Whole genome sequencing identifies novel structural variant in a large Indian family affected with X-linked agammaglobulinemia.
X-linked agammaglobulinemia (XLA, OMIM #300755) is a primary immunodeficiency disorder caused by pathogenic variations in the BTK gene, characterized by failure of development and maturation of B lymphocytes. The estimated prevalence worldwide is 1 in 190,000 male births. Recently, genome sequencing...
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oai:doaj.org-article:b260bd1f9264470b8851b4de048cbdfb2021-12-02T20:15:28ZWhole genome sequencing identifies novel structural variant in a large Indian family affected with X-linked agammaglobulinemia.1932-620310.1371/journal.pone.0254407https://doaj.org/article/b260bd1f9264470b8851b4de048cbdfb2021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0254407https://doaj.org/toc/1932-6203X-linked agammaglobulinemia (XLA, OMIM #300755) is a primary immunodeficiency disorder caused by pathogenic variations in the BTK gene, characterized by failure of development and maturation of B lymphocytes. The estimated prevalence worldwide is 1 in 190,000 male births. Recently, genome sequencing has been widely used in difficult to diagnose and familial cases. We report a large Indian family suffering from XLA with five affected individuals. We performed complete blood count, immunoglobulin assay, and lymphocyte subset analysis for all patients and analyzed Btk expression for one patient and his mother. Whole exome sequencing (WES) for four patients, and whole genome sequencing (WGS) for two patients have been performed. Carrier screening was done for 17 family members using Multiplex Ligation-dependent Probe Amplification (MLPA) and haplotype ancestry mapping using fineSTRUCTURE was performed. All patients had hypogammaglobulinemia and low CD19+ B cells. One patient who underwent Btk estimation had low expression and his mother showed a mosaic pattern. We could not identify any single nucleotide variants or small insertion/ deletions from the WES dataset that correlates with the clinical feature of the patient. Structural variant analysis through WGS data identifies a novel large deletion of 5,296 bp at loci chrX:100,624,323-100,629,619 encompassing exons 3-5 of the BTK gene. Family screening revealed seven carriers for the deletion. Two patients had a successful HSCT. Haplotype mapping revealed a South Asian ancestry. WGS led to identification of the accurate genetic mutation which could help in early diagnosis leading to improved outcomes, prevention of permanent organ damage and improved quality of life, as well as enabling genetic counselling and prenatal diagnosis in the family.Abhinav JainGeeta Madathil GovindarajAthulya EdavazhippurathNabeel FaisalRahul C BhoyarVishu GuptaRamya UppuluriShiny Padinjare ManakkadAtul KashyapAnoop KumarMohit Kumar DivakarMohamed ImranSneha SawantAparna DalviKrishnan ChakyarManisha MadkaikarRevathi RajSridhar SivasubbuVinod ScariaPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 7, p e0254407 (2021) |
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Medicine R Science Q Abhinav Jain Geeta Madathil Govindaraj Athulya Edavazhippurath Nabeel Faisal Rahul C Bhoyar Vishu Gupta Ramya Uppuluri Shiny Padinjare Manakkad Atul Kashyap Anoop Kumar Mohit Kumar Divakar Mohamed Imran Sneha Sawant Aparna Dalvi Krishnan Chakyar Manisha Madkaikar Revathi Raj Sridhar Sivasubbu Vinod Scaria Whole genome sequencing identifies novel structural variant in a large Indian family affected with X-linked agammaglobulinemia. |
| description |
X-linked agammaglobulinemia (XLA, OMIM #300755) is a primary immunodeficiency disorder caused by pathogenic variations in the BTK gene, characterized by failure of development and maturation of B lymphocytes. The estimated prevalence worldwide is 1 in 190,000 male births. Recently, genome sequencing has been widely used in difficult to diagnose and familial cases. We report a large Indian family suffering from XLA with five affected individuals. We performed complete blood count, immunoglobulin assay, and lymphocyte subset analysis for all patients and analyzed Btk expression for one patient and his mother. Whole exome sequencing (WES) for four patients, and whole genome sequencing (WGS) for two patients have been performed. Carrier screening was done for 17 family members using Multiplex Ligation-dependent Probe Amplification (MLPA) and haplotype ancestry mapping using fineSTRUCTURE was performed. All patients had hypogammaglobulinemia and low CD19+ B cells. One patient who underwent Btk estimation had low expression and his mother showed a mosaic pattern. We could not identify any single nucleotide variants or small insertion/ deletions from the WES dataset that correlates with the clinical feature of the patient. Structural variant analysis through WGS data identifies a novel large deletion of 5,296 bp at loci chrX:100,624,323-100,629,619 encompassing exons 3-5 of the BTK gene. Family screening revealed seven carriers for the deletion. Two patients had a successful HSCT. Haplotype mapping revealed a South Asian ancestry. WGS led to identification of the accurate genetic mutation which could help in early diagnosis leading to improved outcomes, prevention of permanent organ damage and improved quality of life, as well as enabling genetic counselling and prenatal diagnosis in the family. |
| format |
article |
| author |
Abhinav Jain Geeta Madathil Govindaraj Athulya Edavazhippurath Nabeel Faisal Rahul C Bhoyar Vishu Gupta Ramya Uppuluri Shiny Padinjare Manakkad Atul Kashyap Anoop Kumar Mohit Kumar Divakar Mohamed Imran Sneha Sawant Aparna Dalvi Krishnan Chakyar Manisha Madkaikar Revathi Raj Sridhar Sivasubbu Vinod Scaria |
| author_facet |
Abhinav Jain Geeta Madathil Govindaraj Athulya Edavazhippurath Nabeel Faisal Rahul C Bhoyar Vishu Gupta Ramya Uppuluri Shiny Padinjare Manakkad Atul Kashyap Anoop Kumar Mohit Kumar Divakar Mohamed Imran Sneha Sawant Aparna Dalvi Krishnan Chakyar Manisha Madkaikar Revathi Raj Sridhar Sivasubbu Vinod Scaria |
| author_sort |
Abhinav Jain |
| title |
Whole genome sequencing identifies novel structural variant in a large Indian family affected with X-linked agammaglobulinemia. |
| title_short |
Whole genome sequencing identifies novel structural variant in a large Indian family affected with X-linked agammaglobulinemia. |
| title_full |
Whole genome sequencing identifies novel structural variant in a large Indian family affected with X-linked agammaglobulinemia. |
| title_fullStr |
Whole genome sequencing identifies novel structural variant in a large Indian family affected with X-linked agammaglobulinemia. |
| title_full_unstemmed |
Whole genome sequencing identifies novel structural variant in a large Indian family affected with X-linked agammaglobulinemia. |
| title_sort |
whole genome sequencing identifies novel structural variant in a large indian family affected with x-linked agammaglobulinemia. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2021 |
| url |
https://doaj.org/article/b260bd1f9264470b8851b4de048cbdfb |
| work_keys_str_mv |
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