Abstract
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.