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Genet Med. 2018 Dec 20. doi: 10.1038/s41436-018-0358-0. [Epub ahead of print]

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

Author information

1
Department of Neurology, Baylor College of Medicine, Houston, TX, USA. emrick@bcm.edu.
2
Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA. emrick@bcm.edu.
3
Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX, USA. emrick@bcm.edu.
4
Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX, USA.
5
Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
6
Baylor Genetics, Houston, TX, USA.
7
Kennedy Krieger Institute, Baltimore, MD, USA.
8
Department of Radiology, Baylor College of Medicine, Houston, TX, USA.
9
Section of Genetics, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA.
10
Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
11
Illumina, San Diego, CA, USA.
12
Dell Children's Medical Center, Austin, TX, USA.
13
LabCorp, Austin, TX, USA.
14
Illumina, Houston, TX, USA.

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

PMID:
30568308
DOI:
10.1038/s41436-018-0358-0

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