Whole Genome Sequencing in the Detection of Rare Undiagnosed Genetic Diseases in Children in China

Study Overview
=================
Brief Summary
-----------------
To assess the indications and diagnostic efficiency of whole genome sequencing (WGS) in pediatric patients with unexplained intellectual disability/developmental delay, multiple congenital abnormalities and other rare and undiagnosed diseases

Detailed Description
-----------------
This project will recruit 100 rare, undiagnosed pediatric genetic disease families (core families: patients, patients' parents, immediate family members such as brothers and sisters, all of them can be enrolled whether they have disease or not, so generally 3, for a few cases 4 or 5) all over the country. The expert team will review the clinical materials, the molecular team will review the experimental process, and the bioinformatics team will review the chip, the analysis of whole exome sequencing data and screen the samples all over the country; Whole-genome sequencing of 100 rare, undiagnosed pediatric genetic disease families (Illumina NovaSeq High-throughput Sequencer); The study will provide preliminarily performance data on the comparison of whole exome data and whole genome data. In addition, it will generate the Chinese Consensus on Clinical Applications of Whole-genome sequencing in the Diagnosis of Birth Defects and Undiagnosed Rare Genetic Diseases in Children based on the statistical analysis of clinical phenotype and genotype association, which could guide the clinical application of pediatrics, laboratory testing and reporting. Construction of the Chinese detection genome database of genetic disease

Official Title
-----------------
Clinical Collaborative Research of Whole Genome Sequencing in the Detection of Rare Undiagnosed Genetic Diseases in Children in China

Conditions
-----------------
Intellectual Disability, Multiple Congenital Anomaly, Rare Diseases

Intervention / Treatment
-----------------
* Diagnostic Test: Whole genome sequencing


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Intelligence tests results of less than 40 (patients <3 years old using the Gesell Developmental Scale for screening; patients of 3-6 years old using Little Wechsler Intelligence Scale for screening; patients >6 years old using Old Wechsler Intelligence Scale for screening). Neurodevelopmental defects can be expressed as mental retardation, motor development retardation, language delay, epilepsy, etc. May have or not have Multiple congenital abnormalities, families with more than one affected patient will be enrolled priority Families went through at least one of the high throughput technology(WES or CMA) and receive the negative result Exclusion Criteria: Intellectual disability caused by pregnancy, perinatal infection, ischemia, and hypoxia and other non-hereditary causes, Obvious genetic metabolic diseases (such as different types of genetic metabolic diseases, bone disease, fragile X syndrome, etc.);

Ages Eligible for Study
-----------------
Maximum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Patients with unexplained DD/ID<br>Whole genome sequencing will be performed on pediatric patients with unexplained developmental delay(DD)/intellectual disability(ID), multiple congenital abnormalities and other rare and undiagnosed diseases. | Diagnostic Test: Whole genome sequencing<br>* WGS will be performed for the trio<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of diagnosed families | Families with rare and undiagnosed pediatric genetic disease will be benefitted by WGS. | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Numbers of pathogenic variants in different variation types | WGS would have the potential to detect different types of genetic alterations, such as structure variations, point mutation, small insertion/deletion, trinucleotide repeat, etc. Some types could not be identified by exome sequencing and chromosomal microarray. The numbers of the pathogenic variants in these types will be calculated to examine the benefit of WGS. | 1 year |