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. 2019 Jul;21(7):1652-1656.
doi: 10.1038/s41436-018-0358-0. Epub 2018 Dec 20.

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

Lisa T Emrick  1   2   3 , Jill A Rosenfeld  4 , Seema R Lalani  5   4   6 , Mahim Jain  4   7 , Nilesh K Desai  8 , Austin Larson  9 , Kimberly Kripps  9 , Adeline Vanderver  10 , Ryan J Taft  11 , Krista Bluske  11 , Denise Perry  11 , Honey Nagakura  12   13 , LaDonna L Immken  12 , Lindsay C Burrage  5   4 , Carlos A Bacino  5   4   6 , John W Belmont  4   14 , Undiagnosed Diseases Network, Brendan Lee  5   4
Affiliations

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

Lisa T Emrick et al. Genet Med. 2019 Jul.

Abstract

Purpose: Brain malformations caused by 17p13.3 deletions include lissencephaly with deletions of the larger Miller-Dieker syndrome region or smaller deletions of only PAFAH1B1, white matter changes, and a 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.

Methods: We analyzed the clinical features of six individuals from five families with 17p13.3 deletions between and not including YWHAE/CRK and PAFAH1B1 identified among individuals undergoing clinical chromosomal microarray testing or research genome sequencing.

Results: Five individuals from four families had multifocal white matter lesions while a sixth had a normal magnetic resonance image. A combination of our individuals 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 phenotype.

Conclusion: While previous literature has hypothesized dysmorphic features and white matter changes related to YWHAE, our cohort contributes evidence to the presence of additional genetic changes within 17p13.3 required for proper brain development.

Keywords: 17p13.3 microdeletion; chromosomal microarray; leukoencephalopathy; white matter.

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Conflict of interest statement

Conflict of interest notification

The remaining authors have no conflicts to declare.

Figures

Figure 1.
Figure 1.. Leukoencephalopathies in individuals with 17p13.3 deletions.
Axial T2 weighted FLAIR (fluid attenuated inversion recovery) images demonstrate bilateral T2 hyperintensities in Subject 1 (A), Subject 2 (B), Subject 3 (C) and Subject 5 (D). (E) Deletions associated with abnormal MRIs in our cohort and review of the literature are red; the individual with a normal MRI is shown in gray. Gray shaded area represents the smallest region of overlap among cases with characteristic leukoencephalopathy. Genes in the region are shown as green boxes, with the critical genes of note flanking the region shown in blue.
See this image and copyright information in PMC

Comment in

  • Leukoencephalopathy caused by a 17p13.3 microdeletion.
    Wade C, Williams T, Labrum R, Patel Y, Cali E, Davagnanam I, Adams ME, Barkhof F, Murphy E, Chataway J, Houlden H, Lynch DS. Wade C, et al. J Neurol Neurosurg Psychiatry. 2024 Feb 14;95(3):290-292. doi: 10.1136/jnnp-2023-331986. J Neurol Neurosurg Psychiatry. 2024. PMID: 37734926 No abstract available.

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