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Early presentation of cystic kidneys in a family with a homozygous INVS mutation
Author(s) -
Oud Machteld M.,
van Bon Bregje W.,
Bongers Ernie M. H. F.,
Hoischen Alexander,
Marcelis Carlo L.,
de Leeuw Nicole,
Mol Suzanne J. J.,
Mortier Geert,
Knoers Nine V. A. M.,
Brunner Han G.,
Roepman Ronald,
Arts Heleen H.
Publication year - 2014
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.36501
Subject(s) - nephronophthisis , cilium , biology , nonsense mutation , mutation , cystic kidney disease , fetus , exome sequencing , mutant , genetics , penetrance , situs inversus , phenotype , kidney , gene , missense mutation , anatomy , pregnancy
Nephronophthisis (NPHP) is an autosomal recessive cystic kidney disease that is the most frequent monogenic cause of end‐stage renal disease in children. Infantile NPHP, often in combination with other features like situs inversus , are commonly caused by mutations in the INVS gene. INVS encodes the ciliary protein inversin, and mutations induce dysfunction of the primary cilia. In this article, we present a family with two severely affected fetuses that were aborted after discovery of grossly enlarged cystic kidneys by ultrasonography before 22 weeks gestation. Exome sequencing showed that the fetuses were homozygous for a previously unreported nonsense mutation, resulting in a truncation in the IQ1 domain of inversin. This mutation induces nonsense‐mediated RNA decay, as suggested by a reduced RNA level in fibroblasts derived from the fetus. However, a significant amount of mutant INVS RNA was present in these fibroblasts, yielding mutant inversin protein that was mislocalized. In control fibroblasts, inversin was present in the ciliary axoneme as well as at the basal body, whereas in the fibroblasts from the fetus, inversin could only be detected at the basal body. The phenotype of both fetuses is partly characteristic of infantile NPHP and Potter sequence. We also identified that the fetuses had mild skeletal abnormalities, including shortening and bowing of long bones, which may expand the phenotypic spectrum associated with INVS mutations. © 2014 Wiley Periodicals, Inc.