Molecular Genetic Analysis of Survival Motor Neuron Gene in 460 Turkish Cases with Suspicious Spinal Muscular Atrophy Disease

How to Cite This Article: Rashnonejad A, Onay H, Atik T, Atan Sahin O, Gokben S, Tekgul H, Ozkinay F. Molecular Genetic Analysis of Survival Motor Neuron Gene in 460 Turkish Cases with Suspicious Spinal Muscular Atrophy Disease. Iran J Child Neurol. Autumn 2016; 10(4):30-35.AbstractObjectiveTo describe 12 yr experience of molecular genetic diagnosis of Spinal Muscular Atrophy (SMA) in 460 cases of Turkish patients. Materials & MethodsA retrospective analysis was performed on data from 460 cases, referred to Medical Genetics Laboratory, Ege University’s Hospital, Izmir, Turkey, prediagnosed as SMA or with family history of SMA between 2003 and 2014.The PCR-restriction fragment length polymorphism (RFLP) and the Multiplex ligation–dependent probe amplification (MLPA) analysis were performed to detect the survival motor neuron (SMN)1 deletions and to estimate SMN1 and SMN2 gene copy numbers. ResultsUsing PCR-RFLP test, 159 of 324 postnatal and 18 of 77 prenatal cases were detected to have SMN1 deletions. From positive samples, 88.13% had a homozygous deletion in both exon 7 and exon 8 of SMN1. Using MLPA, 54.5% of families revealed heterozygous deletions of SMN1, and 2 or 3 copies of SMN2, suggesting a healthy SMA carrier. Among patients referred for SMA testing, the annual percentage of patients diagnosed as SMA has decreased gradually from 90.62% (2003) down to 20.83% (2014). ConclusionAlthough PCR-RFLP method is a reliable test for SMA screening, MLPA is a necessary additional test and provide relevant data for genetic counseling of families having previously affected child. The gradual decrease in the percentage of patients molecularly diagnosed as SMA shows that clinicians have begun to use genetic tests in the differential diagnosis of muscular atrophies. Cost and availability of these genetic tests has greatly attributed to their use.   References1. Brichta L, Holker I, Haug K, Klockgether T, Wirth B. In vivo activation of SMN in spinal muscular atrophy carriers and patients treated with valprotae. Ann Neurol 2006;59:970-5.2. Prior TW, Krainer AR, Hua Y, Swoboda KJ, Snyder PC, Bridgeman SJ, et al. A positive modifier of spinal muscular atrophy in the SMN2 gene. Am J Hum Genet 2009;85:408-13.3. Striano P, Boccella P, Sarappa C, Striano S. Spinal muscular atrophy and progressive myoclonic epilepsy: one case report and characteristics of the epileptic syndrome. Seizure 2004;13:582-6.4. Wirth B. An update of the mutation spectrum of the survival motor neuron gene (SMN1) in autosomal recessive spinal muscular atrophy (SMA). Hum Mutat 2000;15:228-37.5. Van der Steege G, Grootscholten PM, Van der Vlies P, Draaijers TG, Osinga J, Cobben JM, et al. PCR-based DNA test to confirm clinical diagnosis of autosomal recessive spinal muscular atrophy. Lancet 1995;345:985-6.6. Rekik I, Boukhris A, Ketata S, Amri M, Essid N, Feki I, et al. Deletion analysis of SMN and NAIP genes in Tunisian patients with spinal muscular atrophy. Ann Indian Acad Neurol 2013;16:57-61.7. de Souza Godinho FM, Bock H, Gheno TC, Saraiva-Pereira ML. Molecular Analysis of Spinal Muscular Atrophy: A genotyping protocol based on TaqMan realtime PCR. Genet Mol Biol 2012;35:955-9.8. Burghes AH. When deletion is not a deletion? When it is converted? Am J Hum Genet 1997;61:9-15.9. Kubo Y, Nishio H, Saito K. A new method for SMN1 and hybrid SMN gene analysis 1. in spinal muscular atrophy using long-range PCR followed by sequencing. J Hum 2. Genet 2015;60:233-9.10. Ogino S, Leonard DG, Rennert H, Wilson RB. Spinal Muscular Atrophy Genetic Testing Experience at an Academic Medical Center. J Mol Diagn 2002;4:53-8.11. Baumbach-Reardon L, Sacharow S, Ahearn ME. Spinal Muscular Atrophy, X-Linked Infantile. Gene Review 1993.12. Khaniani MS, Derakhshan SM, Abasalizadeh S. Prenatal diagnosis of spinal muscular atrophy: clinical experience and molecular genetics of SMN gene analysis in 36 cases. J Prenat Med 2013;7:32-4.13. Lin SP, Chang JG, Jong YJ, Yang TY, Tsai CH, Wang NM, et al. Prenatal prediction of spinal muscular atrophy in Chinese. Prenat Diagn 1999;19:657-61.14. Cobben JM, Scheffer H, De visser M, Van der Steege G, Verhey JB, Osigna J, et al. Prenatal prediction of spinal muscular atrophy. Experience with linkage studies and consequences of present SMN deletion analysis. Eur J Hum Genet 1996;4:231-6.15. Miskovic M, Lalic T, Radivojevic D, Cirkovic S, Ostojic S, Guc-Scekic M. Ten years of experience in molecular prenatal diagnosis and carrier testing for spinal muscular atrophy among families from Serbia. Int J Gynaecol Obstet 2014;124:55-8.16. Mailman MD, Heinz JW, Papp AC, Snyder PJ, Sedra MS, Burghes AHM, Wirth B, Prior TW. Molecular analysis of spinal muscular atrophy and modification of the phenotype by SMN2. Genet Med 2002;4:20–26.17. Ogino S, Leonard DG, Rennert H, Ewens WJ, Wilson RB. Genetic risk assessment in carrier testing for spinal muscular atrophy. Am J Med Genet 2002;110:301-7.18. Wirth B. An update on the mutation spectrum of the survival motor neuron gene (SMN1) in autosomal recessive spinal muscular atrophy (SMA). Hum Mutat 2000;15:228–37

Early-onset severe obesity due to complete deletion of the leptin gene in a boy

WOS: 000414040800014PubMed ID: 29040067Background: Monogenic obesity results from single gene mutations. Extreme obesity starting at an early age, especially in infancy, which is associated with endocrinopathy and metabolic disturbances is key to the diagnosis of monogenic obesity. Case presentation: A 6-month-old boy was admitted to our clinic with severe obesity and food craving. He was born with a birth weight of 3400 g to first-cousin parents. He started to gain weight at an abnormal rate at the age of 2 months. He had hyperinsulinemia, dyslipidemia and grade 2 hepatosteatosis. He had a 7-year-old, healthy brother with a normal body weight. Because of severe early-onset obesity and abnormal food addiction, his leptin level was measured and found to be 0.55 ng/mL (normal range for his age and sex is 0.7-21 ng/mL). A LEP gene mutation was screened for and a gross leptin gene deletion was detected. To date, no report on a gross deletion of the LEP gene has been published in the literature. Conclusions: To the best of our knowledge, a gross deletion of the LEP gene has not been reported so far in the literature. Here we report a unique case with congenital leptin deficiency. Thus, clinicians should search for monogenic obesity in patients with early-onset severe obesity and endocrinopathy. Measuring the leptin level could aid clinicians to identify children with monogenic obesity

A New Mutation in the TBX5 Gene in Holt-Oram Syndrome: Two Cases in the Same Family and Prenatal Diagnosis

WOS: 000337075700014PubMed ID: 24408148Holt-Oram Syndrome (HOS) is a rare autosomal dominant condition characterized by anomalies of the upper extremity and cardiac malformations. Mutations in the TBX5 gene are what cause HOS. The proband is an 8-year-old male who presented with upper-extremity abnormalities and a chest deformity. He was born to a nonconsanguineous marriage at full term. He has a history of ventricular septal defect. His mother presented with deformation in both hands and forearms, and was 9 weeks' pregnant. Mutation analysis for TBX5 gene revealed heterozygous p.L65Qfs*10 in both the patient and his mother. Molecular analysis of the fetus was normal for TBX5 gene in the 13th week of pregnancy. In conclusion, our case supports the fact that the HOS presents differently, case by case, even within the same family. The novel mutation reported here and phenotypic findings in the affected members may contribute to the phenotype-genotype correlation