Microdeletions excluding YWHAE and PAFAH1B1 cause a unique leukoencephalopathy and hypermobility syndrome: Further delineation of the 17p13.3 microdeletion spectrum

PurposeBrain malformations are caused by 17p13.3 deletions: lissencephaly with deletions of the larger Miller-Dieker syndrome region or smaller deletions of only PAFAH1B1, as well as various abnormalities, including white matter changes, in the distinct syndrome due to deletions including YWHAE and CRK but sparing PAFAH1B1. We sought to understand the significance of 17p13.3 deletions between the YWHAE/CRK and PAFAH1B1 loci.\n\nMethodsWe analyzed the clinical features of five individuals from four families with 17p13.3 deletions between and not including YWHAE/CRK and PAFAH1B1 identified among individuals undergoing clinical chromosomal microarray testing.\n\nResultsFour individuals from three families have multi-focal white matter lesions and hypermobile joints, while a fifth had a normal MRI. A combination of our patients and a review of those in the literature with white matter changes and deletions in this chromosomal region narrows the overlapping region for this brain phenotype to [~]345 kb, including 11 RefSeq genes, with RTN4RL1 haploinsufficiency as the best candidate for causing this.\n\nConclusionWhile previous literature has hypothesized dysmorphic features and white matter changes related to YWHAE, our cohort contributes evidence to the presence of additional genes within 17p13.3 required for proper brain development.