Warburg Mikro Sendromu ile İlişkili TBC1D20 Geninde Yeni Bir Mutasyon

Öz

Amaç: Warburg mikro sendromu (WARBM) RAB3GAP1, RAB3GAP2, RAB18 ve TBC1D20 genlerindeki mutasyonlara bağlı olarak nadir görülen otozomal resesif bir hastalıktır. Sendrom mikrosefali, konjenital katarakt ve mikrokornea gibi oküler bulgular, ağır entellektüel gerilik ve hipogonadizm ile karakterizedir. Olgu: Takipleri sırasında WARBM tanısı konulan 3 yaşında bir erkek çocuğu sunuyoruz. Hastanın genetik analiz sonuçları, TBC1D20 geninde ekzon 3’te patojenik ve WARBM 4 fenotipi ile korele olan bir homozigot mutasyonu (c.259_260delinsCAC; p. Lys87HisfsTer42) ortaya çıkardı. Ebeveynlerin mutasyonu heterozigot olarak taşıdığı gösterildi. Sonuç: WES analizi WARBM’li akraba bir Türk ailesinde TBC1D20 geninde muhtemel patojenik yeni bir mutasyon (c.259_260delinsCAC) gösterdi ve WARBM tanısını koymamızı sağladı.

Anahtar Kelimeler

• konjenital katarakt
• gen mutasyonu
• homozigot
• TBC1D20
• Warburg mikro sendromu
• Tüm ekzom dizileme.

A Novel Mutation in the TBC1D20 Gene with Associated Warburg Micro Syndrome

Öz

Aim: Warburg micro syndrome (WARBM) is a rare autosomal recessive disorder due to mutations in the RAB3GAP1, RAB3GAP2, RAB18, and TBC1D20 genes. The syndrome is characterized by microcephaly, ocular findings such as congenital cataract, microcornea, severe intellectual disability, and hypogonadism. Case: We present a 3-year-old boy who was diagnosed with WARBM during follow-up.The genetic analysis of the patient revealed a pathogenic mutation (c.259 260delinsCAC (p. Lys87HisfsTer42) in exon 3 of the TBC1D20 gene, which correlates with WARBM 4. Their parents were shown to carry the mutation heterozygously. Conclusion: The WES analysis of a consanguineous Turkish family with WARBM showed a novel mutation (c.259_260delinsCAC) in TBC1D20 gene that is most likely pathogenic and allowed us to make the diagnosis of WARBM.

Anahtar Kelimeler

• congenital cataracts
• gene mutation
• homozygous
• TBC1D20
• Warburg micro syndrome
• Whole exome sequencing.

Kaynakça

1. 1. McKusick, V. A. (2018). Online Mendelian Inheritance in Man, OMIM™. Johns Hopkins University: Baltimore. MIM Number:# 193700.
2. 2. Borck, G., Wunram, H., Steiert, A., Volk, A. E., Körber, F., Roters, S., ... & Kubisch, C. (2011). A homozygous RAB3GAP2 mutation causes Warburg Micro syndrome. Human genetics, 129(1), 45-50.
3. 3. Liegel, R. P., Handley, M. T., Ronchetti, A., Brown, S., Langemeyer, L., Linford, A., ... & Sidjanin, D. J. (2013). Loss-of-function mutations in TBC1D20 cause cataracts and male infertility in blind sterile mice and Warburg micro syndrome in humans. The American Journal of Human Genetics, 93(6), 1001-1014.
4. 4. Richards, S., Aziz, N., Bale, S., Bick, D., Das, S., Gastier-Foster, J., ... & Rehm, H. L. (2015). Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genetics in medicine, 17(5), 405-423.
5. 5. Morris-Rosendahl, D. J., Segel, R., Born, A. P., Conrad, C., Loeys, B., Brooks, S. S., ... & Faes, F. (2010). New RAB3GAP1 mutations in patients with Warburg Micro Syndrome from different ethnic backgrounds and a possible founder effect in the Danish. European Journal of Human Genetics, 18(10), 1100-1106.
6. 6. Warburg, M., Sjö, O., Fledelius, H. C., & Pedersen, S. A. (1993). Autosomal recesssive microcephaly, microcornea, congenital cataract, mental retardation, optic atrophy, and Hypogenitalism: micro syndrome. American Journal of Diseases of Children, 147(12), 1309-1312.
7. 7. Handley, M. T., Morris‐Rosendahl, D. J., Brown, S., Macdonald, F., Hardy, C., Bem, D., ... & Aligianis, I. A. (2013). Mutation Spectrum in RAB 3 GAP 1, RAB 3 GAP 2, and RAB 18 and Genotype–Phenotype Correlations in W arburg M icro Syndrome and M artsolf Syndrome. Human mutation, 34(5), 686-696.
8. 8. Xu, W., Plummer, L., Quinton, R., Swords, F., Crowley, W. F., Seminara, S. B., & Balasubramanian, R. (2020). Hypogonadotropic hypogonadism due to variants in RAB3GAP2: expanding the phenotypic and genotypic spectrum of Martsolf syndrome. Molecular Case Studies, 6(3), a005033.

9. 9. Hozhabri, H., Talebi, M., Mehrjardi, M. Y., De Luca, A., & Dehghani, M. (2020). Martsolf syndrome with novel mutation in the TBC1D20 gene in a family from Iran. American Journal of Medical Genetics Part A, 182(5), 957-961.
10. 10. Yildirim, M. S., Zamani, A. G., & Bozkurt, B. (2012). Warburg micro syndrome in two children from a highly inbred Turkish family. Genetic Counseling, 23(2), 169.
11. 11. Derbent, M., Agras, P. I., Gedik, Ş., Oto, S., Alehan, F., & Saatçi, Ü. (2004). Congenital cataract, microphthalmia, hypoplasia of corpus callosum and hypogenitalism: report and review of Micro syndrome. American Journal of Medical Genetics Part A, 128(3), 232-234.
12. 12. Abdel‐Hamid, M. S., Abdel‐Ghafar, S. F., Ismail, S. R., Desouky, L. M., Issa, M. Y., Effat, L. K., & Zaki, M. S. (2020). Micro and Martsolf syndromes in 34 new patients: Refining the phenotypic spectrum and further molecular insights. Clinical Genetics, 98(5), 445-456.