NFIA haploinsufficiency is associated with a CNS malformation syndrome and urinary tract defects.
Complex central nervous system (CNS) malformations frequently coexist with other developmental abnormalities, but whether the associated defects share a common genetic basis is often unclear. We describe five individuals who share phenotypically related CNS malformations and in some cases urinary tract defects, and also haploinsufficiency for the NFIA transcription factor gene due to chromosomal translocation or deletion. Two individuals have balanced translocations that disrupt NFIA. A third individual and two half-siblings in an unrelated family have interstitial microdeletions that include NFIA. All five individuals exhibit similar CNS malformations consisting of a thin, hypoplastic, or absent corpus callosum, and hydrocephalus or ventriculomegaly. The majority of these individuals also exhibit Chiari type I malformation, tethered spinal cord, and urinary tract defects that include vesicoureteral reflux. Other genes are also broken or deleted in all five individuals, and may contribute to the phenotype. However, the only common genetic defect is NFIA haploinsufficiency. In addition, previous analyses of Nfia(-/-) knockout mice indicate that Nfia deficiency also results in hydrocephalus and agenesis of the corpus callosum. Further investigation of the mouse Nfia(+/-) and Nfia(-/-) phenotypes now reveals that, at reduced penetrance, Nfia is also required in a dosage-sensitive manner for ureteral and renal development. Nfia is expressed in the developing ureter and metanephric mesenchyme, and Nfia(+/-) and Nfia(-/-) mice exhibit abnormalities of the ureteropelvic and ureterovesical junctions, as well as bifid and megaureter. Collectively, the mouse Nfia mutant phenotype and the common features among these five human cases indicate that NFIA haploinsufficiency contributes to a novel human CNS malformation syndrome that can also include ureteral and renal defects.
Lu
Weining
W
Genetics Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
Quintero-Rivera
Fabiola
F
Fan
Yanli
Y
Alkuraya
Fowzan S
FS
Donovan
Diana J
DJ
Xi
Qiongchao
Q
Turbe-Doan
Annick
A
Li
Qing-Gang
QG
Campbell
Craig G
CG
Shanske
Alan L
AL
Sherr
Elliott H
EH
Ahmad
Ayesha
A
Peters
Roxana
R
Rilliet
Benedict
B
Parvex
Paloma
P
Bassuk
Alexander G
AG
Harris
David J
DJ
Ferguson
Heather
H
Kelly
Chantal
C
Walsh
Christopher A
CA
Gronostajski
Richard M
RM
Devriendt
Koenraad
K
Higgins
Anne
A
Ligon
Azra H
AH
Quade
Bradley J
BJ
Morton
Cynthia C
CC
Gusella
James F
JF
Maas
Richard L
RL
D000015:Abnormalities, Multiple / Q000235:genetics*; D000818:Animals; D002648:Child; D002675:Child, Preschool; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D004622:Embryo, Mammalian / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D015321:Gene Rearrangement; D020022:Genetic Predisposition to Disease; D006238:Haploidy; D006801:Humans; D007223:Infant; D007668:Kidney / Q000002:abnormalities / Q000196:embryology / Q000378:metabolism; D008297:Male; D051379:Mice; D009154:Mutation / Q000235:genetics; D051839:NFI Transcription Factors / Q000235:genetics* / Q000378:metabolism; D009421:Nervous System Malformations / Q000235:genetics*; D010641:Phenotype; D013116:Spinal Cord / Q000378:metabolism; D013577:Syndrome; D014513:Ureter / Q000002:abnormalities / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D014564:Urogenital Abnormalities / Q000235:genetics*
D051839:NFI Transcription Factors; C497592:NFIA protein, human; C497646:Nfia protein, mouse