Whole-exome sequencing and variant spectrum in children with suspected inherited renal tubular disorder: the East India Tubulopathy Gene Study.
Genetics
India
Next-generation sequencing
Pediatric
Tubulopathy
Journal
Pediatric nephrology (Berlin, Germany)
ISSN: 1432-198X
Titre abrégé: Pediatr Nephrol
Pays: Germany
ID NLM: 8708728
Informations de publication
Date de publication:
08 2022
08 2022
Historique:
received:
05
08
2021
accepted:
10
11
2021
revised:
29
09
2021
pubmed:
11
1
2022
medline:
1
7
2022
entrez:
10
1
2022
Statut:
ppublish
Résumé
Inherited tubulopathies are a heterogeneous group of genetic disorders making whole-exome sequencing (WES) the preferred diagnostic methodology. 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. 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). 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.
Sections du résumé
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.
Identifiants
pubmed: 35006361
doi: 10.1007/s00467-021-05388-y
pii: 10.1007/s00467-021-05388-y
doi:
Types de publication
Journal Article
Multicenter Study
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1811-1836Informations de copyright
© 2022. The Author(s), under exclusive licence to International Pediatric Nephrology Association.
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