Further expansion and confirmation of phenotype in rare loss of YWHAE gene distinct from Miller–Dieker syndrome

Abstract

Deletion of 17p13.3 has varying degrees of severity on brain development based on precise location and size of the deletion. The most severe phenotype is Miller-Dieker syndrome (MDS) which is characterized by lissencephaly, dysmorphic facial features, growth failure, developmental disability, and often early death. Haploinsufficiency of PAFAH1B1 is responsible for the characteristic lissencephaly in MDS. The precise role of YWHAE haploinsufficiency in MDS is unclear. Case reports are beginning to elucidate the phenotypes of individuals with 17p13.3 deletions that have deletion of YWHAE but do not include deletion of PAFAH1B1. Through our clinical genetics practice, we identified four individuals with 17p13.3 deletion that include YWHAE but not PAFAH1B1. These patients have a similar phenotype of dysmorphic facial features, developmental delay, and leukoencephalopathy. In a review of the literature, we identified 19 patients with 17p13.3 microdeletion sparing PAFAH1B1 but deleting YWHAE. Haploinsufficiency of YWHAE is associated with brain abnormalities including cystic changes. These individuals have high frequency of epilepsy, intellectual disability, and dysmorphic facial features including prominent forehead, epicanthal folds, and broad nasal root. We conclude that deletion of 17p13.3 excluding PAFAH1B1 but including YWHAE is associated with a consistent phenotype and should be considered a distinct condition from MDS.

Leukoencephalopathy caused by a 17p13.3 microdeletion

“…Well-characterised phenotypes associated with these deletions, such as Miller-Dieker syndrome (caused by deletions that include genes YWHAE and PAFAH1B1) and isolated lissencephaly sequence (caused by deletions involving only PAFAH1B1 but not YWHAE) are also typically associated with significant symptoms including dysmorphic features, developmental delay and premature life expectancy. 4 Emrick et al recently described six patients with 17p13.3 microdeletions between the YWHAE and PAFAH1B1 loci (online supplemental figure 1). 5 These patients also presented with white matter abnormalities without significant associated intellectual disability.…”