Rajiv Sinha1,2, Subal Pradhan3, Sushmita Banerjee1,4, Afsana Jahan5, Shakil Akhtar1, Amitava Pahari2, Sumantra Raut6, Prince Parakh7, Surupa Basu1, Priyanka Srivastava8, Snehamayee Nayak3, S G Thenral9, V Ramprasad9, Emma Ashton10, Detlef Bockenhauer11, Kausik Mandal12. 1. Institute of Child Health, Kolkata, India. 2. Apollo Hospital, Kolkata, India. 3. SVPPGIP & SCB Medical College, Cuttack, India. 4. Calcutta Medical and Research Institute, Kolkata, India. 5. Renowell Clinic and Pratiksha Hospital, Gauhati, India. 6. North Bengal Medical College, Darjeeling, India. 7. Neotia Getwel Healthcare Center, Siliguri, India. 8. Post Graduate Institute of Medical Education and Research, Chandigarh, India. 9. Medgenome Labs Ltd, Bangalore, India. 10. Rare & Inherited Disease Laboratory, NHS North Thames Genomic Laboratory Hub, Great Ormond Street Hospital for Children, NHS Foundation Trust, London, UK. 11. UCL Department of Renal Medicine and Renal Unit, Great Ormond Street Hospital for Children, NHS Foundation Trust, London, UK. 12. Department of Medical Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, 226014, India. mandal.kausik@gmail.com.
Abstract
BACKGROUND: Inherited tubulopathies are a heterogeneous group of genetic disorders making whole-exome sequencing (WES) the preferred diagnostic methodology. METHODS: This was a multicenter descriptive study wherein children (< 18 years) with clinically suspected tubular disorders were recruited for molecular testing through WES. Multiplex ligation-dependent probe amplification (MLPA) and Sanger sequencing were done when required. Variants were classified as per American College of Medical Genetics 2015 guidelines and pathogenic (P)/likely pathogenic (LP) variants were considered causative. RESULTS: There were 77 index cases (male =73%). Median age at diagnosis was 48 months (IQR 18.5 to 108 months). At recruitment, the number of children in each clinical group was as follows: distal renal tubular acidosis (dRTA) = 25; Bartter syndrome = 18; isolated hypophosphatemic rickets (HP) = 6; proximal tubular dysfunction (pTD) = 12; nephrogenic diabetes insipidus (NDI) = 6; kidney stone/nephrocalcinosis (NC) = 6; others = 4. We detected 55 (24 novel) P/LP variants, providing genetic diagnoses in 54 children (70%). The diagnostic yield of WES was highest for NDI (100%), followed by HP (83%; all X-linked HP), Bartter syndrome (78%), pTD (75%), dRTA (64%), and NC (33%). Molecular testing had a definite impact on clinical management in 24 (31%) children. This included revising clinical diagnosis among 14 children (26% of those with a confirmed genetic diagnosis and 18% of the overall cohort), detection of previously unrecognized co-morbidities among 8 children (sensorineural deafness n = 5, hemolytic anemia n = 2, and dental changes n = 1) and facilitating specific medical treatment for 7 children (primary hyperoxaluria n = 1, cystinosis n = 4, tyrosinemia n = 2). CONCLUSION: WES is a powerful tool in the diagnosis and management of children with inherited tubulopathies in the Indian population. A higher resolution version of the Graphical abstract is available as Supplementary information.
BACKGROUND: Inherited tubulopathies are a heterogeneous group of genetic disorders making whole-exome sequencing (WES) the preferred diagnostic methodology. METHODS: This was a multicenter descriptive study wherein children (< 18 years) with clinically suspected tubular disorders were recruited for molecular testing through WES. Multiplex ligation-dependent probe amplification (MLPA) and Sanger sequencing were done when required. Variants were classified as per American College of Medical Genetics 2015 guidelines and pathogenic (P)/likely pathogenic (LP) variants were considered causative. RESULTS: There were 77 index cases (male =73%). Median age at diagnosis was 48 months (IQR 18.5 to 108 months). At recruitment, the number of children in each clinical group was as follows: distal renal tubular acidosis (dRTA) = 25; Bartter syndrome = 18; isolated hypophosphatemic rickets (HP) = 6; proximal tubular dysfunction (pTD) = 12; nephrogenic diabetes insipidus (NDI) = 6; kidney stone/nephrocalcinosis (NC) = 6; others = 4. We detected 55 (24 novel) P/LP variants, providing genetic diagnoses in 54 children (70%). The diagnostic yield of WES was highest for NDI (100%), followed by HP (83%; all X-linked HP), Bartter syndrome (78%), pTD (75%), dRTA (64%), and NC (33%). Molecular testing had a definite impact on clinical management in 24 (31%) children. This included revising clinical diagnosis among 14 children (26% of those with a confirmed genetic diagnosis and 18% of the overall cohort), detection of previously unrecognized co-morbidities among 8 children (sensorineural deafness n = 5, hemolytic anemia n = 2, and dental changes n = 1) and facilitating specific medical treatment for 7 children (primary hyperoxaluria n = 1, cystinosis n = 4, tyrosinemia n = 2). CONCLUSION: WES is a powerful tool in the diagnosis and management of children with inherited tubulopathies in the Indian population. A higher resolution version of the Graphical abstract is available as Supplementary information.
Authors: Emma J Ashton; Anne Legrand; Valerie Benoit; Isabelle Roncelin; Annabelle Venisse; Maria-Christina Zennaro; Xavier Jeunemaitre; Daniela Iancu; William G Van't Hoff; Stephen B Walsh; Nathalie Godefroid; Annelies Rotthier; Jurgen Del Favero; Olivier Devuyst; Franz Schaefer; Lucy A Jenkins; Robert Kleta; Karin Dahan; Rosa Vargas-Poussou; Detlef Bockenhauer Journal: Kidney Int Date: 2018-02-15 Impact factor: 10.612