J Genet Counsel (2013) 22:858–864 DOI 10.1007/s10897-013-9644-9

GENETIC COUNSELING: A GLOBAL PERSPECTIVE

Genetic Screening Services Provided in Turkey Yurdagül Erdem & Fulya Tekşen

Received: 19 July 2012 / Accepted: 7 August 2013 / Published online: 18 September 2013 # National Society of Genetic Counselors, Inc. 2013

Abstract In Turkey, the rate of consanguineous marriage is quite high (22–24 %) and as a result, the incidence of autosomal recessive diseases and congenital anomalies is also very high and gives rise to a serious public health problem. In the last three decades, great effort has been made to avoid increases in the prevalence of these hereditary diseases. For this purpose, population-based premarital, prenatal, neonatal and adult genetic screening programs are performed in various centers such as Community Health Centers, Early Diagnosis of Cancer and Education Centers (KETEM), Prenatal and Neonatal Departments of Universities and State Hospitals and Thalessemia Screening Centers. Such centers are staffed by health professionals including physicians, family physicians, nurses, midwives, biologists and medical geneticists. Genetic counseling is also provided to patients attending these centers after screening tests are performed. Since there are no specialized training programs for genetic counselors, genetic counseling is generally provided by doctors or medical geneticists. The aim of this paper is to give an overview of the genetic screening services provided in Turkey, the prevalence of genetic diseases and the design of intensive educational programs for health professionals.

Keywords Genetic screening programs . Genetic counseling . Congenital anomalies . Autosomal reccesive diseases . Consanguineous marriages

Y. Erdem (*) Nursing Department, Kırıkkale University Faculty of Health Sciences, Kırıkkale, Turkey e-mail: [email protected] F. Tekşen Medical Biology Department, Ankara University Faculty of Medicine, Ankara, Turkey e-mail: [email protected]

Demographic information about Turkey Turkey (Anatolia) acts as a gateway between Europe and Asia and due to this geographic location has been subject to migration from multiple regions throughout time. According to World Health Organization (WHO 2005), Turkey is a middleincome country with resources that fall between limited and enhanced levels. The official language of the Republic of Turkey is Turkish, and the majority of the people are Muslim (98 %) (Berkman et al. 2008; Yardumian and Schurr 2011). The origins of the population of Turkey are highly complex (Yardumian and Schurr 2011; Gökçümen 2008; Berkman et al. 2008). Berkman et al. (2008) stated that, genetically, Turkish people living in Anatolia (i.e., within the borders of the Republic of Turkey) are more closely related to the Balkan populations than to the Central Asian populations. In the same study, the Central Asian contribution to Anatolia was estimated as 13 % (Berkman et al. 2008). Turkey’s population currently numbers about 74.7 million (Table 1) (Turkish Demographic and Health Survey 2008; TUIK, Population Statistics 2011). Overall the rate of consanguineous marriages (CM) is 20.9 %, but the rate varies significantly according to geographic regions. The total fertility rate in Turkey is 2.15 births per woman. Many factors, including urbanization, increasing involvement in formal education and employment and later age of marriage, have affected the fertility rate (Adalı 2008; Başıbüyük 2004; Tunçbilek and Koç 1994). In Turkey as in other countries, higher maternal age at birth also increases the risk of having a child with a chromosomal abnormality (Dursun et al. 2006).

Health Care System in Turkey In Turkey, the Ministry of Health (MoH) is officially responsible for designing and implementing health policies and

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Table 1 Demographic information about Turkey Total population (million) Total population in cities (%) Total population in villages (%) Population under 14 years (%) Population under 19 years (%) Population between 15 and 64 years (%) Population above 65 years (%) Life expectancy (years) Mean Female Male Total Fertility Rate (TFR) (per women) West East Prenatal care visit (minimum one visit)(%) Delivery at a health facility Neonatal mortality rate (per thousand) Child mortality rate (per thousand) Under 5 mortality rate (per thousand) Perinatal mortality rate (per thousand) Teenage (15–19) pregnancy (%) Median age at first birth (years) Consanguineous Marriages (%) Mean West East Literacy rate (%) Mean Female Male

74.7 70.0 30.0 25.3 34.1 67.1 7.3 75.0 77.0 72.0 2.15 1.88 3.65 92.0–95.0 94.0 4.6 7.7 11.3 13.0 5.9 22.3 20.9 4.8 40.4 93.0 79.0 97.0

delivering health care services nationwide. Health services are organized into primary, secondary and tertiary level care. In 2003, the Health Transformation Program was started as a citizen-centered anthropocentric program. The Law on Family Medicine was enacted in 2004, while the family medicine program was introduced nationally in 2010 (Akdağ 2011). Under this law, a family physician (practitioner) is responsible for the health status and health problems of all members of the family, from childhood to mature adulthood. When treatment is not possible at the primary health care level, the family physician acts as a coordinator and refers the patient to other specialists or secondary/tertiary health institutions. According to the MoH (2010) report, entitled “Statistics of Distribution of Hospital Discharges by ICD-10 Main Diagnosis Codes”, the diseases observed with highest frequency were neoplasm (15.3 %), diseases of the circulatory (34.3 %) and respiratory systems (11.4 %), congenital malformations, deformations and chromosomal abnormalities (1 %) and metabolic diseases (2.9 %) (Akdağ 2011).

Abortion/curettage is legal on request by women up to the tenth week of pregnancy (Family Planning Law 1983; Sadak 2012). In the case of a fetal abnormality that is incompatible with life, curettage or induction is legally permitted and has been carried out up to 25 weeks of pregnancy. Prenatal diagnosis and preimplantation genetic diagnosis (PGD) has been available for the diagnosis of chromosomal and single gene disorders since 1999 (Tunçbilek and Özgüç 2007). The Society of Medical Genetics was founded in 1992 (Tunçbilek et al. 1999). For hereditary diseases, patients are either directed to departments that specialize in the disease, hemoglobinopathies are managed in hematology departments, or to centers that offer genetic counseling services. Today in Turkey, according to MoH Registration, 41 centers offer genetic counseling and provide diagnosis of genetic diseases using cytogenetic and molecular genetics techniques. Among these 41 centers, 7 are governmental, 11 are based in universities, and the rest are private services (Ministry of Health Private Hospitals General Directory Genetic Diseases Diagnostic Centers Report 2010). These centers follow the Genetic Diseases Diagnostic Centers Instruction that was established by the MoH in 1998. These MoH centers are monitored by a 16-member Commission. The commission members include an undersecretary of MoH, three general managers of mother and child health and family planning, basic health care services and treatment services of MoH, legal counsel, two member from the clinical or medical genetics department of local universities, two members from the department of medical biology (molecular biology, molecular genetic), one member each from obstetrics and gynecology (preferably experienced in perinatology), child health and diseases and public health of university hospital, two experts from the obstetrics and gynecology clinics (preferably experienced in perinatology) and one expert from the child health and diseases clinics of state hospital of MoH, and a member from the Turkish Medical Association (Regulation of genetic diseases diagnostic centers 1998).

Education and Training in Genetics In Turkey, most Medical Faculties include basic courses in medical biology and medical genetics in the first year of education, approximately 83 h theoretical and 34 h practical. PhD programs that provide medical genetics training and education started in 1972 as two-year specialty training for medical doctors. In 2003, the length of medical genetics training was increased to 4 years (Tunçbilek et al. 1999). PhD programs in Medical Genetics are available at some universities in the Departments of Pediatrics under the administration of the Institutes of Child Health. PhD programs in Medical Biology are offered under the doctoral program of

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Institutes of Health Sciences. A very few of the nursing school curricula contain undergraduate courses in basic genetics or a medical biology lecture. Currently, Medical Genetics Specialists, Medical Biologists, Physicians or specialists working in Perinatology or Obstetrics and Gynecology Departments are employed in tertiary Genetic Centers as’Genetic Counselors’. However there is still a great need at the first and second level of Health Services for physicians, nurses, midwives and biologists who can provide genetic counseling and as needed, direct patients to the appropriate tertiary centers. In Turkey, there are no special training or certificate programs for genetic counseling available to nurses and midwives. Genetic counseling enables individuals to be informed about their genetic health status and to have the opportunity of early diagnosis and treatment of their diseases. However, studies show that in our country there are not adequate genetic counseling services and potential patients do not have knowledge about genetic screening and diagnostic tests. A study by Teksen in 2000 of 589 individuals with a range of genetic problems found relatively low education levels and limited knowledge about advanced biotechnological procedures that were being used in the early diagnosis of hereditary diseases (Tekşen 2000). A study in 2002 on 125 Turkish Muslem women undergoing prenatal diagnosis found that the majority (86.4 %) were satisfied with being offered one of the prenatal diagnostic tests in their high risk pregnancies, but had no prior knowledge of these tests and were not offered genetic counseling before testing occurred (Tekşen 2002). A study by Terzioğlu (2006) found that the majority (61.5 %) of pregnant women who had amniocentesis for chromosomal analysis required genetic counseling after they received the amniocentesis test result. Similarly other studies in Turkey found that a high percentage of nurses, midwives and primary care physicians have inadequate knowledge about the genetic basis of diseases (Tomatır et al. 2006a, 2006b). In a study of primary care nurses in 2006, 96.4 % admitted that they had insufficient knowledge about the genetic basis of diseases and 100 % did not understand relevant ethical and legal issues (Tomatır et al. 2006a, 2006b). Similar challenges impact primary care physicians who play an important role in monitoring genetic diseases in the general population (Tomatır 2003). In 2007, a study about the basic genetic knowledge of primary care physicians working in the western region of Turkey found that 41.8 % percent knew about chromosomal anomalies, a low percentage (3.8 %) knew about polygenic inheritance, while the majority (83.9 %) would like to attend professional training of genetic counseling and genetic diseases (Tomatır et al. 2007). These studies indicate that there is a need in Turkey for training and education of both the public and health professional about genetic diseases, screening and diagnostic tests.

Erdem and Tekşen

The Genetic Screening Services Provided in Turkey Most of the genetic screening services provided in Turkey are population-based programs. In Turkey, the national screening programs can be categorized as: – – – –

Premarital carrier screening Prenatal screening Newborn screening Cancer screening.

The Premarital Carrier Screening Program Hereditary blood disorders, thalassemia and sickle cell anemia are the two major public health problems in Turkey. The beta-thalassemia incidence ranges between 2.1 % to 13.1 % depending on region (Canatan et al. 2006). The incidence of sickle-cell anemia is 3.7–6:100 overall (Antmen 2009) and 10:100 in the Southern part of Turkey (Çürük et al. 2008). In Turkey, the Law for Fighting against Hereditary Blood Disorders was first published in 1993 and was specifically aimed at preventing and screening for hemoglobinopathies. According to the “Hemoglobinopathy Controlling Program” instructions, dated 2002, thalassemia diagnostic centers were activated by the MoH. Starting in 2002, these programs made the betathalessemia screening test mandatory for all couples who intend to marry in the 33 high-risk cities of Turkey. After these tests are initiated in primary health care setting, the blood samples are sent to Thalessemia Diagnosis Centers for total blood counting and hemoglobin electrophoresis via high-performance liquid chromatography (HPLC). After the screening test is completed, if the carrier test is observed as positive, genetic counseling is provided by professionals either at the thalessemia diagnosis centers or in the primary health care setting. If both the partners are identified as carriers, the couple is referred to a secondary care setting for prenatal diagnosis and preimplantation testing. In accordance with the 82 % of eligible couples were screened. Prenatal Screening Program Prenatal screening programs are used to detect mutations in a fetus’s genes or chromosomes before birth. This type of testing is offered to couples with an increased risk of having a baby with a genetic or chromosomal disorder (Lippman 1994; Chipman 2006; WHO 2006). The non-invasive prenatal screening tests available in Turkey are the triple test (alpha– feto protein, human chorionic gonadotropin and unconjugated estriol) and ultrasonographic examination (Kuşkucu Çınar

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2010). When the results indicate there is a high risk for the fetus, invasive prenatal tests are offered to couples that include chorionic villus sampling (CVS), amniocentesis, cordocentesis or fetal biopsy. The type of test is determined by the gestational age (Kuşkucu Çınar 2010). One of the most common problems in Turkey is the birth of children with congenital anomalies (CA). According to a survey conducted by Tomatır et al. (2009) in the Denizli region of Turkey of 63,159 births, the prevalence of major congenital anomalies was found to be 2.9/1000. In this group, among the congenital anomalies, the most common defects were central nervous system anomalies that account for 31 % of all congenital anomalies. In another study, the incidence of neural tube defects based on records from hospital that included live births, stillbirths and therapeutic abortions was reported as high as 3.58 per 1,000 in Afyonkarahisar, a city in the central part of Anatolia Onrat et al. (2009). There has been considerable variation in the incidence rates of neural tube defects. In 1986 they occurred in 1.9 per 1000 live birth, while in 1989 the incidence rate was 8.9 per 1000 live birth (Çağlayan et al. 1989). This change is believed to be a result of nuclear contamination of the region following the Chernobyl accident in 1986 (Çağlayan et al. 1989; Güvenç et al. 1993). The most frequently observed chromosomal anomalies, namely trisomy 21 (Down syndrome), trisomy 18 (Edwards syndrome), Trisomy 13 (Patau syndrome) and neural tube defects (including anencephaly and spine bifida) can be screened for by a triple test between the 16th to 20th weeks of pregnancy and high resolution ultrasonography examination throughout the pregnancy. The incidence of Down syndrome was 1.2:1.000 live births in Turkey according to a study conducted in 22 university hospitals (this excluded home births) (Tunçbilek et al. 1999). Similarly the incidence of Down syndrome is reported as 1 of every 800–1000 live births in other countries (Egan et al. 2004; Roizen and Patterson 2003). Screening by maternal serum triple test is commonly used in all obstetric clinics of governmental and private hospitals. Between 1998 and 2008 the percentage of women receiving prenatal care from physician, midwives or nurses had increased from 68 % to 92 % (Sivri Aydın and Yayla 2010), And according to TUIK Report 2011, this ratio has also raised to 95 % (Table I). A great improvement for Turkey, but still, the rate of women who have no prenatal care during their pregnancy is 5 %–8 % (Turkey Demographic and Health Survey 2008; TUIK, Population Statistics 2011). All women receiving prenatal care in obstetrics clinics or radiology departments are routinely offered screening via the triple test and ultrasonography examination. Invasive procedures (amniocentesis) usually are offered to women older than 35 years of age or women who have prior history of having a child with a chromosomal

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anomaly. If the result of the screening test is found to be positive, the family is referred to a medical genetic center at the University hospital or governmental hospital, where a team including genetic counselor, clinic geneticist and molecular or cytogenetic specialist evaluate the results and provide genetic counseling. This counseling includes explaining the type of anomaly in detail and offering a suitable prenatal diagnosis technique to the couple (Özkinay 2011). Internationally, in the United States since 2007, the American College of Gynecologists recommended that all women should be eligible for screening regardless of maternal age, whereas previously only women over the age of 35 were automatically offered genetic counseling and amniocentesis or chorionic villus sampling (CVS) (Reynolds 2010). In Australia, the combined test (biochemistry and nuchal translucency ultrasound scan) is recommended for the first trimester and the quadruple test for the second trimester (Reynolds 2010). In Turkey, these non-invasive tests are available in University hospitals, some of the governmental hospitals, and private laboratories. Although the exact rate is not known, approximately 70 % of the population is thought to have an opportunity to access these prenatal tests. Neonatal Screening Program The aim of newborn screening is early detection and (preventive) treatment for affected children, before symptoms begin (WHO 2006). A nationwide screening program for phenylketonuria (PKU) was started in 1986. Screening for congenital hypothyroidism was initiated at the end of 2006, and screening for biotinidase deficiency was initiated at the end of 2008. According to an MoH report (2003–2010), under the newborn screening program, 1,245,724 infants were screened in 2009 and treatment was initiated for 252 infants diagnosed with phenylketonuria, 1983 infants with congenital hypothyroidism (including transient cases) and 170 infants with biotinidase deficiency (Akdağ 2011). The birth prevalence of hyperphenylalaninemia is 1:4192 and of PKU is 1:5049 (Özalp et al. 2001). The prevalence of biotinidase deficiency in Turkey is 1:11000–11614 (Doğan et al. 2005; Baykal et al. 1998). In Turkey, there is no routine screening for galactosemia (Öztürk et al. 2010). The screening process for PKU, congenital hypothyroidism, and biotinidase deficiency involves demonstrating absent enzyme activity in filter paper samples collected ideally on day five after birth. Collected filter papers are sent to metabolic clinics at five Medical Faculties and the results of screening are obtained about 1 week later. A repetition, at the 15th day of the test, is required for premature infants and babies who have had antibiotic treatment. In the event of a

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positive test for any of the disorders, advanced examination of the baby’s blood or urine is performed. Upon verification the family physician explains the results and refers the child and their family to a pediatric specialist who initiates treatment. Newborn screening for congenital deafness was initiated in 2009. Newborn Hearing Screening Units have been established in 227 MoH hospitals in 79 provinces. Approximately 441,332 infants underwent hearing screening in the year 2009, of these 1055 infants were diagnosed with hearing loss and covered under national treatment programs (Akdağ 2010). The most common form of inheritance of genetic deafness in Turkey is autosomal recessive (Tunçbilek and Özgüç 2007; Tekin et al. 2003). The consanguinity rate among the parents of deaf probands has been found to be relatively high (54.1 %) (Tekin 2009). The newborn hearing screening program is hospital-based. It has been established in specific units in each hospital. The test can be provided by family physicians, general practitioners, audiologists and nurses certificated in newborn hearing screening. The Transient Evoked Otoacoustic Emission Test (THEOT) and Audiotory Brainstem Audiometry Screening Test (ABR/BERA), which are used for screening, do not provide complete information about the degree of hearing loss, but instead detect a suspicion of hearing loss. This simple and cheap test gives a result report as “failed” or “succeeded”. As the first test, the Transient Evoked Otoacoustic Emission Test (THEOT) is applied 24 h after birth. After this first test if there is still concern about the baby’s hearing, a retest is done in the same center 15–30 days later. Babies who are still suspected of having hearing loss after the second THEOT are referred to second step centers in the same city for a hearing ABR/BERA test that is administered by audiologists. Those babies considered to have hearing loss after the ABR/BERA test are referred to universities with advanced diagnosis services which have specialized physicians in ear, nose and throat work and audiology clinics. When required, hearing aids are provided in advanced diagnosis centers (National Newborn Hearing Screening Programs 2012). Cancer Screening Program The National Cancer Screening programme was started in 2011 in order to reduce the morbidity and mortality of cancers that can be prevented or successfully treated if diagnosed early. Today, screening is performed for three types of cancer: colorectal cancer, breast cancer and cervical cancer. Colonoscopies are used to screen for colorectal cancer, and physical examination and mammography are used to screen for breast cancer. Genetic testing is available for some genes (i.e., BRCA) as part of research protocols but is not used in routine screening protocols. Cervical cancer screening occurs via a pap-smear.

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Although developed countries report higher rates of breast cancer incidence and mortality, changes in the incidence of breast cancer are most dramatic in low-middle income countries (LMC) including Turkey (Özmen et al. 2009). In 2006 in Europe, 28.9 % of all cancer cases were diagnosed as breast cancer in women (Ferlay et al. 2006). In Mexico between 2005 and 2006, the most recent registry date reported around 12,500 breast cancer cases with around 4,000 deaths from the disease (Rodrigues-Cuevas et al. 2009). In Africa local registries report a doubling of rates over the past 40 years. Breast cancer is reported to be the most common cancer in Arabic women and affects younger women than their counterparts in industrialized nations. In India in 2009, close to 100,000 women were diagnosed with breast cancer; increases were concentrated in urban areas, and a rise to 131,000 cases by 2010 was predicted if this rate of increase continued (Tfayli et al. 2010). China’s urban registries document 20 % to 30 % increases in the past decade alone (Porter 2008). The LMCs incidence rate of deaths from breast cancer have been increasing by up to 5 % per year due to increased life expectancy, increased marital age, delayed parity (Porter 2008), and reduced breast feeding (ChangClaude et al. 2000; Zheng et al. 2001; Porter 2008). Despite the younger age structure of most developing countries, breast cancer accounts for approximately 54 % of the all female annual deaths likely due to a lack of awareness of the benefits of detection and treatment and a scarcity of adequate facilities for detection and diagnosis, as well as poor access to primary treatment (Anderson et al. 2007; Shulmen et al. 2010). The incidence of breast cancer in the western part of Turkey (50/100,000) is more than twice the incidence in eastern regions (20/100,000) due to “Westernizing” life patterns (early menarche, late menopause, first birth >30 years, less breast feeding, etc.), and other related factors (Özmen 2008; Tuncer 2008; National Breast Cancer Registry 2012). In Lebanon an LMC country where the median age of breast cancer diagnosis is 52 years, 49.1 % of cases occur at less than 50 years of age. In developed countries such as USA, the median age of breast cancer diagnosis is 63 years with 50 % of cases over 65 years age (Tfayli et al. 2010). In Turkey, according to data from the National Breast Cancer Registry Program (2008), the mean age of diagnosis of breast cancer is 51.5, and in 20.2 % of patients is <40 years of age (Tuncer 2008). Although <5 % of breast cancer diagnosed in mammographically screened population in the USA are stage III tumors, the status is different in LMCs. The majority of patients from LMCs present with advanced or metastatic diseases; this difference is primarily due to inadequate resources for early diagnosis. In a study in Pakistan, 65.7 % of patients are admitted to clinics with metastasis from the breast and advanced stages III and IV, as compared to an incidence of

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stages III and IV of 11.3 % among American whites (Tfayli et al. 2010). In Turkey, there are many socio-cultural barriers to breast cancer detection. Detection is also impacted by low literacy, economic constraints and a lack of breast health awareness (Özmen 2008). According to the National Breast Cancer Registry Program (2008), breast cancer stages at diagnosis were 27 % (Stage I), 53 % (Stage II), 9 % (Stage III), and 6 % (Stage IV) respectively. 90 % of patients are admitted to the clinics with complaints of a painless mass in the breast (Tuncer 2008; Özmen 2008). The breast and cervical cancer screening programs are monitored by the “Early Diagnosis of Cancer and Education Centers (KETEM)” of various university and state hospitals countrywide without fee since 2005 (Tuncer 2008).

Conclusion The ability to perform screening tests at multiple life stages is vital to the diagnosis of a wide variety of genetic diseases in Turkey. The data obtained from these tests should be used for genetic counseling. There is a great need for the Turkish people to develop mechanisms to identify and limit the recurrence of hereditary diseases, especially autosomal recessive diseases which have a high incidence because of the high consanguinity rate in the country. Health care personnel working in the field of primary health care such as physicians, nurses, midwives or biologists are taking on the role of genetic counselor, however there are no special training or certificate program for genetic counseling as a profession for these health professionals. Effective screening programs can help prevent or reduce the burden of hereditary diseases, but should be managed by appropriately trained health professionals.

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