عنوان

استفاده از روش توالی‌یابی کل اگزوم (WES) در پنج خانواده‌ی ایرانی مبتلا به اسپاستیک پاراپلاژی ارثی (HSP) به منظور شناسایی واریانت‎های ژنی بیماری‎زا

Number

۳۴۹۵پ

.Language of Text, Soundtrack etc

فارسی

Title Proper

استفاده از روش توالی‌یابی کل اگزوم (WES) در پنج خانواده‌ی ایرانی مبتلا به اسپاستیک پاراپلاژی ارثی (HSP) به منظور شناسایی واریانت‎های ژنی بیماری‎زا

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[پایان نامه]

Parallel Title Proper

Introduction: Hereditary spastic paraplegia is a group of neurodegenerative disorders with lower limb spasticity and weakness at their core of clinical characteristics. Degeneration of long axons in the corticospinal tract is the main pathological driver of this disease. Given their clinical spectrum, patients are defined as “pure” or “complicated”; if they present symptoms regarding the pyramidal neural tracts, they belong to the first group and if they display other clinical symptoms, they belong to the latter group. A total of 87 loci and 76 disease-causing genes have been discovered as underlying cause of this disorder, so far, accountable for detection of around 50% of these patients. It is safe to assume that this disorder is genetically more heterogenous than it was expected. Therefore, this study was designed and conducted to identify disease-causing genes in five Iranian families affected by HSP in this center. Methods and materials: Using the Whole-Exome Sequencing (WES) method and broad range of bioinformatics tools, underlying cause of this disorder was investigated in five HSP-affected families. WES was accomplished via Illumina’s HiSeq4000 platform and raw sequencing data was processed and analyzed by an internal pipeline. Afterwards, the most probable variants explaining the highest correlation with clinical profile of patients were selected for the co-segregation analysis via Sanger sequencing. Results: Amongst all families, WES identified mutations in CAMTA1, ALS2, and RNASEH2B genes. The candidate variant in the CAMTA1 gene was a novel heterozygous variation, which requires further investigations. The two other mutations were in homozygous state, which were previously classified as pathogenic variants in literature. For two other families, despite checking two variants, none were definitive for onset of this disease. Discussion: In this study, WES managed to identify disease-causative variations in 60% of all examined families, which is in concordance with similar studies conducted in this and other centers for this disorder. It was concluded that HSP patients shows clinical and genetic overlaps with patients of other conditions, namely amyotrophic lateral sclerosis (ALS) and Aicardi-Goutieres syndrome-type II (AGS-II), in whom mutations in the ALS2 and RNASEH2B genes are underlying causes, respectively. Keywords: hereditary spastic paraplegia, whole-exome sequencing (WES), Sanger sequencing, pyramidal tract abnormality, disease-causative variation

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علوم توان بخشی و سلامت اجتماعیUniversity of Social Walfare and Rehabilitation

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۱۴۰۱

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۱۳۷ص.

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پیوست

Dissertation or thesis details and type of degree

19

Discipline of degree

6

Date of degree

۱۴۰۱/۰۸/۲۲

Text of Note

مقدمه: بیماری اسپاستیک پاراپلاژی ارثی (HSP) گروهی از بیماری‌های تحلیل برنده‌ی سیستم عصبی هستند که شاخصه اصلی بالینی آنها، انقباض و ضعف پیشرونده‌ی عضلات اندام‌های تحتانی است. تحلیل آکسون‌های بلند در مسیر قشری-نخاعی (corticospinal tract) علت اصلی بیماریزایی است. این بیماری بر اساس علائم بالینی، به دو دسته‌ی خالص و پیچیده طبقه‌بندی می‌شود. بیماران دسته اول فقط اختلالات مربوط به اعصاب هرمی (pyramidal nerves) و بیماران دسته دوم علاوه بر این درگیری‌ها، علائم متنوعی را بروز می‌دهند. تا به حال، 87 لوکوس و 76 ژن عامل این بیماری شناسایی شده است که قادر به توجیه فنوتیپِ حدود نیمی از بیماران می‌باشند که بیانگر تنوع ژنتیکی بالای این بیماری می‌باشد. این پروژه در راستای شناسایی ژن‌های عامل بیماری در پنج خانواده‌ی ایرانی مبتلا به HSP، تعریف و در این مرکز اجرا گردید.روش کار: با استفاده از توالی‌یابی کل اگزوم (WES) و ابزارهای بیوانفورماتیکی، به جستجوی علت بیماری در پنج خانواده‌ی مبتلا به HSP پرداخته شد. با استفاده از دستگاه HiSeq4000 شرکت Illumina صورت گرفت و اطلاعات خام توالی‌های بیماران، با استفاده از چهارچوب آنالیزی داخلی، آنالیز شد و واریانت‌هایی که بیشترین همخوانی را با فنوتیپ بیماران داشتند، برای مطالعه co-segregation کاندید و با توالی‌یابی سنگر بررسی شدند. نتایج: واریانت‌های بیماری‌زا در در ژن‌های CAMTA1، ALS2 و RNASEH2B، در سه خانواده شناسایی شد. واریانت CAMTA1 یک واریانت هتروزیگوسِ جدید (novel heterozygous) بود و لذا به عنوان یک واریانت احتمالی مطرح است که باید با مطالعات بیشتر تایید گردد. واریانت‌های هوموزیگوس(homozygous) ALS2 و RNASEH2B قبلا گزارش شده بودند و به صورت پاتوژنیک طبقه‌بندی می‎شدند. در باقیِ خانواده‌ها چند واریانت بررسی گردید که تایید نشدند.نتیجه‌گیری: در این مطالعه با بکارگیری WES، واریانت عامل بیماری در 60% خانواده‌هایِ مورد بررسی شناسایی گردید که مشابه نتایج سایر بررسی‌های صورت گرفته بر روی بیماری HSP در این مرکز و سایر کوهورت‌ها است. همپوشانی ژنتیکی و بالینیِ بیماران با سایر بیماری‌ها مشاهده گردید. برای مثال، جهش‎های ALS2 و RNASEH2B که به ترتیب با بیماری‌های amyotrophic lateral sclerosis (ALS) و Aicardi-Goutieres syndrome-type II (AGS-II) همراه می‌باشند، در بیماران این مطالعه شناسایی شد. کلید واژه‌ها: اسپاستیک پاراپلاژی ارثی، توالی‎یابی کل اگزوم (WES)، توالی‌یابی سنگر، اختلال اعصاب پیرامیدال، واریانت بیماریزا

Text of Note

Introduction: Hereditary spastic paraplegia is a group of neurodegenerative disorders with lower limb spasticity and weakness at their core of clinical characteristics. Degeneration of long axons in the corticospinal tract is the main pathological driver of this disease. Given their clinical spectrum, patients are defined as “pure” or “complicated”; if they present symptoms regarding the pyramidal neural tracts, they belong to the first group and if they display other clinical symptoms, they belong to the latter group. A total of 87 loci and 76 disease-causing genes have been discovered as underlying cause of this disorder, so far, accountable for detection of around 50% of these patients. It is safe to assume that this disorder is genetically more heterogenous than it was expected. Therefore, this study was designed and conducted to identify disease-causing genes in five Iranian families affected by HSP in this center.Methods and materials: Using the Whole-Exome Sequencing (WES) method and broad range of bioinformatics tools, underlying cause of this disorder was investigated in five HSP-affected families. WES was accomplished via Illumina’s HiSeq4000 platform and raw sequencing data was processed and analyzed by an internal pipeline. Afterwards, the most probable variants explaining the highest correlation with clinical profile of patients were selected for the co-segregation analysis via Sanger sequencing.Results: Amongst all families, WES identified mutations in CAMTA1, ALS2, and RNASEH2B genes. The candidate variant in the CAMTA1 gene was a novel heterozygous variation, which requires further investigations. The two other mutations were in homozygous state, which were previously classified as pathogenic variants in literature. For two other families, despite checking two variants, none were definitive for onset of this disease.Discussion: In this study, WES managed to identify disease-causative variations in 60% of all examined families, which is in concordance with similar studies conducted in this and other centers for this disorder. It was concluded that HSP patients shows clinical and genetic overlaps with patients of other conditions, namely amyotrophic lateral sclerosis (ALS) and Aicardi-Goutieres syndrome-type II (AGS-II), in whom mutations in the ALS2 and RNASEH2B genes are underlying causes, respectively.Keywords: hereditary spastic paraplegia, whole-exome sequencing (WES), Sanger sequencing, pyramidal tract abnormality, disease-causative variation

اسپاستیک پاراپلاژی ارثی

, pyramidal tract abnormality

دانایی فرد، فرداد

Danae, fard, Fardad

علوی، آفاق

Country

ایران

Agency

دانشگاه علوم توان بخشی و سلامت اجتماعی

Date of Transaction

20221123

D

TF

279226

a

Y