ORPHAN DISEASE GENOMICS

ORPHAN DISEASE GENOMICS

There are over 8000 Rare or Orphan diseases and about 85% of them are genetic in nature. The low incidence and prevalence of these diseases present significant challenges to improving diagnostics and treatments. The current ‘gold standard’ of molecular genetics diagnostics employing Sanger Sequencing remains the test for choice for clinical genetic testing but it suffers from the following limitations:-

  • Not cost effective.
  • Laborious and time consuming.
  • Inefficient when multiple possible disease causative genes need to be sequenced. Eg:- mutations in 14 different genes have been implicated in Bardet-Biedl syndrome.
  • Critical reliance on syndrome recognition at the start of the process, and this may be difficult or impossible where features are atypical or mild.
  • The precise molecular basis of many genetic syndromes is currently unknown, and up to half of the patients currently receive no molecular diagnosis.


  • Next generation Sequencing based technologies now promises to transform the laboratory diagnosis of genetic disease. Indeed these technologies have already begun to demonstrate their transformational potential in elucidating novel genetic defects underlying human disease, with subsequent major benefits to clinical diagnostics and care once research findings are translated into clinical tests. NGS now allows researchers to take an unbiased approach to gene discovery, and thus to look for ‘unknown unknowns’.

    Why NGS for rare diseases?

    For patients – Accurate diagnosis even if there is no prescribed current therapy for the disease gives a closure to the patient’s family. Better prognosis with ancillary therapies and palliative care can help patient lead a normal life in cases wherever possible. It also gives the parents the opportunity for future family planning options and in utero genetic testing with help of CVS or amniocentesis.

    For Doctors – If therapies available, then after proper clinical diagnosis, the clinician can adjust treatment. Eg:- Patient with seizures, intellectual disability and extensive white matter damage was diagnosed with homozygous mutation in FOLR1 gene which leads to ‘cerebral folate transporter deficiency’. Improved seizure control was achieved using Folinic acid.

    Leucine Rich Bio’s robust platform (AGIS) is a powerful tool for diagnosis of Genetic and Mendelian Disorders. We provide comprehensive reports on the causative genetic variants. Our proprietary ranking algorithm help rank the variants that can help narrow down the causative genetic mutation.
    Pathologic interpretation follows the ACMG guidelines for reporting sequencing variants which stratify variants as follows:

    Category 1 (Known Mutations): Previously reported variants recognized as pathogenic.

    Category 2: Previously unreported variants that are of a type expected to cause the disorder (frame shifts, nonsense, disruption of ATG or normal stop codon, splice junction mutations or deletion of one or more exons to shift reading frame).

    Category 3: Previously unreported variants that are of a type that may or may not be pathogenic (cryptic splice site mutations, in-frame amino acid insertion/deletion, in-frame exon deletion or any missense mutation);

    Category 4: Previously unreported variants that are unlikely to be disease causing. They include synonymous or intronic variants unlikely to affect splicing. Recognized neutral variants will not be reported.

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