Mutations in WDR4 as a new cause of Galloway-Mowat syndrome.

TitleMutations in WDR4 as a new cause of Galloway-Mowat syndrome.
Publication TypeJournal Article
Year of Publication2018
AuthorsBraun, DA, Shril, S, Sinha, A, Schneider, R, Tan, W, Ashraf, S, Hermle, T, Jobst-Schwan, T, Widmeier, E, Majmundar, AJ, Daga, A, Warejko, JK, Nakayama, M, Schapiro, D, Chen, J, Airik, M, Rao, J, Schmidt, JMagdalena, Hoogstraten, CA, Hugo, H, Meena, J, Lek, M, Laricchia, KM, Bagga, A, Hildebrandt, F
JournalAm J Med Genet A
Date Published2018 Nov

Galloway-Mowat syndrome (GAMOS) is a phenotypically heterogeneous disorder characterized by neurodevelopmental defects combined with renal-glomerular disease, manifesting with proteinuria. To identify additional monogenic disease causes, we here performed whole exome sequencing (WES), linkage analysis, and homozygosity mapping in three affected siblings of an Indian family with GAMOS. Applying established criteria for variant filtering, we identify a novel homozygous splice site mutation in the gene WDR4 as the likely disease-causing mutation in this family. In line with previous reports, we observe growth deficiency, microcephaly, developmental delay, and intellectual disability as phenotypic features resulting from WDR4 mutations. However, the newly identified allele additionally gives rise to proteinuria and nephrotic syndrome, a phenotype that was never reported in patients with WDR4 mutations. Our data thus expand the phenotypic spectrum of WDR4 mutations by demonstrating that, depending on the specific mutated allele, a renal phenotype may be present. This finding suggests that GAMOS may occupy a phenotypic spectrum with other microcephalic diseases. Furthermore, WDR4 is an additional example of a gene that encodes a tRNA modifying enzyme and gives rise to GAMOS, if mutated. Our findings thereby support the recent observation that, like neurons, podocytes of the renal glomerulus are particularly vulnerable to cellular defects resulting from altered tRNA modifications.

Alternate JournalAm. J. Med. Genet. A
PubMed ID30079490
PubMed Central IDPMC6289609
Grant ListUM1 HG008900 / HG / NHGRI NIH HHS / United States
UL1 TR001863 / TR / NCATS NIH HHS / United States
FP01014311 / / ASN Benjamin J. Lipps Research Fellowship Award /
R01 DK076683 / DK / NIDDK NIH HHS / United States
T32DK007726-31A1 / / National Institutes of Health /
DK076683 / / National Institutes of Health, NIDDK /
LPDS-2015-07 / / German National Academy of Sciences Leopoldina /
5/7/1090/2013-RHN / / Indian Council of Medical Research /
HE 7456/1-1 / / German Research Foundation (DFG) /
HG008900 / / National Institutes of Health /
T32 DK007726 / DK / NIDDK NIH HHS / United States
/ / Harvard Stem Cell Institute, Kidney Group /
Jo 1324/1-1 / / German Research Foundation (DFG) /
DK076683 / / National Institutes of Health /