the genes identified in this study results in aberrant MEK/ERK signaling as well as disruption of F-actin polymerization and cell intercalation. Moreover, these phenotypes could be rescued in zebrafish models by rebalancing MEK/ERK signaling via administration of small molecule inhibitors of MEK. Taken together, our studies suggest that the KS pathophysiology overlaps with the RASopathies and provide a potential direction for treatment design.Item Further characterization of ATP6V0A2-related autosomal recessive cutis laxa(SPRINGER, 2012-01-01) Fischer, Bjoern; Dimopoulou, Aikaterini; Egerer, Johannes; Gardeitchik, Thatjana; Kidd, Alexa; Jost, Dominik; Kayserili, Hulya; Alanay, Yasemin; Tantcheva-Poor, Iliana; Mangold, Elisabeth; Daumer-Haas, Cornelia; Phadke, Shubha; Peirano, Reto I.; Heusel, Julia; Desphande, Charu; Gupta, Neerja; Nanda, Arti; Felix, Emma; Berry-Kravis, Elisabeth; Kabra, Madhulika; Wevers, Ron A.; van Maldergem, Lionel; Mundlos, Stefan; Morava, Eva; Kornak, UweAutosomal recessive cutis laxa (ARCL) syndromes are phenotypically overlapping, but genetically heterogeneous disorders. Mutations in the ATP6V0A2 gene were found to underlie both, autosomal recessive cutis laxa type 2 (ARCL2), Debr, type, and wrinkly skin syndrome (WSS). The ATP6V0A2 gene encodes the a2 subunit of the V-type H+-ATPase, playing a role in proton translocation, and possibly also in membrane fusion. Here, we describe a highly variable phenotype in 13 patients with ARCL2, including the oldest affected individual described so far, who showed strikingly progressive dysmorphic features and heterotopic calcifications. In these individuals we identified 17 ATP6V0A2 mutations, 14 of which are novel. Furthermore, we demonstrate a localization of ATP6V0A2 at the Golgi-apparatus and a loss of the mutated ATP6V0A2 protein in patients' dermal fibroblasts. Investigation of brefeldin A-induced Golgi collapse in dermal fibroblasts as well as in HeLa cells deficient for ATP6V0A2 revealed a delay, which was absent in cells deficient for the ARCL-associated proteins GORAB or PYCR1. Furthermore, fibroblasts from patients with ATP6V0A2 mutations displayed elevated TGF-beta signalling and increased TGF-beta 1 levels in the supernatant. Our current findings expand the genetic and phenotypic spectrum and suggest that, besides the known glycosylation defect, alterations in trafficking and signalling processes are potential key events in the pathogenesis of ATP6V0A2-related ARCL.Item Mutations in the interleukin receptor IL11RA cause autosomal recessive Crouzon-like craniosynostosis(WILEY, 2013-01-01) Keupp, Katharina; Li, Yun; Vargel, Ibrahim; Hoischen, Alexander; Richardson, Rebecca; Neveling, Kornelia; Alanay, Yasemin; Uz, Elif; Elcioglu, Nursel; Rachwalski, Martin; Kamaci, Soner; Tuncbilek, Gokhan; Akin, Burcu; Grotzinger, Joachim; Konas, Ersoy; Mavili, Emin; Muller-Newen, Gerhard; Collmann, Hartmut; Roscioli, Tony; Buckley, Michael F.; Yigit, Gokhan; Gilissen, Christian; Kress, Wolfram; Veltman, Joris; Hammerschmidt, Matthias; Akarsu, Nurten A.; Wollnik, BerndWe have characterized a novel autosomal recessive Crouzon-like craniosynostosis syndrome in a 12-affected member family from Antakya, Turkey, the presenting features of which include: multiple suture synostosis, midface hypoplasia, variable degree of exophthalmos, relative prognathism, a beaked nose, and conductive hearing loss. Homozygosity mapping followed by targeted next-generation sequencing identified a c.479+6T>G mutation in the interleukin 11 receptor alpha gene (IL11RA) on chromosome 9p21. This donor splice-site mutation leads to a high percentage of aberrant IL11RA mRNA transcripts in an affected individual and altered mRNA splicing determined by in vitro exon trapping. An extended IL11RA mutation screen was performed in a cohort of 79 patients with an initial clinical diagnosis of Crouzon syndrome, pansynostosis, or unclassified syndromic craniosynostosis. We identified mutations segregating with the disease in five families: a German patient of Turkish origin and a Turkish family with three affected sibs all of whom were homozygous for the previously identified IL11RA c.479+6T>G mutationItem A Chaperone Complex Formed by HSP47, FKBP65, and BiP Modulates Telopeptide Lysyl Hydroxylation of Type I Procollagen(WILEY, 2017-01-01) Duran, Ivan; Martin, Jorge H.; Weis, Mary Ann; Krejci, Pavel; Konik, Peter; Li, Bing; Alanay, Yasemin; Lietman, Caressa; Lee, Brendan; Eyre, David; Cohn, Daniel H.; Krakow, DeborahLysine hydroxylation of type I collagen telopeptides varies from tissue to tissue, and these distinct hydroxylation patterns modulate collagen cross-linking to generate a unique extracellular matrix. Abnormalities in these patterns contribute to pathologies that include osteogenesis imperfecta (OI), fibrosis, and cancer. Telopeptide procollagen modifications are carried out by lysyl hydroxylase 2 (LH2)Item Successful application of genome sequencing in a diagnostic setting: 1007 index cases from a clinically heterogeneous cohort(SPRINGERNATURE, 2021-01-01) Bertoli-Avella, Aida M.; Beetz, Christian; Ameziane, Najim; Rocha, Maria Eugenia; Guatibonza, Pilar; Pereira, Catarina; Calvo, Maria; Herrera-Ordonez, Natalia; Segura-Castel, Monica; Diego-Alvarez, Dan; Zawada, Michal; Kandaswamy, Krishna K.; Werber, Martin; Paknia, Omid; Zielske, Susan; Ugrinovski, Dimitar; Warnack, Gitte; Kampe, Kapil; Iurascu, Marius-Ionut; Cozma, Claudia; Vogel, Florian; Alhashem, Amal; Hertecant, Jozef; Al-Shamsi, Aisha M.; Alswaid, Abdulrahman Faiz; Eyaid, Wafaa; Al Mutairi, Fuad; Alfares, Ahmed; Albalwi, Mohammed A.; Alfadhel, Majid; Al-Sannaa, Nouriya Abbas; Reardon, Willie; Alanay, Yasemin; Rolfs, Arndt; Bauer, PeterDespite clear technical superiority of genome sequencing (GS) over other diagnostic methods such as exome sequencing (ES), few studies are available regarding the advantages of its clinical application. We analyzed 1007 consecutive index cases for whom GS was performed in a diagnostic setting over a 2-year period. We reported pathogenic and likely pathogenic (P/LP) variants that explain the patients' phenotype in 212 of the 1007 cases (21.1\%). In 245 additional cases (24.3\%), a variant of unknown significance (VUS) related to the phenotype was reported. We especially investigated patients which had had ES with no genetic diagnosis (n = 358). For this group, GS diagnostic yield was 14.5\% (52 patients with P/LP out of 358). GS should be especially indicated for ES-negative cases since up to 29.6\% of them could benefit from GS testing (14.5\% with P/LP, n = 52 and 15.1\% with VUS, n = 54). Genetic diagnoses in most of the ES-negative/GS-positive cases were determined by technical superiority of GS, i.e., access to noncoding regions and more uniform coverage. Importantly, we reported 79 noncoding variants, of which, 41 variants were classified as P/LP. Interpretation of noncoding variants remains challenging, and in many cases, complementary methods based on direct enzyme assessment, biomarker testing and RNA analysis are needed for variant classification and diagnosis. We present the largest cohort of patients with GS performed in a clinical setting to date. The results of this study should direct the decision for GS as standard second-line, or even first-line stand-alone test.Item Defining mitochondrial protein functions through deep multiomic profiling(NATURE PORTFOLIO, 2022-01-01) Rensvold, Jarred W.; Shishkova, Evgenia; Sverchkov, Yuriy; Miller, Ian J.; Cetinkaya, Arda; Pyle, Angela; Manicki, Mateusz; Brademan, Dain R.; Alanay, Yasemin; Raiman, Julian; Jochem, Adam; Hutchins, Paul D.; Peters, Sean R.; Linke, Vanessa; Overmyer, Katherine A.; Salome, Austin Z.; Hebert, Alexander S.; Vincent, Catherine E.; Kwiecien, Nicholas W.; Rush, Matthew J. P.; Westphall, Michael S.; Craven, Mark; Akarsu, Nurten A.; Taylor, Robert W.; Coon, Joshua J.; Pagliarini, David J.Mitochondria are epicentres of eukaryotic metabolism and bioenergetics. Pioneering efforts in recent decades have established the core protein componentry of these organelles(1) and have linked their dysfunction to more than 150 distinct disorders(2,3). Still, hundreds of mitochondrial proteins lack clear functions(4), and the underlying genetic basis for approximately 40\% of mitochondrial disorders remains unresolved(5). Here, to establish a more complete functional compendium of human mitochondrial proteins, we profiled more than 200 CRISPR-mediated HAP1 cell knockout lines using mass spectrometry-based multiomics analyses. This effort generated approximately 8.3 million distinct biomolecule measurements, providing a deep survey of the cellular responses to mitochondrial perturbations and laying a foundation for mechanistic investigations into protein function. Guided by these data, we discovered that PIGY upstream open reading frame (PYURF) is an S-adenosylmethionine-dependent methyltransferase chaperone that supports both complex I assembly and coenzyme Q biosynthesis and is disrupted in a previously unresolved multisystemic mitochondrial disorder. We further linked the putative zinc transporter SLC30A9 to mitochondrial ribosomes and OxPhos integrity and established RAB5IF as the second gene harbouring pathogenic variants that cause cerebrofaciothoracic dysplasia. Our data, which can be explored through the interactive online MITOMICS.app resource, suggest biological roles for many other orphan mitochondrial proteins that still lack robust functional characterization and define a rich cell signature of mitochondrial dysfunction that can support the genetic diagnosis of mitochondrial diseases.Item Chromosome 22q12.1 microdeletions: confirmation of the MN1 gene as a candidate gene for cleft palate(NATURE PUBLISHING GROUP, 2016-01-01) Breckpot, Jeroen; Anderlid, Britt-Marie; Alanay, Yasemin; Blyth, Moira; Brahimi, Afane; Duban-Bedu, Benedicte; Goze, Odile; Firth, Helen; Yakicier, Mustafa Cengiz; Hens, Greet; Rayyan, Maissa; Legius, Eric; Vermeesch, Joris Robert; Devriendt, KoenWe report on seven novel patients with a submicroscopic 22q12 deletion. The common phenotype constitutes a contiguous gene deletion syndrome on chromosome 22q12.1q12.2, featuring NF2-related schwannoma of the vestibular nerve, corpus callosum agenesis and palatal defects. Combining our results with the literature, eight patients are recorded with palatal defects in association with haploinsufficiency of 22q12.1, including the MN1 gene. These observations, together with the mouse expression data and the finding of craniofacial malformations including cleft palate in a Mn1-knockout mouse model, suggest that this gene is a candidate gene for cleft palate in humans.Item Prepubertal Unilateral Gynecomastia: Report of 2 Cases(GALENOS YAYINCILIK, 2014-01-01) Demirbilek, Huseyin; Bacak, Gokhan; Baran, Riza Taner; Avci, Yahya; Baran, Ahmet; Keles, Aysenur; Ozbek, Mehmet Nuri; Alanay, Yasemin; Hussain, KhalidPrepubertal unilateral gynecomastia is an extremely rare condition. At present, its etiology and management strategy are not well known. Two unrelated prepubertal boys of ages 8 and 9 who presented with complaints of unilateral enlargement of breast tissue are reported. Physical examination, biochemical, hormonal and oncologic work-up findings were normal. Both patients were treated with peripheral liposuction successfully. Histopathological and immunohistochemical examinations showed benign fibroglandular gynecomastia and intensive (3+) estrogen receptor expression in 100\% of periductal epithelial cells. Although an extremely rare and generally benign condition, patients with prepubertal unilateral gynecomastia should have a full endocrine and oncologic work-up.Item A Review of the Principles of Radiological Assessment of Skeletal Dysplasias(GALENOS YAYINCILIK, 2011-01-01) Alanay, Yasemin; Lachman, Ralph S.There are more than 450 well-characterized skeletal dysplasias classified primarily on the basis of clinical, radiographic, and molecular criteria. In the latest 2010 revision of the Nosology and Classification of Genetic Skeletal Disorders, an increase from 372 to 456 disorders had occurred in the four years since the classification was last revisited in 2007. These entities in total represent about 5\% of children with birth defects. An accurate diagnosis of a skeletal dysplasia is still based on detailed evaluation of clinical and radiographic {[}as well as chondro-osseous] findings. Regardless of the specific diagnosis, skeletal dysplasias in general share clinical and radiological findings helping us to group them in several ways. This review aims to outline the diagnostic approach to disproportionate short stature with special emphasis on radiological findings.