Ayça Dilruba ASLANGER, Oya UYGUNER, Birsen KARAMAN, Seher BAŞARAN, Hülya KAYSERİLİ

LİZENSEFALİ SPEKTRUMU OLGULARINDA GENOTİP-FENOTİP İLİŞKİSİ

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.

Anahtar Kelimeler:

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

GENOTYPE-PHENOTYPE CORRELATION IN CASES WITH LISSENCEPHALY SPECTRUM

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,

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