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4-in-1 Genetic Screening

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 Condition Description  Indications
 Detection  References

 

Condition Description

Individuals have been reported to be carrier of one or more founder mutations, each associated with a specific inherited disease. Such founder mutations are known to contribute to a higher risk and prevalence of genetic disorders in a particular population (Agarwal/Agrawal community). 4-in-1 panel test for founder mutations associated with following diseases:

Limb-Girdle Muscular Dystrophy (LGMD) is a descriptive term applied to a clinically and genetically heterogeneous group of childhood or adult onset muscular dystrophies. Individuals with LGMD in general, have elevated serum creatine kinase (CK) levels and an abnormal muscle biopsy with dystrophic changes. The average age of onset of LGMD is 8-15 years. LGMD2A is a subtype of LGMDs which is also referred to as calpainopathy. It is an autosomal recessive disease caused by pathogenic variants in the CAPN3 gene and is one of the most frequent forms of LGMD. Megalencephalic Leukoencephalopathy (MLC) with subcortical cysts is a progressive condition that affects brain development and function. A distinct clinical syndrome characterized by megalencephaly, mild to moderate cognitive decline, slowly progressive spasticity, ataxia, occasional seizures, and extensive white matter changes with temporal cysts by imaging studies has been described in a particular ethnic group in India.  the MLC1 gene.

Heme Oxygenase-1 (HO-1) Deficiency (HMOX1D) is characterized by inadequate expression or functioning of the Heme oxygenase-1 (HO-1) enzyme. HO-1 is a stress-induced enzyme that catalyzes the oxidation of heme to biliverdin. The clinical presentation of HMOX1D includes growth delay, anaemia, leukocytosis, thrombocytosis, coagulation abnormality and hyperlipidemia. Pathogenic variants in the HMOX1 gene cause HMOX1D.

Hallervorden-Spatz Disease (HSD) is an autosomal recessive inherited neurodegenerative disorder with an onset at late childhood or early adolescence. HSD is characterized by progressive dementia, spasticity, rigidity, dystonia, choreoathetosis and pigmentary retinopathy. Pathogenic variants PANK2 gene cause HSD.

Genes (4)

CAPN3, MLC1, HMOX1, PANK2

This test is appropriate for:

Confirmation of a clinical diagnosis of LGMD2A, MLC, HO-1 deficiency or HSD in individuals of Agarwal/Agrawal community

Carrier testing in individuals of Agarwal/ Agrawal community who may or may not have a family history of LGMD2A, MLC, HO-1 deficiency or HSD.

Methodology

Sanger Sequencing:  Genomic regions of the four genes, CAPN3, MLC1, HMOX1, PANK2, containing the targeted founder mutations are amplified by polymerase chain reaction (PCR) using the patient’s DNA. Sequencing of PCR amplification products is performed bi-directionally for mutation detection.

Detection

  • Clinical Sensitivity:The actual contribution of these founder mutations to disease prevalence is unknown; however based on current reports this may range from 50% to 100% for each of them.
  • Pathogenic variants in regions other than the targeted area will not be detected by this test.
  • For patients in whom mutations are not identified are suggested to go for full gene and/or deletion/duplication analysis by Next Generation Sequencing/Microarray.

Specimen Requirements

  • Type: EDTA Whole Blood; Infants upto (2 years): 1-2 ml blood; Children & Adults: 3-5 ml blood 
  • Specimen Collection and Shipping: Refrigerate until time of shipment. Ship the sample at 4-8°C.

Special Instructions

  • Patient’s consent form should be submitted along with the samples.
  • When available, physicians are requested to forward patient’s biochemical or other related diagnostic test results.
  • * TAT applicable from the date of receipt of sample at ECGI