Targeted exome sequencing in anti-factor H antibody negative HUS reveals multiple variations.

Abstract:

BACKGROUND:Genetic susceptibility to atypical hemolytic uremic syndrome (aHUS) may lie within genes regulating or activating the alternate complement and related pathways converging on endothelial cell activation. METHODS:We tested 32 Indian patients of aHUS negative for antibodies to complement factor H for genetic variations in a panel of 15 genes, i.e., CFH, CFHR1-5, CFI, CFB, C3, CD46, MASP2, DGKE, ADAMTS13, THBD and PLG using next-generation DNA sequencing and for copy number variation in CFHR1-3. RESULTS:Despite absence of a public database of exome variations in the Indian population and limited functional studies, we could establish a genetic diagnosis in 6 (18.8%) patients using a stringent scheme of prioritization. One patient carried a likely pathogenic variation. The number of patients carrying possibly pathogenic variation was as follows: 1 variation: 5 patients, 2 variations: 9 patients, 3 variations: 5 patients, 4 variations: 9 patients, 5 variations: 2 patients and 6 variations: 2 patients. Homozygous deletion of CFHR1-3 was present in five patients; none of these carried a diagnostic genetic variation. Patients with or without diagnostic variation did not differ significantly in terms of enrichment of genetic variations that were rare/novel or predicted deleterious, or for possible environmental triggers. CONCLUSION:We conclude that genetic testing for multiple genes in patients with aHUS negative for anti-FH antibodies reveals multiple candidate variations that require prioritization. Population data on variation frequency of the Indian population and supportive functional studies are likely to improve diagnostic yield.

journal_name

Clin Exp Nephrol

authors

Thergaonkar RW,Narang A,Gurjar BS,Tiwari P,Puraswani M,Saini H,Sinha A,Varma B,Mukerji M,Hari P,Bagga A

doi

10.1007/s10157-017-1478-6

subject

Has Abstract

pub_date

2018-06-01 00:00:00

pages

653-660

issue

3

eissn

1342-1751

issn

1437-7799

pii

10.1007/s10157-017-1478-6

journal_volume

22

pub_type

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