Recurrent FAN1 p.W707X Pathogenic Variant Originating Before ad 1800 Underlies High Frequency of Karyomegalic Interstitial Nephritis in South Pacific Islands

Lorraine Gueguen,Ronan Delaval,Maud Blanluet,Hervé Sartelet,Sylvie Leou,Catherine Dubois D’Enghien,Lisa Golmard,Dominique Stoppa-Lyonnet,Pascale Testevuide,Stanislas Faguer

doi:10.1016/j.ekir.2021.05.010

Abstract

Recurrent FAN1 p.W707X Pathogenic Variant Originating Before ad 1800 Underlies High Frequency of Karyomegalic Interstitial Nephritis in South Pacific Islands

Highlights

Karyomegalic interstitial nephritis (KMIN; OMIM 814617, ORPHA 401996) is a very rare autosomal recessive inherited systemic disease caused by germline pathogenic variants in the FAN1 gene, which encodes the FANCD2/FANCI-associated nuclease 1.1 Kidneys are involved in most if not all patients with KMIN, with characteristics of chronic tubulointerstitial nephropathy at presentation
In the 8 tested patients, genetic analysis identified a recurrent homozygous FAN1 c.2120G>A, p.(W707X) variant that was classified as pathogenic according to the American College of Medical Genetics and Genomics (ACMG) guidelines as it leads to a premature termination codon in the exon 8 of FAN1, which contains 15 exons, and it is absent in individuals from the Genome Aggregation Database, v2.1.1, whereas it has been identified in several patients with KMIN.S1 This variant had been previously observed with a homozygous status in 2 brothers with KMIN living in New Zealand.[1]
We identified KMIN as a frequent disease in French Polynesia, a territory located in southwest Pacific and characterized by insularity

Summary

INTRODUCTION

Karyomegalic interstitial nephritis (KMIN; OMIM 814617, ORPHA 401996) is a very rare autosomal recessive inherited systemic disease caused by germline pathogenic variants in the FAN1 gene, which encodes the FANCD2/FANCI-associated nuclease 1.1 Kidneys are involved in most if not all patients with KMIN, with characteristics of chronic tubulointerstitial nephropathy at presentation. KMIN was first described in 1974 in a young woman with liver carcinoma and interstitial nephritis with dysplastic tubules.[4] In rare patients, lung disease is at the forefront and may culminate in severe respiratory failure requiring lung transplantation,[5] but extrarenal symptoms are often absent or mild (recurrent upper respiratory tract infections and abnormal liver tests) even if tissue examination of lung, heart, brain, gut, Kidney International Reports (2021) 6, 2207–2211 vessels, skin, or thyroid frequently show pathologic changes.[3] In contrast, progression toward chronic kidney disease (CKD) and end-stage renal disease before 50 years of age is the rule.[3]. The 12 affected patients from 5 families were homozygous for the FAN1 c.2120G>A, p.(W707X) pathogenic variant, previously identified in 2 siblings without reported consanguinity and of Maori descent from New Zealand.[1]

RESULTS

DISCUSSION

DISCLOSURE