Copy number variation and regions of homozygosity analysis in patients with MÜLLERIAN aplasia.

BACKGROUND: Little is known about the genetic contribution to Müllerian aplasia, better known to patients as Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome. Mutations in two genes (WNT4 and HNF1B) account for a small number of patients, but heterozygous copy number variants (CNVs) have been described. However, the significance of these CNVs in the pathogenesis of MRKH is unknown, but suggests possible autosomal dominant inheritance. We are not aware of CNV studies in consanguineous patients, which could pinpoint genes important in autosomal recessive MRKH. We therefore utilized SNP/CGH microarrays to identify CNVs and define regions of homozygosity (ROH) in Anatolian Turkish MRKH patients. RESULTS: Five different CNVs were detected in 4/19 patients (21%), one of which is a previously reported 16p11.2 deletion containing 32 genes, while four involved smaller regions each containing only one gene. Fourteen of 19 (74%) of patients had parents that were third degree relatives or closer. There were 42 regions of homozygosity shared by at least two MRKH patients which was spread throughout most chromosomes. Of interest, eight candidate genes suggested by human or animal studies (RBM8A, CMTM7, CCR4, TRIM71, CNOT10, TP63, EMX2, and CFTR) reside within these ROH. CONCLUSIONS: CNVs were found in about 20% of Turkish MRKH patients, and as in other studies, proof of causation is lacking. The 16p11.2 deletion seen in mixed populations is also identified in Turkish MRKH patients. Turkish MRKH patients have a higher likelihood of being consanguineous than the general Anatolian Turkish population. Although identified single gene mutations and heterozygous CNVs suggest autosomal dominant inheritance for MRKH in much of the western world, regions of homozygosity, which could contain shared mutant alleles, make it more likely that autosomal recessively inherited causes will be manifested in Turkish women with MRKH.

Chromosome abnormalities identified in 457 spontaneous abortions and their histopathological findings.

OBJECTIVE: About 15% of clinically recognized pregnancies result in spontaneous abortion in the first trimester and the vast majority of these are the result of chromosome abnormalities. Studies of chromosomal constitutions of first trimester spontaneous abortions have revealed that at least 50% of the abortions have an abnormal karyotype. In this study we aimed to report the single centre experience of anomalies detected in spontaneous abortions. MATERIAL AND METHOD: We present rare numerical and structural cytogenetic abnormalities detected in spontaneous abortion materials and the histopathological findings of rest material of abortion specimens in our study population. RESULTS: Among 457 cases, 382 were successfully karyotyped while cell culture of 75 cases failed. Cytogenetic abnormalities were detected in 127 of 382 cases (33.24%). Autosomal trisomies were the predominant chromosomal abnormalities with a frequency of 48.8%. Structural chromosomal abnormalities were infrequent in conception materials. The mean age of the mothers was highest in trisomy group, the difference being significantly important (ANOVA p < 0.001). The most frequent chromosomal abnormalities were Turner syndrome, triploidy and trisomy of chromosome 16 followed by trisomy of chromosomes 22 and 21 and tetraploidy. Double trisomies and structural chromosomal abnormalities were rare. Trisomies were more frequent in advanced maternal age. CONCLUSION: Detection of chromosomal abnormalities in spontaneous abortion materials is very important to clarify the causes of loss of pregnancy. Detection of structural chromosomal abnormalities in the cases and their carrier parents can provide proper genetic counseling to these families. These families can be directed towards pre-implantation genetic diagnosis to prevent further pregnancies with complications.

Rare structural chromosomal abnormalities in prenatal diagnosis; clinical and cytogenetic findings on 10125 prenatal cases.

UNLABELLED: Objective: The aim of this study was presentation of the ultrasonographic findings and perinatal autopsy of cases with rare chromosomal abnormalities. MATERIAL AND METHOD: A total of 10125 prenatal cases over 17 years including 8731 amniocentesis, 973 chorionic villus sampling, and 421 fetal blood sampling cases were evaluated for prenatal cytogenetic diagnosis. Conventional cytogenetic studies, fluorescence in situ hybridization studies, and Array-CGH analysis techniques were used for genetic analysis. RESULTS: A structural chromosomal abnormality was observed in 95 cases. The most frequently observed structural abnormalities were balanced translocations with a frequency of 53.7% (51 cases) followed by unbalanced translocations (16.8%), inversions (11.6%), supernumerary marker chromosomes (8.4%), duplications (4.2%), deletions and ring chromosomes (2.1%) and complex translocation (1.1%). Rare structural chromosomal abnormalities including de novo balanced translocations, unbalanced translocations, inversions, duplications, deletions, ring chromosomes, and supernumerary marker chromosomes were detected in 24 cases. CONCLUSION: The rate of rare chromosomal abnormalities varies from 2.4% (South East Ireland) to 12.9% (Northern England) in Europe with a total rate of 7.4/10 000 births. In our study, the overall rate of chromosomal abnormality in prenatal cytogenetic diagnosis was 3.7%, similar to South East Ireland. Ultrasonographic and perinatal autopsy findings of the cases with rare structural chromosomal abnormalities are important for proper genetic counseling for further similar cases.

Assessment of women who applied for the uterine transplant project as potential candidates for uterus transplantation.

AIM: To review the medical charts of women who applied for the uterine transplant project from June 2008 to June 2011 in our hospital retrospectively (18-40 years). METHODS: The data for 144 women were retrieved, and information was collected on the etiology of uterine factor infertility(UFI); ovarian reserve tests; and accompanying anatomic, infectious, genetic and endocrinological problems. RESULTS: There were 119 patients with primary amenorrhea and uterovaginal agenesis and 25 patients with a history of hysterectomy. The complete Müllerian agenesis patients formed the largest group of the UFI patients with better anti-Müllerian hormone levels and antral follicle count. Anatomical anomalies such as a solitary pelvic kidney may accompany Mayer-Rokitansky-Kuster-Hauser syndrome (MRKH) and impede surgery. The mean ages in MRKH, hysterectomy and complete androgen insensitivity syndrome (CAIS) cases were 24.7, 35.0 and 34.4 years, respectively. The karyotype analysis showed 46XX (MRKH) in 109 patients and 46XY (CAIS) in 10 of the primary amenorrhea patients. CONCLUSION: Hysterectomy may deteriorate ovarian blood flow and decrease ovarian reserve. Fertility preservation may be considered in young woman undergoing hysterectomy.

Mitochondrial ATPase subunit 6 and cytochrome B gene variations in obese Turkish children.

OBJECTIVE: Due to the importance of energy metabolism in mitochondria, mitochondrial genome variations are evaluated in energy-related diseases such as obesity. To date, several nuclear genes were found to be related to obesity. Our aim in this study was to investigate the presence of polymorphisms in mitochondrial ATPase subunit 6 (mt-ATP6) and cytochrome b (mt-CytB) genes that may be associated with childhood obesity. METHODS: The mt-ATP6 and mt-CytB genes were amplified and entirely sequenced in a series of 100 obese and in an equal number of healthy Turkish children aged between 6-14 years. RESULTS: A total of 118 synonymous and nonsynonymous variations were detected in the obese and control groups. Only two previously reported synonymous substitutions (mt.8614T>C and mt.8994G>A) in the mt-ATP6 gene were found to be significantly higher in the obese group compared to the control group (p<0.05). In the mt-ATP6 gene, one novel nonsynonymous substitution (mt.8726C>T) and one novel synonymous substitution (mt.9108A>T) were found. In the mt-CytB gene, one nonsynonymous substitution (mt.14880T>C) and two synonymous substitutions (mt.14891C>T and mt.15091C>T) were novel substitutions. CONCLUSION: Two synonymous substitutions (mt.8614T>C and mt.8994G>A) in the mt-ATP6 gene may be associated with childhood obesity. Our study provides the first data about mitochondrial genome variations in a Turkish obese population and also the first in obese children. More cases should be screened in obese groups in order to understand the effects of mitochondrial polymorphisms in the development of obesity.

Clinicogenetic study of Turkish patients with syndromic craniosynostosis and literature review.

BACKGROUND: Fibroblast growth factor receptor 2 mutations have been associated with the craniosynostotic conditions of Apert, Crouzon, Pfeiffer, Saethre-Chotzen, Jackson-Weiss, Beare-Stevenson cutis gyrata, and Antley-Bixler syndromes in various ethnic groups. METHODS: Thirty-three unrelated Turkish patients (12 with Apert syndrome, 14 with Crouzon syndrome, six with Pfeiffer syndrome, and one with Saethre-Chotzen syndrome) and 67 nonsyndromic craniosynostosis patients were screened for mutations in exons IIIa and IIIc of the FGFR2 gene by denaturing high-performance liquid chromatography and confirmed by direct sequencing. RESULTS: We detected several pathogenic mutations in 11/33 (33%) patients with Apert syndrome (four with p.Pro253Arg; seven with p.Ser252Trp) and 8/33 (24%) patients with Crouzon syndrome (three with p.Trp290Arg, one with p.Cys342Tyr, p.Cys278Phe, p.Gln289Pro, and a novel p.Tyr340Asn mutation) and five (15%) with Pfeiffer syndrome (p.Cys342Arg, p.Pro253Arg, p.Trp290Arg, and p.Ser351Cys). No FGFR2 gene mutation was detected in any of the patients with Saethre-Chotzen syndrome and nonsyndromic craniosynostosis. CONCLUSIONS: Our results indicate that the majority of Turkish patients with syndromic craniosynostosis have detectable genetic changes with an overall frequency of 72.7%. Because this is the first molecular genetic report from a Turkish cohort, the identified spectrum profile of FGFR2 mutations of the syndromic craniosynostotic patients would be very helpful for understanding the genotype-phenotype relationship and has a great value for diagnosis, prognosis, and genetic counseling.

Mixed gonadal dysgenesis in a patient with de novo tas(Y;19)(p11.3;q13.4) and 45,X mosaicism.

We report a patient with a de novo telomeric association between chromosomes 19 and Y in conjunction with mixed gonadal dysgenesis. The patient was first admitted to the clinic because of abnormal external genitalia. Laparoscopic evaluation revealed (1) a rudimentary uterus, one fallopian tube, and a small gonad resembling an ovary on the right side, and (2) an immature fallopian tube, a vas deferens, and a gonad resembling a testis on the left side. Conventional cytogenetic analysis performed on cultivated peripheral blood cells, and tissue obtained from the phallus and a gonadal structure which resembled a testis revealed two different cell lines with the 46,X,tas (Y;19)(p11.3;q13.4) and 45,X karyotype. Y chromosome microdeletion analysis showed that the patient did not have any genomic deletions in the AZFa, b, c, or SRY regions on the long arm of the Y chromosome. This is the first report of a patient with mixed gonadal dysgenesis that is accompanied by a telomeric association between chromosomes 19 and Y with 45,X mosaicism.

The association of Klinefelter syndrome and multiple pterygium syndrome: an unusual presentation.

Multiple pterygium syndrome is characterized by a number of phenotypic features, small stature, webbing of the neck, elbows, and/or knees, and joint contractures. In this report, we present an 11-year-old boy who had the classical findings of multiple pterygium syndrome, and his chromosomal analysis revealed a 47,XXY karyotype. Interestingly, he did not show any of the main clinical signs of Klinefelter syndrome. This patient appears to be the first reported case in the literature in which a non-mosaic 47,XXY karyotype has been found in a patient with multiple pterygium syndrome. The aim of the present report is to describe a non-classic Klinefelter syndrome associated with multiple pterygium syndrome and to emphasize the importance of karyotype analysis in patients with multiple pterygium syndrome.

Absence of the SLC22A12 gene mutation in Turkish population with primary gout disease.

The aim of the study was to examine whether SLC22A12 gene mutations might be influenced in primary gout disease. We included 32 patients with diagnosis of primary gout disease and 100 healthy volunteers. DNA was purified from peripheral blood, and all exons of the SLC22A12 gene were sequenced. We did not find any mutations in the SLC22A12 gene in all of the patients, but found 5 polymorphisms in exons 1 (g.T258C, g.C246T), 2 (g.C1246T) and 8 (g.T8011C) and in intron 9 (g.C8577T). However, we have not found any significant differences in the frequency of the individual genotypes between patients with primary gout disease and control group. In addition, the polymorphisms were not associated with hyperuricemia in our patients with primary gout disease. There was no previously reported mutation/polymorphisms of SLC22A12 gene in Turkish population. Our study is the first one in Turkish population and suggests that there is no association between primary gout disease and SLC22A12 gene polymorphisms. Sequence changes in the promotor and intronic regions of SLC22A12 gene should be investigated further with larger case groups.

Exceptional complex chromosomal rearrangement and microdeletions at the 4q22.3q23 and 14q31.1q31.3 regions in a patient with azoospermia.

In this report we describe the first patient ever found to have azoospermia in association with both exceptional complex chromosomal rearrangements and microdeletions at two translocation breakpoints. A 36-year-old male who had been suffering from male factor infertility was admitted to our clinic. The patient also displayed mild dysmorphia. An analysis of the patient's semen revealed azoospermia. GTG banding revealed the presence of an exceptional complex chromosomal rearrangement involving chromosomes 1, 4, 10 and 14. Using subtelomeric FISH analysis, the patient's karyotype was designated as 46,XY,t(1;10)(q43q44;q21q26.1)(CEB108/T7+,D1S3738-;10PTEL006+,D10S2290+, D1S3738+), ins(14;4) (q31.3;q23q33)(D14S1420+; D4S3359+, D4S2930+). Array-CGH analysis revealed two microdeletions at the 4q22.3q23 and 14q31.1q31.3 chromosomal regions. We suggest that microdeletions at the 4q22.3q23 and 14q31.1q31.3 chromosomal regions associated with both an exceptional complex chromosomal rearrangement and the Homo sapiens chromosome 4 open reading frame 37 (C4orf37) gene located at the 4q22.3q23 region might be associated with male factor infertility.

A 5q12.1-5q12.3 microdeletion in a case with a balanced exceptional complex chromosomal rearrangement.

Complex chromosomal rearrangements are very rare chromosomal abnormalities. Individuals with a complex chromosomal rearrangement can be phenotypically normal or display a clinical abnormality. It is believed that these abnormalities are due to either microdeletions or microduplications at the translocation breakpoints or as a result of disruption of the genes located in the breakpoints. In this study we describe a 2-year-old child with mental retardation and developmental delay in whom a de novo apparently balanced exceptional complex chromosomal rearrangement was found through conventional cytogenetic analysis. Using both cytogenetic and FISH analysis, the patient's karyotype was found to be: 46,XY,der(5)t(5;7)(p15.1;7q34),t(5;8)(q13.1;8q24.1)dn. A large, clinically significant deletion which encompassed 887.69kb was detected at the 5q12.1-5q12.3 (chr5:62.886.523-63.774.210) genomic region using array-CGH. This deleted region includes the HTR1A and RNF180 genes. This is the first report of an individual with an apparently balanced complex chromosomal rearrangement in conjunction with a microdeletion at 5q12.1-5q12.3 in which there are both mental-motor retardation and dysmorphia.

Pulmonary alveolar microlithiasis with homozygous c.316G > C (p.G106R) mutation: a case report.

Pulmonary alveolar microlithiasis is characterized by the presence of calcospherites in alveolar spaces. Sporadic cases are more common, but the disease also presents in an inherited familial form. The greatest number of reported cases is from Europe and especially Turkey. We present a 43-year-old female with complaints of dyspnea for many years. She had a suspicious familial history of pulmonary alveolar microlithiasis. The surgical lung biopsy specimen appeared gritty and firm. Histological sections showed diffuse involvement of the lung parenchyma by innumerable tiny calcospherites. Genetic studies showed a homozygous c.316G > C (p.G106R) mutation in exon 4 and confirmed the diagnosis of pulmonary alveolar microlithiasis. The present report aims to contribute to the literature with a pathologically and genetically confirmed new case to add insight into the etiology of this rare disease. This case confirms an autosomal recessive inheritance and does not support the role of non-genetic and other factors in the pathogenesis of pulmonary alveolar microlithiasis.

A patient with Down syndrome with a de novo derivative chromosome 21.

Pure partial trisomy of chromosome 21 is a rare event. The patients with this aberration are very important for setting up precise karyotype-phenotype correlations particularly in Down syndrome phenotype. We present here a patient with Down syndrome with a de novo derivative chromosome 21. Karyotype of the patient was designated as 46,XY,der(21)(p13)dup(21)(q11.2q21.3)dup(21)(q22.2q22.3) with regard to cytogenetic, FISH and array-CGH analyses. Non-continuous monosomic, disomic and trisomic chromosomal segments through the derivative chromosome 21 were detected by array-CGH analysis. STR analyses revealed maternal origin of the de novo derivative chromosome 21. The dual-specificity tyrosine (Y)-phosphorylation regulated kinase 1A (DYRK1A) and Down Syndrome Critical Region 1 (DSCR1) genes that are located in Down syndrome critical region, are supposed to be responsible for most of the clinical findings of Down syndrome. However, our patient is the first patient with Down syndrome whose clinical findings were provided in detail, with a de novo derivative chromosome 21 resulting from multiple chromosome breaks excluding DYRK1A and DSCR1 gene regions.

Aberrations of chromosomes 9 and 22 in acute lymphoblastic leukemia cases detected by ES-fluorescence in situ hybridization.

A reciprocal translocation between chromosomes 9 and 22 creates oncogenic BCR/ABL fusion in the breakpoint region of the derivative chromosome 22. The aim of this study was to evaluate the importance of atypical fluorescence in situ hybridization (FISH) signal patterns in pediatric and adult acute lymphoblastic leukemia (ALL) cases. We evaluated t(9;22) translocation in 208 cases with ALL (294 tests), including 139 childhood and 69 adult cases by FISH technique using BCR/ABL extra signal (ES) probe. FISH signal patterns observed in pediatric ALL cases were as follows; Major-BCR/ABL (M-BCR/ABL) (1.4%), minor-BCR/ABL (m-BCR/ABL) (3.6%), trisomy 9 (4.3%), trisomy 22 (4.3%), trisomy or tetrasomy of both chromosomes 9 and 22 (2.9%), monosomy 9 (1.4%), monosomy 22 (0.7%), ABL gene amplification (1.4%), derivative chromosome 9 deletion (1.4%), and extra copies of the Philadelphia chromosome (1.4%). FISH signal patterns observed in adult ALL cases were as follows; M-BCR/ABL (5.8%), m-BCR/ABL (11.6%), two different cell clones with major and minor BCR/ABL signal pattern (2.9%), extra copies of Philadelphia chromosome (4.3%), derivative chromosome 9 deletion (1.4%), trisomy 9 (2.9%), tetraploidy (1.4%), monosomy 9 (1.4%), trisomy 22 (1.4%), and coexistence of both trisomy 22 and monosomy 9 (1.4%). Trisomy 9, trisomy 22, and polyploidy of chromosomes 9 and 22 were specific atypical FISH signal patterns for childhood B cell acute lymphoblastic leukemia (B-ALL) patients. However, monosomy 9 and ABL gene amplification were highly specific for childhood T cell acute lymphoblastic leukemia (T-ALL) patients. Our report presents the correlation between atypical FISH signal patterns and clinical findings of a large group of ALL cases.

Pure and complete 12p trisomy due to a maternal centric fission of chromosome 12.

Pure and complete 12p trisomy are rare. Here, we report on a unique patient with trisomy 12p syndrome due to centric fission of maternal chromosome 12. Conventional cytogenetic and fluorescence in situ hybridization (FISH) techniques revealed the proposita's karyotype to be 47,XX,+fis(12)(p10)mat whereas the maternal one was 47,XX,-12,+fis(12)(p10),+fis(12) (q10). This is the first report on centric fission of chromosome 12 leading to stable telocentrics, each with a fully functional centromere. Our observation shows that the centric fission of chromosome 12 can be a new mechanism for generation of a partial centromere and trisomy 12p syndrome.

Prenatal diagnosis of ß-thalassemia and other hemoglobinopathies in southwestern Turkey.

Our aim was to evaluate the prenatal diagnosis of ß-thalassemia (ß-thal) and other hemoglobinopathies in a region with high frequency. After detection by premarital or antenatal screening, 312 patients underwent 420 prenatal diagnostic procedures for 407 fetuses in a 10-year period. Fetal samples were collected by chorionic villi sampling (CVS) in the first trimester and amniocentesis and cordocentesis in the second trimester. Mutation analyses of ß-globin and cytogenetic analyses were performed and the most common mutations detected were: IVS-I-110 (G>A), IVS-II-1 (G>A), IVS-I-6 (T>C) and IVS-II-745 (C>G). Hb S [ß6(A3)Glu→Val, GAG>GTG)] was the most common hemoglobin (Hb) variant with a frequency of 6.3%. Among 407 fetuses, 105 (25.8%) were diagnosed as affected, while 201 (49.4%) were carriers and 101 (24.8%) were normal. Cytogenetic analyses revealed nine fetuses (2.3%) with numerical chromosomal abnormalities as regular or mosaicism. Prenatal diagnosis of common hemoglobinopathies is safe and effective. Performing cytogenetic analysis in excess fetal material is an acceptable option.

Genomic large rearrangement screening of BRCA1 and BRCA2 genes in high-risk Turkish breast/ovarian cancer patients by using multiplex ligation-dependent probe amplification assay.

In this study, MLPA assay was performed for detection of large rearrangements of BRCA1 and BRCA2 genes in 16 familial, 29 early onset, 3 male breast cancer, and 2 bilateral breast/ovarian cancer high risk Turkish index cases. MLPA assay for all exons of both genes and for 1100delC variant of CHEK2 gene were performed. Analyses, revealed no large genomic rearrangements in both genes, and, no 1100del variant in CHEK2 gene. Our data which represents the first results for Turkish patients, suggest that, the frequency of BRCA1 and BRCA2 genes' large rearrangements is very low.

Complete gonadal dysgenesis 46,XY (Swyer syndrome) in two sisters and their mother's maternal aunt with a female phenotype.

OBJECTIVE: To present a familial case of Swyer syndrome. DESIGN: Case report. SETTING: Academic medical center. PATIENT(S): Two sisters with a main complaint of primary amenorrhea and another case, their mother's maternal aunt with the same history of primary amenorrhea but married with no consanguinity and no children. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The patients were studied from clinical, endocrinologic, and genetic perspectives. RESULT(S): Chromosome analyses revealed a 46,XY male karyotype with no detectable mosaicism in both sisters and their mother's maternal aunt. Molecular studies of sex-determining region Y and molecular investigation undertaken for the two sisters revealed SRY negativity. CONCLUSION(S): Gonadal dysgenesis can also be inherited as an X-linked disorder, and evidence exists from familial studies of perhaps autosomal inheritance.

Germline mutations of BRCA1 and BRCA2 genes in Turkish breast, ovarian, and prostate cancer patients.

Distribution and prevalence of germline mutations in BRCA1 and BRCA2 differ among different populations. For the Turkish population, several studies have addressed high-risk breast cancer and ovarian cancer (BC-OC) patients. In most studies, both genes were analyzed in part, and a quite heterogeneous mutation spectrum was observed. For high-risk Turkish prostate cancer (PCa) patients, however, there are no data available about mutations of germline BRCA genes. To accurately determine the contribution of germline mutations in BRCA1 and BRCA2 in Turkish BC, OC, and PCa high-risk patients, 106 high-risk BC-OC patients, 50 high-risk PCa patients, and 50 control subjects were recruited. The study represents the only full screening, to date, of a large series of Turkish high-risk BC-OC patients and the only study in Turkish high-risk PCa patients. Mutation screenings were performed on coding exons of both genes with either denaturing gradient gel electrophoresis or denaturing high performance liquid chromatography, or with both techniques. Three deleterious mutations in BRCA1 and three deleterious mutations in BRCA2 were detected in different BC-OC patients, and one truncating mutation was detected in a high-risk PCa patient. In addition, 28 different unclassified and mostly novel variants were detected in both genes, as well as several silent polymorphisms. These findings reflect the genetic heterogeneity of the Turkish population and are relevant to genetic counseling and clinical management.

Analysis of TPO gene in Turkish children with iodide organification defect: identification of a novel mutation.

The objective was to determine molecular genetic analysis of the TPO gene in Turkish children with iodide organification defect (IOD). Patients with a diagnosis of primary hypothyroidism were evaluated. Subjects having a definite diagnosis of autoimmune thyroiditis, thyroid gland dysplasia and, or iodine deficiency were excluded. A total of 10 patients from nine unrelated Turkish families, with an unknown etiology of hypothyroidism, and with a presumptive diagnosis of IOD were included in the study. A perchlorate discharge test (PDT) was performed to all subjects, and sequence analysis of TPO gene was applied in patients with a positive PDT. Five out of 10 patients have a total IOD, while the five remaining patients have a partial IOD according to PDT results. In two sisters, one has a partial and the other one has a total IOD a novel homozygous nonsense p.Q315X mutation was found in exon 8. Additionally, a previously known homozygous missense p.R314W mutation was detected in the same exon in another patient with a total IOD. No TPO gene mutation was detected in any of the seven remaining patients. Two different TPO gene mutations were found to be responsible for IOD in two unrelated Turkish families from the same ethnic background. More subjects should be screened for detecting the prevalence and spectrum profile of TPO mutations in our population that might be helpful for understanding the pathophysiology of congenital hypothyroidism.