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Abstrak :
Mukopolisakaridosis (MPS) tipe VI adalah kelainan genetik langka berupa defisiensi enzim arylsulfatase B (ARSB) akibat kemunculan varian pathogenic gen ARSB. Gejala MPS tipe VI meliputi kornea berkabut, fitur wajah kasar, abnormalitas tulang dan persendian, serta kelainan saluran pernapasan dan pembengkakan organ. Diagnosis MPS tipe VI dilakukan dengan pengukuran aktivitas enzim serta konfirmasi melalui analisis varian gen ARSB. Varian gen pathogenic yang paling umum dilaporkan pada pasien MPS tipe VI terletak di rentang ekson 5—8, yaitu c.962T>C (p.Leu321Pro), c.1197C>G (p.Phe399Leu), dan beberapa varian pada asam amino Arg315 di ekson 5. Analisis varian gen ARSB belum pernah dilakukan di Indonesia walapun sudah ada pelaporan kasus MPS tipe VI. Tujuan dari analisis varian gen ARSB di Indonesia adalah mengidentifikasi dan mengklasifikasi varian gen ARSB serta mendapatkan profil genetik gen ARSB pada pasien MPS tipe VI di Indonesia. Analisis varian gen ARSB dilakukan pada dua pasien MPS tipe VI dan sepuluh individu normal sebagai kelompok kontrol menggunakan sekuensing Sanger. Penelitian tidak menemukan adanya varian pathogenic pada gen ARSB ekson 5—8 pasien MPS tipe VI. Penelitian berhasil menemukan varian benign c.1072G>A (p.Val358Met) pada ekson 5, c.1142+233C>T dan c.1143-27A>C pada intron 5, dan c.1337-32C>G pada intron 7 serta satu varian likely benign c.1213+149C>G pada intron 6 yang sudah pernah dilaporkan sebelumnya. Ditemukan juga satu varian novel c.1142+213C>T pada intron 5 dengan klasifikasi variant of uncertain significance. Penambahan individu dalam kelompok kontrol disarankan agar frekuensi alel dalam populasi lebih tercerminkan dengan baik. ......Mucopolysaccharidosis (MPS) type VI is a rare genetic disorder due to arylsulfatase B (ARSB) enzyme deficiency caused by the presence of pathogenic variant in ARSB ene. Clinical symptoms of MPS type VI are corneal clouding, coarse facial features, joint and skeletal abnormalities, respiratory problems, and enlarged organs. Diagnosis of MPS type VI is done by evaluating ARSB enzyme activity and is confirmed by ARSB gene analysis. The most commonly reported pathogenic variants in MPS type VI patients are located in exon 5—8, such as c.962T>C (p.Leu321Pro), c.1197C>G (p.Phe399Leu), dan numerous variants involving Arg315 at exon 5. Analysis of ARSB gene has not been done in Indonesia although one MPS type VI case has been reported. Analysis of ARSB gene in Indonesia is done to identify and classify the ARSB gene variants and to also obtain genetic profile of MPS type VI patients in Indonesia. The analysis is done to two MPS type VI patients along with ten normal individuals as control group using Sanger sequencing. This study has found no pathogenic variants in exon 5—8 of ARSB gene. This study have identified benign variants c.1072G>A (p.Val358Met) at exon 5, c.1142+233C>T and c.1143-27A>C at intron 5, and c.1337-32C>G at intron 7 along with one likely benign variant c.1213+149C>G at intron 6 which have been previously reported before. One novel variant c.1142+213C>T at intron 5 was also found and classified as variant of uncertain significance. A larger control group is advised to better reflect the allele frequency in population.

Abstrak :
Mukopolisakaridosis tipe VI (MPS tipe VI) merupakan gangguan metabolisme yang diakibatkan defisiensi aktivitas enzim pengolah glycosaminoglycan (GAG) jenis dermatan sulfat, yaitu arylsulfatase B (ARSB). Prevalensi MPS tipe VI di dunia tercatat dalam rentang 0,03—7,85 per 100.000 kelahiran. Gejala MPS tipe VI meliputi coarse facies, dysostosis multiplex, gangguan pendengaran, pernapasan, dan penglihatan, serta penebalan katup jantung, tetapi tidak disertai kelainan sistem saraf pusat. Varian pathogenic gen Arylsulfatase B (ARSB) pada ekson 1—4 telah dilaporkan sebagai pemicu manifestasi MPS tipe VI pada pasien dari berbagai belahan dunia, salah satunya dari Thailand. Laporan varian gen ARSB pada ekson 1—4 pasien MPS tipe VI di Indonesia belum ditemukan sehingga penelitian ini bertujuan mengidentifikasi dan mengklasifikasikan tingkat patogenisitas varian gen ARSB pada ekson 1—4 pasien MPS tipe VI di Indonesia. Gen ARSB dua pasien MPS tipe VI dan 10 individu normal diamplifikasi menggunakan polymerase chain reaction (PCR) dan disekuensing menggunakan metode Sanger. Patogenisitas varian gen ARSB yang teridentifikasi diklasifikasikan menurut panduan yang diterbitkan American College of Medical Genetics (ACMG). Identifikasi varian gen ARSB pada ekson 1—4 pasien MPS tipe VI di Indonesia berhasil dilakukan dengan temuan sejumlah delapan varian. Satu varian novel berhasil diklasifikasikan sebagai varian likely pathogenic, yaitu c.235_236delinsCC (p.Gly79Pro) yang ditemukan pada ekson 1 kedua pasien MPS tipe VI. Enam varian reported yang ditemukan pada intron 1 individu-individu normal berhasil diklasifikasikan sebagai varian likely benign, yaitu c.312+167G>A, c.312+229C>A, c.312+304C>T, c.313-81G>A, c.313-77G>A, dan c.313-26T>C. Satu varian reported yang ditemukan pada ekson 1 dua individu normal diklasifikasikan sebagai variant of uncertain significance (VUS), yaitu c.181G>A (p.Gly61Ser). Penelitian lebih lanjut yang melibatkan lebih banyak individu normal diperlukan untuk memperoleh data frekuensi alel kedelapan gen ARSB tersebut dalam populasi normal di Indonesia sehingga spesifisitas klasifikasi varian dapat meningkat menjadi varian pathogenic atau benign. ......Mucopolysaccharide type VI (MPS tipe VI) is a metabolic disorder caused by deficient activity of arylsulfatase B (ARSB) enzyme, which processes a type of glycosaminoglycan (GAG) known as dermatan sulfate. Worldwide prevalence of MPS tipe VI ranges from 0.03—7.85 per 100,000 live births. Symptoms of MPS tipe VI include coarse facies, dysostosis multiplex, eyes, lungs, and ears disorders, as well as valvular stenosis, but without central nervous system abnormalities. Pathogenic variants of Arylsulfatase B (ARSB) gene in exons 1—4 has been reported to cause MPS tipe VI manifestation in patients from multiple countries, including Thailand. No report of ARSB gene variants in exons 1—4 of Indonesian MPS tipe VI patients have been found. This study aims to identify and classify the pathogenicity of ARSB gene variants in exons 1—4 of Indonesian MPS tipe VI patients. ARSB gene of two patients and 10 healthy individuals were amplified using polymerase chain reaction (PCR) and Sanger sequenced. Pathogenicity of identified ARSB gene variants were classified according to the American College of Medical Genetics (ACMG) guidelines. Identification of ARSB gene variants in exons 1—4 of MPS type VI patients in Indonesia was successfully carried out with a finding of eight gene variants. A novel variant found in exon 1 of both MPS type VI patients was classified as a likely pathogenic, notated as c.235_236delinsCC (p.Gly79Pro). Six reported variants found in intron 1 of healthy individuals were classified as likely benign, each notated as c.312+167G>A, c.312+229C>A, c.312+304C>T, c.313-81G> A, c.313-77G>A, and c.313-26T>C. One reported variant found in exon 1 of two healthy individuals was classified as a variant of uncertain significance (VUS), notated as c.181G>A (p.Gly61Ser). Further research involving more healthy individuals is required to obtain frequency allele data of the eight ARSB gene variants in the Indonesian normal population, which supports the increase of each variant’s classification specificity into pathogenic or benign.