Rainbow Pedi 1000™ Whole Genome Sequencing Test

Introduction

Over 8,000 human diseases can be classified as monogenic/Mendelian disorders, and these conditions affect millions of people worldwide. Mendelian disorders also significantly contribute to morbidity and mortality of hospital-based pediatric cases. In fact, childhood Mendelian disorders account for approximately half of blindness, deafness, severe mental retardation cases, and 40-50% of childhood deaths.  

Majority of childhood neurological disorders have been shown to possess variable degrees of genetic heritability. In addition, an accurate genetic diagnosis is critical because increasing numbers of clinical therapeutics are gene mutation specific. Genomic testing provides a relatively-high diagnostic yield in selected patients with complex neurological disorders.

An early and accurate diagnosis not only helps physicians improve patient management and avoid unnecessary invasive procedures, it also alleviates distress in parents who can now plan for their children's future healthcare needs, including the quality of life of the affected children, in the context of social and communication development, behavior and learning.

Clinical tests based on whole genome sequencing have been demonstrated to be effective in identifying genetic causes of monogenic diseases. This complex diagnostic process allows the examination of 3 billion base pairs and approximately 20,000 genes, to improve the yield of diagnosis.

The Rainbow Whole Genome Sequencing test is designed for pediatric patients with clinical findings that suggest an underlying genetic etiology.

Examples of Conditions

• Developmental Delay

• Speech Delay

• Intellectual Disability

• Neurological Disorders including Epilepsy/Seizure

• Dysmorphic Features

• Congenital Heart Disease

• Congenital Eye Disorders

• Pediatric growth abnormalities such as

  • Tall/Short stature

  • Early Puberty

  • Abnormal Genital Morphology

• Hypo- or Hyper-Pigmentation

• Skeletal Abnormalities

• RASopathy

• Connective Tissue Disorders such as Ehlers-Danlos syndromes

• Congenital Hearing Loss

• Metabolic Disorders

Rainbow Pedi 1000™ Pediatric Care Test

Clinical whole genome sequencing is particularly useful for children with Mendelian disorders. This includes cases without a prior genetic syndrome from any family members. Often, these young patients went through multiple genetic and biochemical testing without obtaining a diagnosis, thus delaying the treatment of their conditions.

The Rainbow Pediatric Care test integrates multiple genomic technologies and bioinformatics platforms, with primary testing based on whole genome sequencing, to push for high diagnostic yield for pediatric patients affected by rare diseases, developmental, behavioral and neurological disorders. Suitable conditions include various developmental delays, behavioral disorders, movement abnormalities, epilepsy, autism, hypotonia, childhood-onset ataxia, and dysmorphic features, etc.

Proband vs. Trio sequencing

In pediatric cases, it has been shown that sequencing both parents in addition to sequencing the child (a trio) increases the yield of a diagnosis, particularly for cases where there were no prior family histories. One reason for the higher diagnostic rate is because of the successful identification of de novo and compound heterozygous mutations via trio sequencing. Rainbow Genomics recommends trio sequencing whenever possible.

Whole Genome Sequencing

Physician can choose from various options of whole genome sequencing, with singleton, duo or trio sequencing & clinical interpretation

• With its U.S., U.K. and Israeli technology partners, Rainbow offers whole genome sequencing coupled with a 1.6Kb high-resolution microarray as a standard test approach.

  • This initial test determines challenging mutations including copy number variants and large structural genetic changes.

  • RNA sequencing and Sanger sequencing with compelling informatics tools are used to determine variants not readily confirmed by whole genome sequencing alone, including intronic, mosaic and splice variants.

  • Long-read sequencing platforms are also used to further validate complex copy number variants.

  • The combination of these technologies enables the confirmation of novel variants detected in Asians and other minority populations, often without prior evidence from any international databases. Timely diagnosis can be achieved without lengthy sequential testing, a process often used by local hospitals.

Bioinformatics & Clinical Interpretation

• Multiple pipelines and interpretation platforms, including a range of analytics are used to improve the entire analysis and clinical interpretation process:

  • Advanced algorithms

  • Artificial intelligence

  • Natural language processors

  • Automated variant classification tools

References

• Case for genome sequencing in infants and children with rare, undiagnosed or genetic diseases. J Med Genet 2019; 56:783–791.

• Whole genome sequencing reveals that genetic conditions are frequent in intensively ill children. Intensive Care Med 2019; 45:627–636.

• Clinical genome sequencing in an unbiased pediatric cohort. Genetics in Medicine volume 21, pages 303–310; 2019.

• Outcome of Whole Exome Sequencing for Diagnostic Odyssey Cases of an Individualized Medicine Clinic: The Mayo Clinic Experience. Mayo Clin Proc. 2016 Mar;91(3):297-307

• A clinical utility study of exome sequencing versus conventional genetic testing in pediatric neurology. Genet Med. 2017 Sep;19(9):1055-1063.

• Diagnostic Yield of Whole Exome Sequencing in Pediatric Dilated Cardiomyopathy. J. Cardiovasc. Dev. Dis. 2017, 4, 11

• Diagnostic Impact and Cost-effectiveness of Whole-Exome Sequencing for Ambulant Children With Suspected Monogenic Conditions. JAMA Pediatr. 2017 Sep 1;171(9):855-862

• Clinical Exome Sequencing for Genetic Identification of Rare Mendelian Disorders. JAMA. 2014; 312(18):1880-1887.

• Molecular Findings Among Patients Referred for Clinical Whole-Exome Sequencing. JAMA. 2014 November 12;312(18): 1870–1879

• Recommendations for the integration of genomics into clinical practice. Genet Med. 2016 May 12

• The usefulness of whole-exome sequencing in routine clinical practice. Genetics in Medicine (2014) 16, 922–931