Hatip Aydin

Molecular etiology of arthrogryposis in multiple families of mostly Turkish origin

BACKGROUND Arthrogryposis, defined as congenital joint contractures in 2 or more body areas, is a clinical sign rather than a specific disease diagnosis. To date, more than 400 different disorders have been described that present with arthrogryposis, and variants of more than 220 genes have been associated with these disorders; however, the underlying molecular etiology remains unknown in the considerable majority of these cases. METHODS We performed whole exome sequencing (WES) of 52 patients with clinical presentation of arthrogryposis from 48 different families. RESULTS Affected individuals from 17 families (35.4%) had variants in known arthrogryposis-associated genes, including homozygous variants of cholinergic γ nicotinic receptor (CHRNG, 6 subjects) and endothelin converting enzyme-like 1 (ECEL1, 4 subjects). Deleterious variants in candidate arthrogryposis-causing genes (fibrillin 3 [FBN3], myosin IXA [MYO9A], and pleckstrin and Sec7 domain containing 3 [PSD3]) were identified in 3 families (6.2%). Moreover, in 8 families with a homozygous mutation in an arthrogryposis-associated gene, we identified a second locus with either a homozygous or compound heterozygous variant in a candidate gene (myosin binding protein C, fast type [MYBPC2] and vacuolar protein sorting 8 [VPS8], 2 families, 4.2%) or in another disease-associated genes (6 families, 12.5%), indicating a potential mutational burden contributing to disease expression. CONCLUSION In 58.3% of families, the arthrogryposis manifestation could be explained by a molecular diagnosis; however, the molecular etiology in subjects from 20 families remained unsolved by WES. Only 5 of these 20 unrelated subjects had a clinical presentation consistent with amyoplasia; a phenotype not thought to be of genetic origin. Our results indicate that increased use of genome-wide technologies will provide opportunities to better understand genetic models for diseases and molecular mechanisms of genetically heterogeneous disorders, such as arthrogryposis. FUNDING This work was supported in part by US National Human Genome Research Institute (NHGRI)/National Heart, Lung, and Blood Institute (NHLBI) grant U54HG006542 to the Baylor-Hopkins Center for Mendelian Genomics, and US National Institute of Neurological Disorders and Stroke (NINDS) grant R01NS058529 to J.R. Lupski.

DNA damage is increased in lymphocytes of patients with metabolic syndrome

We assessed DNA damage in patients with metabolic syndrome (MetS) by performing comet and micronucleus (MN) assays on peripheral blood lymphocyte cultures from study participants. 52 MetS patients and 35 age-matched healthy controls were evaluated for abdominal obesity, body-mass index (BMI), blood pressure, serum triglycerides, HbA1c, HDL-C, and fasting blood glucose levels. In addition, malondialdehyde (MDA) levels and activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) were determined. Serum levels of triglycerides, HbA1c, fasting blood glucose and waist circumference, systolic blood pressure, diastolic blood pressure, and BMI of the subjects in the MetS group were significantly higher than those of the control group (for each, p<0.001). However, the mean level of HDL-C in the MetS group was lower than in the control group (p<0.001). In the study, the length of comet tails was significantly higher in the MetS patients (10.23±1.98, range 5.72-15.08) than in the controls (3.12±1.73, range 0.6-7.1) (p<0.001). MN frequency was also significantly increased in MetS patients (3.68±1.27 per 1000 cells) compared to that of the control group (1.81±0.84 per 1000 cells) (p<0.001). Micronucleated cell frequency and comet-tail length in subjects showed positive correlations with waist circumference, BMI, and plasma triglyceride levels (p<0.01) and negative correlations with HDL-C levels (p<0.01). Among the oxidative stress factors, MDA levels were significantly higher in MetS patients than in the controls. However, SOD and GSH-Px enzyme activities were significantly lower in the MetS group than in the controls. These findings suggest that patients with MetS have increased DNA damage and oxidative stress.

Whole-exome sequencing links TMCO1 defect syndrome with cerebro-facio-thoracic dysplasia

Whole-exome sequencing (WES) is a type of disruptive technology that has tremendous influence on human and clinical genetics research. An efficient and cost-effective method, WES is now widely used as a diagnostic tool for identifying the molecular basis of genetic syndromes that are often challenging to diagnose. Here we report a patient with a clinical diagnosis of cerebro-facio-thoracic dysplasia (CFTD; MIM#213980) in whom we identified a homozygous splice-site mutation in the transmembrane and coiled-coil domains 1 (TMCO1) gene using WES. TMCO1 mutations cause craniofacial dysmorphism, skeletal anomalies characterized by multiple malformations of the vertebrae and ribs, and intellectual disability (MIM#614132). A retrospective review revealed that clinical manifestations of both syndromes are very similar and overlap remarkably. We propose that mutations of TMCO1 are not only responsible for craniofacial dysmorphism, skeletal anomalies and mental retardation syndrome but also for CFTD.

Exome Sequencing Identifies a Homozygous C5orf42 Variant in a Turkish Kindred With Oral- Facial-Digital Syndrome Type VI

Oral‐facial‐digital syndrome type VI (OFDVI) is a rare ciliopathy in the spectrum of Joubert syndrome (JS) and distinguished from other oral‐facial‐digital syndromes by metacarpal abnormalities with central polydactyly and by a molar tooth sign on cranial MRI. Additional characteristic features include short stature, micrognathia, posteriorly rotated low‐set ears, hypertelorism, epicanthal folds, broad nasal tip, tongue hamartoma, upper lip notch, intraoral frenula, cleft lip/palate, and renal anomalies. Recently, novel mutations in C5orf42 were identified in 9 out of 11 OFDVI families. In a subsequent study C5orf42 was found to be mutated in only 2 out of 17 OFDVI probands while 28 patients with a pure JS phenotype also had pathogenic mutations of C5orf42.

Evaluation of maternal serum folate, vitamin B12, and homocysteine levels andfactor V Leiden, factor II g.20210G>A, and MTHFR variations in prenatallydiagnosed neural tube defects

BACKGROUND/AIM Neural tube defects (NTDs) are common congenital malformations that develop as a result of interactions between several genes and environmental factors. Many factors have been investigated in order to understand the etiology of NTDs, and many studies have identified folate intake as a common contributing factor. The exact etiology of the disease is still unknown. MATERIALS AND METHODS In this study, we compared serum folate, vitamin B12, and homocysteine levels, along with common thrombophilia-related genetic variations, including factor V Leiden, factor II g.20210G>A, MTHFR c.677C>T, and MTHFR c.1298A>C, in 35 pregnant women with fetal NTDs and 38 pregnant women with healthy fetuses. RESULTS A significant difference in serum vitamin B12 level and factor V Leiden frequency was detected between the two groups. On the other hand, serum folate, homocysteine levels, and factor II g.20210G>A, MTHFR c.677C>T, and MTHFR c.1298A>C were not significantly different in the NTD group compared to the controls. CONCLUSION These results indicate that vitamin B12 supplementation along with folate may help in lowering NTD frequency. In addition, this is the first study that provides evidence for a possible relationship between increased NTD risk and factor V Leiden.

Evaluation of Factor V Leiden, Prothrombin G20210A, MTHFR C677T and MTHFR A1298C gene polymorphisms in retinopathy of prematurity in a Turkish cohort.

ABSTRACT Background: To assess Factor V Leiden (FVL) (rs6025), Prothrombin G20210A (rs1799963), MTHFR C677T (rs1801133), and MTHFR A1298C (rs1801131) gene mutations as risk factors in the development of retinopathy of prematurity (ROP). Materials and methods: A total of 105 children were included in this cross-sectional study. Patients were divided into two groups. The study group consisted of 55 infants with a history of ROP and the control group comprised 50 healthy infants with term birth. All subjects were screened for the presence of certain mutations (FVL, Prothrombin G20210A, MTHFR C677T and MTHFR A1298C) by Real-Time PCR at 1 year of age. Results: The mean gestational age (GA) and birth weight (BW) of the study group were, 28.65 ± 2.85 weeks and 1171 ± 385.74 g, respectively. There were no significant differences of genotype and allele frequency of Prothrombin G20210A, MTHFR A1298C and MTHFR C677T between the study and control groups (p > 0.05). Eight children (14.5 %) had heterozygous and one child (1.8%) had homozygous FVL mutation in the study group. One child (2%) in the control group had heterozygous FVL mutation. There was statistically significant differences of FVL allele and genotype frequencies between the groups (p < 0.05). Conclusions: The prevalence of FVL polymorphism (16.3 %) was higher in ROP patients than control subjects in this Turkish cohort. We suggest a possible association of FVL mutation with ROP at the end of the study.

A rare case of rhombencephalosynapsis and prenatal diagnosis

Rhombencephalosynapsis (RES) is an extremely rare cerebellar malformation that is characterised by vermian agenesis associated with fusion of the cerebellar hemispheres and peduncles. RES is often ...

Prenatal diagnosis and outcome of lymphangiomas and its relationship with fetal chromosomal abnormalities

Abstract Objectives: Our aim was to evaluate ultrasound findings and perinatal outcome after prenatal diagnosis of lymphangioma. Methods: This was a retrospective case series study. We searched the archives of our ultrasound database at our center for cases with the prenatal diagnosis of the lymphangioma in the period between January 2008 and November 2014. We described maternal, fetal and perinatal variables for all cases. Results: Nine fetuses with lymphangioma were identified. All cases were diagnosed during the second and third trimesters with the average gestational age of 22.6 ± 3.9 weeks. The average diameter of lymphangioma was 55.4 ± 20.1 mm at the time of diagnosis. Five fetuses (55.6%) had lymphangioma on the neck, and four fetuses (44.4%) had lymphangioma on other localizations. Normal fetal karyotype was detected in all cases. There were a total of six live births, one intrauterine death and two medical terminations of pregnancy following the diagnosis of lymphangioma. No abnormal Doppler finding or hydrops were detected in the antenatal follow-up of remaining six cases. Conclusion: The risk of chromosomal abnormalities is very low in pregnancies with isolated lymphangioma. The outcome of pregnancies with lymphangioma is generally favorable and prognosis depends on their locations and size.

A novel frameshift mutation and infrequent clinical findings in two cases with Dyggve-Melchior-Clausen syndrome.

Dyggve–Melchior–Clausen syndrome (DMC) (MIM #223800) is a rare autosomal-recessive type of skeletal dysplasia accompanied by variable degrees of intellectual disability (ID). It is characterized by progressive spondyloepimetaphyseal dysplasia leading to disproportionate short stature, microcephaly, and coarse facies. The radiographic appearance of generalized platyspondyly with double-humped end plates and the lace-like appearance of iliac crests are pathognomonic in this syndrome. The disorder results from mutations in the dymeclin (DYM) mapped to the 18q12–12.1 chromosomal region. Here, we report two cases with DMC: one with disproportionate short stature, developmental delay, and severe ID with a novel frameshift mutation (c.1028_1056del29) leading to a premature stop codon, and the second patient with classical clinical and radiological features of DMC with mild ID and rectal prolapse, which is very rare. The clinical diagnosis was confirmed with molecular analysis of DYM with a known mutation at c.580C>T (p.R194X). The parents and sibling of the second patient were heterozygous carriers with mild skeletal changes and short stature.

Geç Tanılı Rubinstein-Taybi Sendromlu Bir Olgu

Rubinstein-Taybi Sendromu (RSTS) karakteristik yuz bulgulari, kisa boy, orta-agir entelektuel yetersizlik, genis el ve ayak basparmaklari ile seyreden nadir bir genetik hastaliktir. Hastalarin yasamlarinin ilk yillarinda karsilastiklari problemlere dogru ve daha cozumcul yaklasilabilmesi icin taninin erken konulabilmesi oldukca onemlidir. Bu yazida gec tanili RSTS’li bir olgu sunulmaktadir.