Mutation screening of the EYA1, SIX1 and SIX5 genes in a large cohort of patients harboring branchio-oto-renal syndrome calls into question the pathogenic role of SIX5 mutations

Pauline Krug (1) , Vincent Moriniere (2) , Sandrine Marlin (3) , Gabriel Heinz (4) , Valérie Koubi (2) , Dominique Bonneau (5) , Estelle Colin (5) , Remi Salomon (1, 6) , Corinne Antignac (7) , Laurence Heidet (8)

1 Service de néphrologie pédiatrique [CHU Necker]
2 Service de Génétique Médicale [CHU Necker]
3 CHU Trousseau [APHP]
4 Diagenos
5 Service de génétique [Angers]
6 AP-HP Centre de référence des maladies rénales héréditaires de l'enfant et de l'adulte
7 UPD5 - Université Paris Descartes - Paris 5
8 Service de Néphrologie Pédiatrique

Branchio-oto-renal (BOR) syndrome is an autosomal dominant disorder characterized by branchial, ear and renal anomalies. Over 80 mutations in EYA1 have been reported in BOR. Mutations in SIX1, a DNA binding protein that associates with EYA1, have been reported less frequently. One group has recently described 4 missense mutations in SIX5 in 5 unrelated patients with BOR. Here, we report a screening of these three genes in a cohort of 140 patients from 124 families with BOR. We identified 36 EYA1 mutations in 42 unrelated patients, 2 mutations and one change of unknown significance in SIX1 in 3 unrelated patients, but no mutation in SIX5. We did not find correlation between genotype and phenotype, and observed a high phenotypic variability between and within BOR families. We show the difficulty in establishing a molecular diagnosis strategy in BOR syndrome: the screening focusing on patients with typical BOR would detect a mutation rate of 76%, but would also miss mutations in 9% of patients with atypical BOR. We detected a deletion removing three EYA1 exons in a patient who was previously reported to carry the SIX5 Thr552Met mutation. This led us to reconsider the role of SIX5 in the development of BOR.

Mots clés: Life Sciences

Pauline Krug, Vincent Moriniere, Sandrine Marlin, Gabriel Heinz, Valérie Koubi, et al.. Mutation screening of the EYA1, SIX1 and SIX5 genes in a large cohort of patients harboring branchio-oto-renal syndrome calls into question the pathogenic role of SIX5 mutations. Human Mutation, 2011, 32 (2), pp.183. ⟨10.1002/humu.21402⟩. ⟨hal-00612007⟩