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Development, validation and application of single molecule molecular inversion probe based novel integrated genetic screening method for 29 common lysosomal storage disorders in India.
Sheth, Harsh; Nair, Aadhira; Bhavsar, Riddhi; Kamate, Mahesh; Gowda, Vykuntaraju K; Bavdekar, Ashish; Kadam, Sandeep; Nampoothiri, Sheela; Panigrahi, Inusha; Kaur, Anupriya; Shah, Siddharth; Mehta, Sanjeev; Jagadeesan, Sujatha; Suresh, Indrani; Kapoor, Seema; Bajaj, Shruti; Devi, Radha Rama; Prajapati, Ashka; Godbole, Koumudi; Patel, Harsh; Luhar, Zulfiqar; Shah, Raju C; Iyer, Anand; Bijarnia, Sunita; Puri, Ratna; Muranjan, Mamta; Shah, Ami; Magar, Suvarna; Gupta, Neerja; Tayade, Naresh; Gandhi, Ajit; Sowani, Ajit; Kale, Shrutikaa; Jalan, Anil; Solanki, Dhaval; Dalal, Ashwin; Mane, Shrikant; Prabha, C Ratna; Sheth, Frenny; Joshi, Chaitanya G; Joshi, Madhvi; Sheth, Jayesh.
Affiliation
  • Sheth H; FRIGE Institute of Human Genetics, FRIGE House, Jodhpur Village Road, Satellite, Ahmedabad, India, 380015. harsh.sheth@frige.co.in.
  • Nair A; FRIGE Institute of Human Genetics, FRIGE House, Jodhpur Village Road, Satellite, Ahmedabad, India, 380015.
  • Bhavsar R; FRIGE Institute of Human Genetics, FRIGE House, Jodhpur Village Road, Satellite, Ahmedabad, India, 380015.
  • Kamate M; KLES Prabhakar Kore Hospital, Belgaum, Karnataka, India.
  • Gowda VK; Department of Pediatric Neurology, Indira Gandhi Institute of Child Health, Bangalore, India.
  • Bavdekar A; Department of Pediatrics, K.E.M Hospital, Pune, India.
  • Kadam S; Department of Pediatrics, K.E.M Hospital, Pune, India.
  • Nampoothiri S; Department of Paediatrics, Amrita School of Medicine, Kochi, India.
  • Panigrahi I; Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.
  • Kaur A; Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.
  • Shah S; Royal Institute of Child Neurosciences, Vastrapur, Ahmedabad, India.
  • Mehta S; Royal Institute of Child Neurosciences, Vastrapur, Ahmedabad, India.
  • Jagadeesan S; Department of Clinical Genetics and Genetic Counselling, Mediscan Systems, Chennai, India.
  • Suresh I; Department of Clinical Genetics and Genetic Counselling, Mediscan Systems, Chennai, India.
  • Kapoor S; Division of Genetics and Metabolism Department of Pediatrics, Lok Nayak Hospital and Maulana Azad Medical College, New Delhi, India.
  • Bajaj S; The Purple Gene Clinic, Simplex Khushaangan, SV Road, Malad West, Mumbai, India.
  • Devi RR; Rainbow Children's Hospital, Hyderabad, India.
  • Prajapati A; Genetic Care Clinic, Ahmedabad, India.
  • Godbole K; Deenanath Mangeshkar Hospital &Amp; Research Centre, Pune, India.
  • Patel H; Zydus Hospital & Healthcare Research Pvt Ltd, Ahmedabad, India.
  • Luhar Z; Civil Hospital, Asarwa, Ahmedabad, India.
  • Shah RC; Ankur Institute of Child Health, Ahmedabad, India.
  • Iyer A; Neurokids Clinic, Ahmedabad, India.
  • Bijarnia S; Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi, India.
  • Puri R; Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi, India.
  • Muranjan M; Department of Paediatrics, KEM Hospital, Parel, Mumbai, India.
  • Shah A; BJ Wadia Hospital for Children, Parel, Mumbai, India.
  • Magar S; MGM Medical College, Aurangabad, India.
  • Gupta N; Division of Genetics, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India.
  • Tayade N; Department of Pediatrics, Dr. Panjabrao Deshmukh Memorial Medical College, Amravati, India.
  • Gandhi A; Unique Hospital, Solapur, India.
  • Sowani A; Zydus Hospital & Healthcare Research Pvt Ltd, Ahmedabad, India.
  • Kale S; FRIGE Institute of Human Genetics, FRIGE House, Jodhpur Village Road, Satellite, Ahmedabad, India, 380015.
  • Jalan A; NIRMAN, Vashi, India.
  • Solanki D; Mantra Child Neurology and Epilepsy Hospital, Bhavnagar, India.
  • Dalal A; Diagnostics Division, Centre for DNA Fingerprinting and Diagnostics, Hyderabad, India.
  • Mane S; Department of Genetics, Yale School of Medicine, Yale Center for Genome Analysis, West Haven, CT, USA.
  • Prabha CR; Department of Biochemistry, Faculty of Science, The M. S. University of Baroda, Vadodara, India.
  • Sheth F; FRIGE Institute of Human Genetics, FRIGE House, Jodhpur Village Road, Satellite, Ahmedabad, India, 380015.
  • Joshi CG; Gujarat Biotechnology Research Centre, Gandhinagar, Gujarat, India.
  • Joshi M; Gujarat Biotechnology Research Centre, Gandhinagar, Gujarat, India.
  • Sheth J; FRIGE Institute of Human Genetics, FRIGE House, Jodhpur Village Road, Satellite, Ahmedabad, India, 380015. Jayesh.sheth@frige.co.in.
Hum Genomics ; 18(1): 46, 2024 May 10.
Article in En | MEDLINE | ID: mdl-38730490
ABSTRACT

BACKGROUND:

Current clinical diagnosis pathway for lysosomal storage disorders (LSDs) involves sequential biochemical enzymatic tests followed by DNA sequencing, which is iterative, has low diagnostic yield and is costly due to overlapping clinical presentations. Here, we describe a novel low-cost and high-throughput sequencing assay using single-molecule molecular inversion probes (smMIPs) to screen for causative single nucleotide variants (SNVs) and copy number variants (CNVs) in genes associated with 29 common LSDs in India.

RESULTS:

903 smMIPs were designed to target exon and exon-intron boundaries of targeted genes (n = 23; 53.7 kb of the human genome) and were equimolarly pooled to create a sequencing library. After extensive validation in a cohort of 50 patients, we screened 300 patients with either biochemical diagnosis (n = 187) or clinical suspicion (n = 113) of LSDs. A diagnostic yield of 83.4% was observed in patients with prior biochemical diagnosis of LSD. Furthermore, diagnostic yield of 73.9% (n = 54/73) was observed in patients with high clinical suspicion of LSD in contrast with 2.4% (n = 1/40) in patients with low clinical suspicion of LSD. In addition to detecting SNVs, the assay could detect single and multi-exon copy number variants with high confidence. Critically, Niemann-Pick disease type C and neuronal ceroid lipofuscinosis-6 diseases for which biochemical testing is unavailable, could be diagnosed using our assay. Lastly, we observed a non-inferior performance of the assay in DNA extracted from dried blood spots in comparison with whole blood.

CONCLUSION:

We developed a flexible and scalable assay to reliably detect genetic causes of 29 common LSDs in India. The assay consolidates the detection of multiple variant types in multiple sample types while having improved diagnostic yield at same or lower cost compared to current clinical paradigm.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Genetic Testing / Lysosomal Storage Diseases / DNA Copy Number Variations / High-Throughput Nucleotide Sequencing Limits: Female / Humans / Male Country/Region as subject: Asia Language: En Journal: Hum Genomics Journal subject: GENETICA Year: 2024 Document type: Article

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Genetic Testing / Lysosomal Storage Diseases / DNA Copy Number Variations / High-Throughput Nucleotide Sequencing Limits: Female / Humans / Male Country/Region as subject: Asia Language: En Journal: Hum Genomics Journal subject: GENETICA Year: 2024 Document type: Article