Clinical, Radiological, and Molecular Findings in Cases with TRAPPopathies

Year 2023, Volume: 23 Issue: 3, 203 - 209, 24.10.2023

Ayça Dilruba Aslanger Esma Şengenç Emrah Yücesan Beyza Göncü Akın İşcan Gözde Yeşil Sayın

https://doi.org/10.26650/jchild.2023.1294229

Abstract

Objective: Pathologies occurring in Transport Protein Particles (TRAPP) involved in vesicular traffic are rare diseases called TRAPPopathies. The aim of this study was to present a case series of TRAPPopathies, to describe the clinical and molecular findings, and additionally to review our cases together with other cases reported from Turkiye.
Materials and Methods: Patients with neurological findings such as microcephaly, epilepsy, muscular dystrophy, and intellectual disability who were referred to Bezmialem Vakıf University, Faculty of Medicine, Department of Medical Genetics between March 2018 and March 2020 were reviewed for this study. Patients with pathogenic variants in genes with TRAPP complex family with known phenotype or not yet associated any human disease were included in the study. Clinical, radiological, and molecular findings obtained by whole exome sequences of cases were re-evaluated.
Results: Molecular analysis revealed homozygous c.454+3A>G p.(?) variant in TRAPPC4 (NM_016146.5) gene in Case 1 with neuromotor retardation, intractable seizures, postnatal microcephaly, and cerebralcerebellar atrophy, homozygous novel c.57C>G p.(Try19Ter) variant in TRAPPC6B (NM_001079537.1) in Case 2 with epilepsy, postnatal microcephaly, severe neuromotor retardation, and autism, and homozygous c.2938G>A p.(Gly980Arg) variant in TRAPPC11 (NM_021942.5) gene in Case 3 with muscular dystrophy, cataract, neuromotor retardation, and microcephaly.
Conclusion: This study showed that newly identified genes in TRAPPopathies are responsible for microcephaly, developmental delay, epilepsy, intellectual disability, cerebral-cerebellar atrophy, and autism. Although the genes in the TRAPP family work independently of each other, the diseases in this group are called TRAPPopathies because their phenotypes overlap. The aim of our study was to discuss the clinical findings and to summarize the mutation profile of the genes in the TRAPP family in Turkiye.

Keywords

Microcephaly, rare diseases, TRAPPopathies

TRAPPopatili Olgularda Klinik, Radyolojik ve Moleküler Bulgular

Abstract

Amaç: Vezikül trafiği ile ilişkili Taşıyıcı Protein Parçacıklarında (TRAPP) meydana gelen patolojiler TRAPPopatiler olarak adlandırılan nadir hastalıklardır. Bu çalışmanın amacı, bir TRAPPopati vaka serisini sunmak, klinik ve moleküler bulguları tanımlamak ve ayrıca vakalarımızı Türkiye’den bildirilen diğer vakalarla birlikte gözden geçirmektir.
Gereç ve Yöntem: Mart 2018-Mart 2020 tarihleri arasında Bezmialem Vakıf Üniversitesi Tıp Fakültesi, Tıbbi Genetik Anabilim Dalı’na sevk edilen mikrosefali, epilepsi, kas distrofisi ve zihinsel yetersizlik gibi nörolojik bulguları olan olgular bu çalışma için gözden geçirildi. Fenotipi bilinen veya henüz herhangi bir insan hastalığı ile ilişkili olmayan TRAPP kompleks familyasına sahip genlerde patojenik varyantları olan hastalar çalışmaya dahil edildi. Klinik, radyolojik ve tüm ekzom dizilerinden elde edilen moleküler bulgular yeniden değerlendirildi.
Bulgular: Nöromotor retardasyon, nöbet, postnatal mikrosefali ve serebral-serebellar atrofili Olgu 1’de TRAPPC4 geninde (NM_016146.5) homozigot c.454+3A>G p.(?) varyantı, epilepsi, postnatal mikrosefali, nöromotor retardasyon ve otizmi olan Olgu 2’de TRAPPC6B geninde (NM_001079537.1) homozigot daha önce bildirilmemiş yeni c.57C>G p.(Try19Ter) varyantı ile musküler distrofi, katarakt, nöromotor retardasyon and mikrosefalili Olgu 3’te TRAPPC11 geninde (NM_021942.5) homozigot c.2938G>A p. (Gly980Arg) varyantı saptandı.
Sonuç: Bu çalışma, TRAPPopatilerde yeni tanımlanan genlerin mikrosefali, gelişimsel gecikme, epilepsi, zihinsel yetersizlik, serebral-serebellar atrofi ve otizm bulgularından sorumlu olduğunu göstermiştir. TRAPP ailesindeki genler birbirinden bağımsız çalışsa da bu gruptaki hastalıklara fenotipleri örtüştüğü için TRAPPopatiler adı verilir. Çalışmamızda klinik bulguların tartışılması ve Türkiye’deki TRAPP ailesindeki genlerin mutasyon profilinin özetlenmesi amaçlanmıştır.

Keywords

Mikrosefali, TRAPPopati, nadir hastalıklar

References

• Garda-Cazorla A, Oyarzabal A, Saudubray JM, Martinelli D, Dionisi-Vici C. Genetic disorders of cellular trafficking. Trends Genet 2022;38(7):724-51. google scholar
• Sacher M, Kim YG, Lavie A, Oh BH, Segev N. The TRAPP complex: insights into its architecture and function. Traffic 2008;9(12):2032-42. google scholar
• Scrivens PJ, Noueihed B, Shahrzad N, Hul S, Brunet S, Sacher M. C4orf41 and TTC-15 are mammalian TRAPP components with a role at an early stage in ER-to-Golgi trafficking. Mol Biol Cell 2011;22(12):2083-93. google scholar
• Sacher M, Shahrzad N, Kamel H, Milev MP. TRAPPopathies: an emerging set of disorders linked to variations in the genes encoding transport protein particle (TRAPP)-associated proteins. Traffic 2019;20(01):5—26. google scholar
• Van Bergen NJ, Guo Y, Al-Deri N, Lipatova Z, Stanga D, Zhao S, et al. Deficiencies in vesicular transport mediated by TRAPPC4 are associated with severe syndromic intellectual disability. Brain 2020;143(1):112-30. google scholar
• Ghosh SG, Scala M, Beetz C, Helman G, Stanley V, Yang X, et al. A relatively common homozygous TRAPPC4 splicing variant is associated with an early-infantile neurodegenerative syndrome. Eur J Hum Genet 2021;29(2):271-79. google scholar
• Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. ACMG Laboratory Quality Assurance Committee. 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. Genet Med 2015;17(5):405-24. google scholar
• Stanga D, Zhao Q, Milev MP, Saint-Dic D, Jimenez-Mallebrera C, Sacher M. TRAPPC11 functions in autophagy by recruiting ATG2B-WIPI4/WDR45 to preautophagosomal membranes. Traffic 2019;20(5):325-45. google scholar
• Lamb CA, Nühlen S, Judith D, Frith D, Snijders AP, Behrends C, Tooze SA. TBC1D14 regulates autophagy via the TRAPP complex and ATG9 traffic. EMBO J 2016;35(3):281-301. google scholar
• Behrends C, Sowa ME, Gygi SP, Harper JW. Network organization of the human autophagy system. Nature 2010;466(7302):68-76. google scholar
• Olmez A, Zeybek S. Severe Microcephaly and Rapid Deterioration Due to Cortical Atrophy in Early Infancy: Consider TRAPPC4 Trappopathy. Ann Indian Acad Neurol 2022;25(4):735-8. google scholar
• Majethia P, Do Rosario MC, Kaur P, Karanvir, Shankar R, Sharma S, et al. Further evidence of muscle involvement in neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy. Ann Hum Genet 2022;86(2):94-101. google scholar
• Kümmel D, Müller JJ, Roske Y, Misselwitz R, Büssow K, Heinemann U. The structure of the TRAPP subunit TPC6 suggests a model for a TRAPP subcomplex. EMBO Rep 2005;6(8):787-93. google scholar
• Marin-Valencia I, Novarino G, Johansen A, Rosti B, Issa MY, Musaev D, et al. A homozygous founder mutation in TRAPPC6B associates with a neurodevelopmental disorder characterised by microcephaly, epilepsy and autistic features. J Med Genet 2018;55(1):48-54. google scholar
• Bögershausen N, Shahrzad N, Chong JX, von Kleist-Retzow JC, Stanga D, Li Y, et al. Recessive TRAPPC11 mutations cause a disease spectrum of limb girdle muscular dystrophy and myopathy with movement disorder and intellectual disability. Am J Hum Genet 2013;93(1):181-90. google scholar
• Koehler K, Milev MP, Prematilake K, Reschke F, Kutzner S, Jühlen R, et al. A novel TRAPPC11 mutation in two Turkish families associated with cerebral atrophy, global retardation, scoliosis, achalasia and alacrima. J Med Genet 2017;54(3):176-85. google scholar
• Aslanger AD, Demiral E, Sonmez-Sahin S, Guler S, Goncu B, Yucesan E, et al. Expanding Clinical Phenotype of TRAPPC12-Related Childhood Encephalopathy: Two Cases and Review of Literature. Neuropediatrics 2020;51(6):430-4. google scholar
• Aslanger AD, Goncu B, Duzenli OF, Yucesan E, Sengenc E, Yesil G. Biallelic loss of TRAPPC9 function links vesicle trafficking pathway to autosomal recessive intellectual disability. J Hum Genet 2022;67(5):279-84. google scholar
• Bolat H, Ünsel-Bolat G, Derin H, Şen A, Ceylaner S. Distinct Autism Spectrum Disorder Phenotype and Hand-Flapping Stereotypes: Two Siblings with Novel Homozygous Mutation in TRAPPC9 Gene and Literature Review. Mol Syndromol 2022;13(4):263-269. d google scholar
• Rawlins LE, Almousa H, Khan S, Collins SC, Milev MP, Leslie J, et al. Biallelic variants in TRAPPC10 cause a microcephalic TRAPPopathy disorder in humans and mice. PLoS Genet 2022;18(3):e1010114. google scholar
• Mohamoud HS, Ahmed S, Jelani M, Alrayes N, Childs K, Vadgama N, et al. A missense mutation in TRAPPC6A leads to build-up of the protein, in patients with a neurodevelopmental syndrome and dysmorphic features. Sci Rep 2018;8(1):2053. google scholar