Although mutations in the GJB2 gene sequence make up the majority of variants causing autosomal-recessive non-syndromic hearing loss, few large deletions have been shown to contribute to DFNB1 deafness. Currently, genetic testing for DFNB1 hearing loss includes GJB2 sequencing and DFNB1 deletion analysis for two common large deletions, del(GJB6-D13S1830) and del(GJB6-D13S1854). Here, we report frequency in Russia, clinical significance and evolutionary origins of a 101 kb deletion, del(GJB2-D13S175), recently identified by us. In multiethnic cohort of 1104 unrelated hearing loss patients with biallelic mutations at the DFNB1 locus, the del(GJB2-D13S175) allele frequency of up to 0.5% (11/2208) was determined and this allele was shown to be predominantly associated with profound sensorineural hearing loss. Additionally, eight previously unpublished GJB2 mutations were described in this study. All patients carrying del(GJB2-D13S175) were of the Ingush ancestry. Among normal hearing individuals, del(GJB2-D13S175) was observed in Russian Republic of Ingushetia with a carrier rate of ~1% (2/241). Analysis of haplotypes associated with the deletion revealed a common founder in the Ingushes, with age of the deletion being ~3000 years old. Since del(GJB2-D13S175) was missed by standard methods of GJB2 analysis, del(GJB2-D13S175) detection has been added to our routine testing strategy for DFNB1 hearing loss.

Phenylketonuria is an inherited disease caused by mutations in the phenylalanine hydroxylase gene PAH. Different PAH pathogenic variants occur in different ethnic groups with various frequencies and the incidence of the disease itself varies from country to country. In the Caucasus region of Russia, some ethnoses are geographically and culturally isolated from each other. The tradition of monoethnic marriages may cause decreased genetic variability in those populations. In the Karachay-Cherkess Republic (Russia), the highest incidence of phenylketonuria in the world has been detected (1:850 newborns) in the region and 1:332 among the titular nation Karachays. Here, we showed that this phenomenon is due to the widespread prevalence of the p.Arg261* variant. Its allele frequency among Karachay patients with PKU was 68.4% and the carrier frequency in Karachays was 1:16 healthy individuals. PAH haplotype analysis showed a unique common origin. The founder haplotype and mutation “age” were estimated by analyzing the linkage disequilibrium between p.Arg261* and extragenic short tandem repeat loci. The p.Arg261* variant occurred in the Karachays population 10.2 ± 2.7 generations ago (275 ± 73 years) and its spread occurred in parallel with the growth of the population.

// <![CDATA[ $('.header-date').hide();$('#titleAuthors').hide();$('#abstractHeader').hide(); // ]]> Stian Knappskog1,2, Liv B. Gansmo1,2, Khadizha Dibirova3, Andres Metspalu4, Cezary Cybulski5, Paolo Peterlongo6,7, Lauri Aaltonen8, Lars Vatten9 , Pål Romundstad9, Kristian Hveem9, Peter Devilee10,11, Gareth D. Evans12, Dongxin Lin13, Guy Van Camp14, Vangelis G. Manolopoulos15, Ana Osorio16, Lili Milani4, Tayfun Ozcelik17, Pierre Zalloua18, Francis Mouzaya18, Elena Bliznetz3, Elena Balanovska3, Elvira Pocheshkova19,Vaidutis Kučinskas20, Lubov Atramentova21, Pagbajabyn Nymadawa22, Konstantin Titov23, Maria Lavryashina24, Yuldash Yusupov25, Natalia Bogdanova26,27, Sergey Koshel28, Jorge Zamora29, David C. Wedge29, Deborah Charlesworth30, Thilo Dörk31, Oleg Balanovsky3,32 and Per E. Lønning1,2 1 Section of Oncology, Department of Clinical Science, University of Bergen, 5020 Bergen, Norway 2 Department of Oncology, Haukeland University Hospital, 5021 Bergen, Norway 3 Research Centre for Medical Genetics, Russian Academy of Medical Sciences, 115478 Moscow, Russia 4 Estonian Genome Center, University of Tartu, Tartu, Estonia 5 Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland 6 IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Milan, Italy 7 Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy 8 Department of Medical Genetics, University of Helsinki, Helsinki 00014, Finland 9 Department of Public Health, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim 7489, Norway 10 Department of Human Genetics, Leiden University Medical Center, RC Leiden 2300, The Netherlands 11 Department of Pathology, Leiden University Medical Center, RC Leiden 2300, The Netherlands 12 Genetic Medicine, MAHSC, University of Manchester, St. Mary’s Hospital, Manchester, M13 OJH, UK 13 Department of Etiology and Carcinogenesis, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China 14 Department of Medical Genetics, University of Antwerp, Antwerp, Belgium 15 Laboratory of Pharmacology, Democritus University of Thrace Medical School, Alexandroupolis, Greece 16 Human Genetics Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre, CNIO, Madrid, Spain 17 Bilkent University, Faculty of Science, Department of Molecular Biology and Genetics, Ankara, Turkey 18 Lebanese American University, Chouran, Beirut, Lebanon 19 Kuban Medical University, Krasnodar, Russia 20 Department of Human and Medical Genetics, Vilnius University, Faculty of Medicine, Vilnius, Lithuania 21 Department of Genetics and Cytology, Karazin Kharkiv National University, Kharkiv, Ukraine 22 Mongolian Academy of Medical Sciences, Ulaanbaatar, Mongolia 23 N.N. Blokhin Russian Cancer Research Center RAMS, Russia 24 Kemerovo State University, Kemerovo, Russia 25 Institute for Humanities Research of the Republic of Bashkortostan 26 N.N. Alexandrov Research Institute of Oncology and Medical Radiology, Minsk, Belarus 27 Department of Radiation Oncology, Hannover Medical School, Hannover, Germany 28 Department of Cartography, Lomonosov Moscow State University, Moscow, Russia 29 Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK 30 University of Edinburgh, Institute of Evolutionary Biology, Edinburgh, Midlothian, Scotland 31 Department of Obstetrics and Gynecology, Hannover Medical School, Hannover, Germany 32 Vavilov Institute of General Genetics RAS, Moscow, Russia Correspondence: Per Lønning, email: // <![CDATA[ mail("per.lonning","helse-bergen",29,"") // ]]> Keywords: MDM2, SNP285, SNP309, polymorphism, promoter Received: February 17, 2014 Accepted: April 16, 2014 Published: April 18, 2014 Abstract The MDM2 promoter SNP285C is located on the SNP309G allele. While SNP309G enhances Sp1 transcription factor binding and MDM2 transcription, SNP285C antagonizes Sp1 binding and reduces the risk of breast-, ovary- and endometrial cancer. Assessing SNP285 and 309 genotypes across 25 different ethnic populations (>10.000 individuals), the incidence of SNP285C was 6-8% across European populations except for Finns (1.2%) and Saami (0.3%). The incidence decreased towards the Middle-East and Eastern Russia, and SNP285C was absent among Han Chinese, Mongolians and African Americans. Interhaplotype variation analyses estimated SNP285C to have originated about 14,700 years ago (95% CI: 8,300 – 33,300). Both this estimate and the geographical distribution suggest SNP285C to have arisen after the separation between Caucasians and modern day East Asians (17,000 - 40,000 years ago). We observed a strong inverse correlation (r = -0.805; p < 0.001) between the percentage of SNP309G alleles harboring SNP285C and the MAF for SNP309G itself across different populations suggesting selection and environmental adaptation with respect to MDM2 expression in recent human evolution. In conclusion, we found SNP285C to be a pan-Caucasian variant. Ethnic variation regarding distribution of SNP285C needs to be taken into account when assessing the impact of MDM2 SNPs on cancer risk.

Molecular testing for mutations in the connexin 26 gene ( GJB2) is a routine diagnostic analysis for subjects with hereditary hearing loss worldwide. However, till now there is no assessment of the di