LİZENSEFALİ SPEKTRUMU OLGULARINDA GENOTİP-FENOTİP İLİŞKİSİ

Year 2022, Volume: 5 Issue: 3, 160 - 166, 16.11.2022

Ayça Dilruba Aslanger , Oya Uyguner , Birsen Karaman , Seher Başaran , Hülya Kayserili

https://doi.org/10.26650/JARHS2022-1107813

Abstract

Amaç: Çalışmamızda lizensefali tanısı alan altı olgunun genotip-fenotip ilişkisi açısından değerlendirilmesi amaçlanmıştır. Gereç ve Yöntem: Bu çalışmaya Tıbbi Genetik Anabilim Dalı polikliniğinde lizensefali tanısı ile izlenen altı olgu dâhil edilmiştir. Ağır lizensefali olan dismorfizmin eşlik ettiği iki olgu, izole lizensefali tanılı iki olgu, subkortikal band heterotopisi olan bir olgu ve serebellar hipoplazinin eşlik ettiği lizensefali tanılı bir olguda genotip-fenotip ilişkisi göz önüne alınarak sitogenetik (karyotip ve 17p13 FISH analizi) ile moleküler testler (LIS1, DCX ve RELN genlerinin Sanger yöntemi ile dizilenmesi) uygulanmıştır. Bulgular: Olgu 1 ve Olgu 2’de 17p13 delesyonu saptanarak Miller-Dieker sendromu tanısı konuldu. İzole lizensefalisi olan Olgu 3 ve 4’te beynin posteriyorunun daha belirgin etkilenmesi nedeniyle yapılan LIS1 geninde sırasıyla bilinen heterozigot c.337C>T (p.Arg113Ter) ve heterozigot c.946G>C (p.Asp317His) mutasyonları saptandı. Subkortikal band heterotopisi olan olguda (Olgu 5) DCX geninde heterozigot c.605_607delAGA (p.Lys202del) novel varyantı bulundu. Lizensefaliye serebellar hipoplazinin eşlik ettiği Olgu 6’da RELN geninde homozigot c.204C>G (p.Tyr68Ter) novel varyantı saptandı. Sonuç: Genotip-fenotip ilişkisi göz önüne alındığında, klinik ve radyolojik özellikler lizensefali olgularında genetik mutasyonların belirlenmesine yardımcı olmuştur. Ayrıca, DCX ve RELN genlerinde patojenik olduğu tahmin edilen daha önce bildirilmemiş iki varyantın tespiti, lizensefali ile ilişkili genotip bilgisine katkı sağlamıştır.

Keywords

Lizensefali, nöronal migrasyon anomalisi, Miller-Dieker sendromu, lissencephaly, neuronal migration anomalies, Miller-Dieker syndrome

Supporting Institution

İstanbul Üniversitesi Bilimsel Araştırma Projeleri Birimi

Project Number

3574

GENOTYPE-PHENOTYPE CORRELATION IN CASES WITH LISSENCEPHALY SPECTRUM

Abstract

Objective: In this study, we aimed to evaluate six cases diagnosed with lissencephaly in terms of the genotype-phenotype correlation. Materials and Methods: Six cases with lissencephaly, which were followed up in our outpatient clinic, were included in the study. Two cases had lissencephaly and dysmorphic facial features, two cases had isolated lissencephaly, one case had subcortical band heterotopia, and one case had lissencephaly and cerebellar hypoplasia. Cytogenetic analysis (karyotyping and fluorescence in situ hybridization technique) and molecular tests (Sanger sequencing of the LIS1, DCX, and RELN genes) were selected according to genotype-phenotype correlation. Results: 17p13 deletions were detected in two cases (Case 1 and Case 2), and Miller-Dieker syndrome was diagnosed. In Cases 3 and 4 with posterior dominant isolated lissencephaly, sequencing of the LIS1 gene revealed heterozygous c.337C>T (p.Arg113Ter) and heterozygous c.946G>C (p.Asp317His) mutations, respectively. A heterozygous novel c.605_607delAGA (p.Lys202del) mutation in the DCX gene was found in a female case (Case 5) with subcortical band heterotopia. In Case 6 with lissencephaly accompanied by cerebellar hypoplasia, a homozygous c.204C>G (p.Tyr68Ter) novel variant was detected in the RELN gene. Conclusion: When the genotype-phenotype correlation approach was chosen for lissencephaly, clinical and radiological features helped in pinpointing the genetic mutations in cases of lissencephaly. In addition, the detection of two previously unreported variants that were predicted to be pathogenic in the DCX and RELN genes contributes to the genotype information associated with lissencephaly.

Keywords

lissencephaly, neuronal migration anomalies, Miller-Dieker syndrome

Project Number

3574

References

• 1. Dobyns WB, Guerrini R, Leventer RL. Malformations of cortical development. İn: Swaiman KF, Ashwal S, Ferriero DM, Schor NF, editors. Swaiman’s Pediatric Neurology: Principles and Practice. ed 5. Edinburgh: Elsevier Saunders; 2012. p. 202-31. google scholar
• 2. Di Donato N, Timms AE, Aldinger KA, Mirzaa GM, Bennett JT, Collins S, et al. Analysis of 17 genes detects mutations in 81% of 811 patients with lissencephaly. Genet Med 2018;20(11):1354-64. google scholar
• 3. Di Donato N, Chiari S, Mirzaa GM, Aldinger K, Parrini E, Olds C, et al. Lissencephaly: Expanded imaging and clinical classification. Am J Med Genet A 2017;173(6):1473-88. google scholar
• 4. Kars ME, Basak AN, Onat OE, Bilguvar K, Choi J, İtan Y, et al. The genetic structure of the Turkish population reveals high levels of variation and admixture. PNAS 2021;118 (36):e2026076118. doi. org/10.1073/pnas.202607611 google scholar
• 5. Dobyns WB, Elias ER, Newlin AC, Pagon RA, Ledbetter DH. Causal heterogeneity in isolated lissencephaly. Neurology 1992;42(7):1375-88. google scholar
• 6. Dobyns WB, Truwit CL, Ross ME, Matsumoto N, Pilz DT, Ledbetter DH, et al. Differences in the gyral pattern distinguish chromosome 17-linked and X-linked lissencephaly. Neurology 1999;53(2):270-7. google scholar
• 7. Kato M, Dobyns WB. Lissencephaly and the molecular basis of neuronal migration. Hum Mol Genet 2003;12 Spec No 1:R89-96. google scholar
• 8. Feng Y, Olson EC, Stukenberg PT, Flanagan LA, Kirschner MW, Walsh CA. LİS1 regulates CNS lamination by interacting with mNudE, a central component of the centrosome. Neuron 2000;28(3):665-79. google scholar
• 9. Reiner O, Carrozzo R, Shen Y, Wehnert M, Faustinella F, Dobyns WB, et al. İsolation of a Miller-Dieker lissencephaly gene containing G protein beta-subunit-like repeats. Nature 1993;364(6439):717-21. google scholar
• 10. Sicca F, Kelemen A, Genton P, et al. Mosaic mutations of the LİS1 gene cause subcortical band heterotopia. Neurology 2003;61(8):1042-6. google scholar
• 11. Saillour Y, Carion N, Quelin C, Leger PL, Boddaert N, Elie C, et al. LİS1-related isolated lissencephaly: spectrum of mutations and relationships with malformation severity. Arch Neurol 2009;66(8):1007-15. google scholar
• 12. Cardoso C, Leventer RJ, Matsumoto N, Kuc JA, Ramocki MB, Mewborn SK, et al. The location and type of mutation predict malformation severity in isolated lissencephaly caused by abnormalities within the LİS1 gene. Hum Mol Genet 2000;9(20):3019-28. google scholar
• 13. Mohan R, John A. Microtubule-associated proteins as direct crosslinkers of actin filaments and microtubules. İUBMB Life 2015;67(6):395-403. google scholar
• 14. des Portes V, Francis F, Pinard JM, Desguerre İ, Moutard ML, Snoeck İ, et al. Doublecortin is the major gene causing X-linked subcortical laminar heterotopia (SCLH). Hum Mol Genet 1998;7(7):1063-70. google scholar
• 15. Gleeson JG, Allen KM, Fox JW, Lamperti ED, Berkovic S, Scheffer İ, et al. Doublecortin, a brain-specific gene mutated in human X-linked lissencephaly and double cortex syndrome, encodes a putative signaling protein. Cell 1998;92(1):63-72. google scholar
• 16. Poretti A, Boltshauser E, Doherty D. Cerebellar hypoplasia: differential diagnosis and diagnostic approach. Am J Med Genet C Semin Med Genet 2014;166C(2):211-6. google scholar
• 17. Boycott KM, Bonnemann C, Herz J, Neuert S, Beaulieu C, Scott JN, et al. Mutations in VLDLR as a cause for autosomal recessive cerebellar ataxia with mental retardation (dysequilibrium syndrome). J Child Neurol 2009;24(10):1310-5. google scholar