NPHP4 Variants Are Associated With Pleiotropic Heart Malformations

Vanessa French, Ingrid De Graaf - van de Laar, Marja Wessels, Christan Rohe, Jolien Roos - Hesselink, GL Wang, Ingrid Mulder, Lies-anne Severijnen, Bianca de Graaf, Rachel Schot, Guido Breedveld, Edwin Mientjes, Marianne Tienhoven, E Jadot, ZX Jiang, A (Ton) Verkerk, Sigrid Swagemakers, H Venselaar, Z Rahimi, H NajmabadiH Meijers-Heijboer, Esther Graaff, W.A. Helbing, Rob Willemsen, K DeVriendt, JW Belmont, Ben Oostra, JD Amack, AM Bertoli Avella

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39 Citations (Scopus)


Rationale: Congenital heart malformations are a major cause of morbidity and mortality, especially in young children. Failure to establish normal left-right (L-R) asymmetry often results in cardiovascular malformations and other laterality defects of visceral organs. Objective: To identify genetic mutations causing cardiac laterality defects. Methods and Results: We performed a genome-wide linkage analysis in patients with cardiac laterality defects from a consanguineous family. The patients had combinations of defects that included dextrocardia, transposition of great arteries, double-outlet right ventricle, atrioventricular septal defects, and caval vein abnormalities. Sequencing of positional candidate genes identified mutations in NPHP4. We performed mutation analysis of NPHP4 in 146 unrelated patients with similar cardiac latera Conclusions: NPHP4 mutations are associated with cardiac laterality defects and heterotaxy. In zebrafish, nphp4 is essential for the development and function of Kupffer's vesicle cilia and is required for global L-R patterning. (Circ Res. 2012;110:1564-1574.)
Original languageUndefined/Unknown
Pages (from-to)1564-1574
Number of pages11
JournalCirculation Research
Issue number12
Publication statusPublished - 2012

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