Идёт набор NCT06796751

PREcision Diagnostics in Rare genetIC Diseases and Tumors - Long Read Sequencing

— Наблюдательное Whole Exome Sequencing Rare Diseases

Ориентир для пациента и семьи

Простыми словами

Автоматическая сводка по структурированным данным реестра. Она помогает сориентироваться, но не заменяет официальный протокол или оценку врача.

Что изучают: В протоколе указаны: DNA/RNA sequencing and bioinformatic data analysis.
Кому может быть актуально: Состояния в реестре: Whole Exome Sequencing, Rare Diseases. Базовые параметры: от 28 Days · Все.
Что важно проверить: Возраст, диагноз и пол — только базовые ориентиры. Предыдущее лечение, анализы и другие обязательные условия указаны ниже в критериях участия.
Где проводится: Италия
Следующий шаг: Сохраните исследование, покажите его лечащему врачу и уточните актуальный статус у исследовательского центра. Расходы, документы и поездка →

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Обзор

Using long-read sequencing (LRS) technology to achieve molecular diagnosis in patients with rare genetic diseases who have already been tested by state-of-the-art genetic analysis with ambiguous or negative results. This will lead to efficient and reliable identification and clinical interpretation of cryptic and complex structural genomic variants, which represent the central challenge for the coming decades in human genetics.

Подробное описание

The application of LRS to a diagnostic setting could have an impact on detection rate and diagnostic yield, leading to a better understanding of the etiology, prognosis and recurrence risk of rare genetic diseases (RGD), but also to a targeted treatment. One of the main benefits of LRS is the detection of balanced and unbalanced structural variants (SVs), including complex rearrangements, with high sensitivity and accuracy, through reliable alignment and precise breakpoint definition.

Among the main challenges of modern genetics, are identified 4 subgroups of patients that would benefit from the application of LRS to better characterize the genetic diagnosis and disease mechanisms.

* The first subgroup of patients are those with SVs of unknown significance or uncertain disease mechanism. In particular, clinical interpretation of duplications is challenging, due to the inability of Array Comparative Genomic Hybridization (aCGH) to detect whether they occur in tandem or are duplicated and inserted elsewhere in the genome, thus possibly disrupting genes involved in the duplication or altering their regulation. * Other complex rearrangements can be studied with LRS to gain a better understanding of the molecular mechanisms of pathogenicity. A better definition of complex SVs, together with an accurate description of the phenotype, will allow the genotype-phenotype correlation to be determined. * A third subgroup of patients eligible for the study are those with identified monoallelic alteration in autosomal recessive (AR) genes. The aim is to conduct a targeted analysis of the specific gene in order to look for a second mutation that wasn't detected by previous analysis (i.e. intronic variants, SVs, variants in difficult genomic regions). * Lastly, patients with a phenotype that is strongly suggestive for a genetic condition, in whom several analyses, including Whole Exome-Sequencing (WES), retrieved negative results, could benefit from LRS. In this context, the aim is to apply a whole genome LRS approach to identify missed coding variants in difficult-to-sequence regions, variants in non-coding regions or SVs.

Вмешательства

Генная терапия DNA/RNA sequencing and bioinformatic data analysis
DNA will be extracted from peripheral blood or from somatic tissues. In some cases a skin biopsy will be performed to obtain fibroblasts for further analysis (DNA/RNA extraction and preparation of cell culture for high-throughput genomic and epigenomic technique (Hi-C). LRS will be performed on extracted DNA using Oxford Nanopore Technology by two different approaches: * Target, in samples with monoallelic alterations in genes related to autosomal recessive disease; * Genomic in other cases.

Первичные конечные точки

The first aim of this study is to use LRS to reach a molecular diagnosis in patients with RGD that were already tested with state-of-the-art genetic analysis, with ambiguous or negative results. [Срок оценки: 10 months]

Вторичные конечные точки (1)

The secondary objective of this study is to analyze with a multi-omics approach, through the integration of other technologies supporting LRS (e.g. Hi-C, RNAseq), cases of particular complexity in which the molecular causative mechanism of the phenotype [Срок оценки: 10 months]

Критерии участия

Критерии включения

patients/relatives of patients with Copy Number Variations (CNVs), previously detected by aCGH, with uncertain clinical significance;
patients/relatives of patients with inconclusive WES and aCGH data (no pathogenic/likely pathogenic variant);
patients/relatives of patients with a known single hit (a pathogenic or likely pathogenic variant) in an AR gene detected with WES or aCGH;
patients/relatives of patients with a finding of complex structural variants whose molecular disease mechanism is to be elucidated.