title: The phenotypic and molecular genetic spectrum of Alström syndrome in 44 Turkish kindreds and a literature review of Alström syndrome in Turkey.
abstract: Alström syndrome (ALMS) is an autosomal recessive disease characterized by multiple organ involvement, including neurosensory vision and hearing loss, childhood obesity, diabetes mellitus, cardiomyopathy, hypogonadism, and pulmonary, hepatic, renal failure and systemic fibrosis. Alström Syndrome is caused by mutations in ALMS1, and ALMS1 protein is thought to have a role in microtubule organization, intraflagellar transport, endosome recycling and cell cycle regulation. Here, we report extensive phenotypic and genetic analysis of a large cohort of Turkish patients with ALMS. We evaluated 61 Turkish patients, including 11 previously reported, for both clinical spectrum and mutations in ALMS1. To reveal the molecular diagnosis of the patients, different approaches were used in combination, a cohort of patients were screened by the gene array to detect the common mutations in ALMS1 gene, then in patients having any of the common ALMS1 mutations were subjected to direct DNA sequencing or next-generation sequencing for the screening of mutations in all coding regions of the gene. In total, 20 distinct disease-causing nucleotide changes in ALMS1 have been identified, eight of which are novel, thereby increasing the reported ALMS1 mutations by 6% (8/120). Five disease-causing variants were identified in more than one kindred, but most of the alleles were unique to each single patient and identified only once (16/20). So far, 16 mutations identified were specific to the Turkish population, and four have also been reported in other ethnicities. In addition, 49 variants of uncertain pathogenicity were noted, and four of these were very rare and probably or likely deleterious according to in silico mutation prediction analyses. ALMS has a relatively high incidence in Turkey and the present study shows that the ALMS1 mutations are largely heterogeneous; thus, these data from a particular population may provide a unique source for the identification of additional mutations underlying Alström Syndrome and contribute to genotype-phenotype correlation studies.
authors.affiliation: Institute of Child Health and Metabolism Unit, Department of Pediatrics, Faculty of Medicine, Hacettepe University, Ankara, Turkey.
authors.forename: Ayşegül
authors.initials: A
authors.lastname: Ozantürk
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, USA.
authors.forename: Jan D
authors.initials: JD
authors.lastname: Marshall
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, USA.
authors.forename: Gayle B
authors.initials: GB
authors.lastname: Collin
authors.affiliation: Department of Medical Genetics, Abant İzzet Baysal University, Bolu, Turkey.
authors.forename: Selma
authors.initials: S
authors.lastname: Düzenli
authors.affiliation: Alström Syndrome International, Mount Desert, ME, USA.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Marshall
authors.affiliation: Department of Medical Genetics, Atatürk State Hospital, Balıkesir, Turkey.
authors.forename: Şükrü
authors.initials: Ş
authors.lastname: Candan
authors.affiliation: Dr. Sami Ulus Maternity and Children's Hospital, Ankara, Turkey.
authors.forename: Tülay
authors.initials: T
authors.lastname: Tos
authors.affiliation: Ankara Pediatric Health and Hematology Oncology Hospital, Ankara,Turkey.
authors.forename: İhsan
authors.initials: İ
authors.lastname: Esen
authors.affiliation: Department of Pediatrics, Dicle University, Diyarbakır, Turkey.
authors.forename: Mustafa
authors.initials: M
authors.lastname: Taşkesen
authors.affiliation: Pediatric Endocrinology Unit, Department of Medical Genetics, Atatürk University and Erzurum Regional Training and Research Hospital, Erzurum, Turkey.
authors.forename: Atilla
authors.initials: A
authors.lastname: Çayır
authors.affiliation: Department of Medical Genetics, Istanbul Medical Faculty, İstanbul University, İstanbul, Turkey.
authors.forename: Şükrü
authors.initials: Ş
authors.lastname: Öztürk
authors.affiliation: Department of Endocrinology, Mustafa Kemal University Hospital, Hatay, Turkey.
authors.forename: İhsan
authors.initials: İ
authors.lastname: Üstün
authors.affiliation: Department of Medical Genetics, Ege University, İzmir, Turkey.
authors.forename: Esra
authors.initials: E
authors.lastname: Ataman
authors.affiliation: 304;zmir Tepecik Training and Research Hospital Genetic Diagnostic Center, İzmir, Turkey.
authors.forename: Emin
authors.initials: E
authors.lastname: Karaca
authors.affiliation: 304;zmir Tepecik Training and Research Hospital Genetic Diagnostic Center, İzmir, Turkey.
authors.forename: Taha Reşid
authors.initials: TR
authors.lastname: Özdemir
authors.affiliation: Division of Pediatric Neurology, Adana Teaching and Medical Research Center, Başkent University, Adana, Turkey.
authors.forename: İlknur
authors.initials: İ
authors.lastname: Erol
authors.affiliation: Nephrology Unit, Department of Pediatrics, Hacettepe University, Ankara, Turkey.
authors.forename: Fehime Kara
authors.initials: FK
authors.lastname: Eroğlu
authors.affiliation: Gülhane Military Medical Faculty, Department of Medical Genetics, Ankara, Turkey.
authors.forename: Deniz
authors.initials: D
authors.lastname: Torun
authors.affiliation: Department of Medical Genetics, Ege University, İzmir, Turkey.
authors.forename: Erhan
authors.initials: E
authors.lastname: Parıltay
authors.affiliation: Kanuni Sultan Süleyman Training and Research Hospital, İstanbul, Turkey.
authors.forename: Elif
authors.initials: E
authors.lastname: Yılmaz-Güleç
authors.affiliation: Kanuni Sultan Süleyman Training and Research Hospital, İstanbul, Turkey.
authors.forename: Ender
authors.initials: E
authors.lastname: Karaca
authors.affiliation: Department of Pediatric Endocrinology, Necmettin Erbakan University, Konya, Turkey.
authors.forename: M Emre
authors.initials: ME
authors.lastname: Atabek
authors.affiliation: Department of Pediatric Genetics, Marmara University Pendik Hospital, İstanbul, Turkey.
authors.forename: Nursel
authors.initials: N
authors.lastname: Elçioğlu
authors.affiliation: Division of Endocrinology and Metabolism, İstanbul Faculty of Medicine, İstanbul University, İstanbul, Turkey.
authors.forename: İlhan
authors.initials: İ
authors.lastname: Satman
authors.affiliation: Department Audiology, The Swedish Institute for Disability Research, Örebro University Hospital, Örebro, Sweden.
authors.forename: Claes
authors.initials: C
authors.lastname: Möller
authors.affiliation: 1] Laboratoire ICUBE, UMR CNRS 7357, LBGI, Université de Strasbourg, Strasbourg, France [2] Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), CNRS UMR 7104/INSERM U964/Université de Strasbourg, Illkirch, France [3] Laboratoire de diagnostic génétique, Hôtpitaux Universitaires de Strasbourg, Strasbourg, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Muller
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, USA.
authors.forename: Jürgen K
authors.initials: JK
authors.lastname: Naggert
authors.affiliation: Institute of Child Health and Metabolism Unit, Department of Pediatrics, Faculty of Medicine, Hacettepe University, Ankara, Turkey.
authors.forename: Rıza Köksal
authors.initials: RK
authors.lastname: Özgül
mesh_terms: D000293:Adolescent; D056769:Alstrom Syndrome / Q000235:genetics* / Q000473:pathology; D018797:Cell Cycle Proteins; D015331:Cohort Studies; D003241:Consanguinity; D004252:DNA Mutational Analysis; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D020033:Protein Isoforms / Q000235:genetics; D011506:Proteins / Q000235:genetics; D014421:Turkey
chemical_list: C490729:ALMS1 protein, human; D018797:Cell Cycle Proteins; D020033:Protein Isoforms; D011506:Proteins