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J Hum Genet. 2015 Jan;60(1):1-9. doi: 10.1038/jhg.2014.85. Epub 2014 Oct 9.

The phenotypic and molecular genetic spectrum of Alström syndrome in 44 Turkish kindreds and a literature review of Alström syndrome in Turkey.

Author information

1
Institute of Child Health and Metabolism Unit, Department of Pediatrics, Faculty of Medicine, Hacettepe University, Ankara, Turkey.
2
The Jackson Laboratory, Bar Harbor, ME, USA.
3
Department of Medical Genetics, Abant İzzet Baysal University, Bolu, Turkey.
4
Alström Syndrome International, Mount Desert, ME, USA.
5
Department of Medical Genetics, Atatürk State Hospital, Balıkesir, Turkey.
6
Dr. Sami Ulus Maternity and Children's Hospital, Ankara, Turkey.
7
Ankara Pediatric Health and Hematology Oncology Hospital, Ankara,Turkey.
8
Department of Pediatrics, Dicle University, Diyarbakır, Turkey.
9
Pediatric Endocrinology Unit, Department of Medical Genetics, Atatürk University and Erzurum Regional Training and Research Hospital, Erzurum, Turkey.
10
Department of Medical Genetics, Istanbul Medical Faculty, İstanbul University, İstanbul, Turkey.
11
Department of Endocrinology, Mustafa Kemal University Hospital, Hatay, Turkey.
12
Department of Medical Genetics, Ege University, İzmir, Turkey.
13
304;zmir Tepecik Training and Research Hospital Genetic Diagnostic Center, İzmir, Turkey.
14
Division of Pediatric Neurology, Adana Teaching and Medical Research Center, Başkent University, Adana, Turkey.
15
Nephrology Unit, Department of Pediatrics, Hacettepe University, Ankara, Turkey.
16
Gülhane Military Medical Faculty, Department of Medical Genetics, Ankara, Turkey.
17
Kanuni Sultan Süleyman Training and Research Hospital, İstanbul, Turkey.
18
Department of Pediatric Endocrinology, Necmettin Erbakan University, Konya, Turkey.
19
Department of Pediatric Genetics, Marmara University Pendik Hospital, İstanbul, Turkey.
20
Division of Endocrinology and Metabolism, İstanbul Faculty of Medicine, İstanbul University, İstanbul, Turkey.
21
Department Audiology, The Swedish Institute for Disability Research, Örebro University Hospital, Örebro, Sweden.
22
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.

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.

PMID:
25296579
PMCID:
PMC5460767
DOI:
10.1038/jhg.2014.85
[Indexed for MEDLINE]
Free PMC Article

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