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. 2013 Oct;34(10):1415-23.
doi: 10.1002/humu.22384. Epub 2013 Aug 13.

Recurrent HERV-H-mediated 3q13.2-q13.31 deletions cause a syndrome of hypotonia and motor, language, and cognitive delays

Andrey Shuvarikov  1 , Ian M Campbell, Piotr Dittwald, Nicholas J Neill, Martin G Bialer, Christine Moore, Patricia G Wheeler, Stephanie E Wallace, Mark C Hannibal, Michael F Murray, Monica A Giovanni, Deborah Terespolsky, Sandi Sodhi, Matteo Cassina, David Viskochil, Billur Moghaddam, Kristin Herman, Chester W Brown, Christine R Beck, Anna Gambin, Sau Wai Cheung, Ankita Patel, Allen N Lamb, Lisa G Shaffer, Jay W Ellison, J Britt Ravnan, Paweł Stankiewicz, Jill A Rosenfeld
Affiliations

Recurrent HERV-H-mediated 3q13.2-q13.31 deletions cause a syndrome of hypotonia and motor, language, and cognitive delays

Andrey Shuvarikov et al. Hum Mutat. 2013 Oct.

Abstract

We describe the molecular and clinical characterization of nine individuals with recurrent, 3.4-Mb, de novo deletions of 3q13.2-q13.31 detected by chromosomal microarray analysis. All individuals have hypotonia and language and motor delays; they variably express mild to moderate cognitive delays (8/9), abnormal behavior (7/9), and autism spectrum disorders (3/9). Common facial features include downslanting palpebral fissures with epicanthal folds, a slightly bulbous nose, and relative macrocephaly. Twenty-eight genes map to the deleted region, including four strong candidate genes, DRD3, ZBTB20, GAP43, and BOC, with important roles in neural and/or muscular development. Analysis of the breakpoint regions based on array data revealed directly oriented human endogenous retrovirus (HERV-H) elements of ~5 kb in size and of >95% DNA sequence identity flanking the deletion. Subsequent DNA sequencing revealed different deletion breakpoints and suggested nonallelic homologous recombination (NAHR) between HERV-H elements as a mechanism of deletion formation, analogous to HERV-I-flanked and NAHR-mediated AZFa deletions. We propose that similar HERV elements may also mediate other recurrent deletion and duplication events on a genome-wide scale. Observation of rare recurrent chromosomal events such as these deletions helps to further the understanding of mechanisms behind naturally occurring variation in the human genome and its contribution to genetic disease.

Keywords: 3q13; HERV-H; NAHR; developmental delay; hypotonia; microarray; microdeletion; recurrent.

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Figures

Figure 1
Figure 1. Microarray characterization of recurrent 3q13.2q13.31 deletions
(A) Schematic of molecularly characterized deletions in the literature overlapping the recurrently deleted region from this report. The purple bars represent the minimum size of the reported deletions, and, where available, horizontal black lines extend to show the maximum deletion size. The vertical dashed lines and light blue bar represent the recurrently deleted region. (B) Zoomed-in view of the recurrently deleted region with a representative microarray plot showing the deletion in patient 4, as characterized by a 135K whole-genome oligonucleotide-based array. Probes are ordered on the x-axis according to physical mapping positions, with the most proximal 3q13.2 probes to the left and the most distal 3q13.31 probes to the right. Values along the y-axis represent log2 ratios of patient:control signal intensities. Results are visualized using custom aCGH analysis software (Genoglyphix, Signature Genomics). Genes in the region are represented by yellow boxes. All coordinates shown are according to the hg19 build of the human genome, and the shaded gray region extending through the figure represents the SRO previously defined by Molin et al [2012].
Figure 2
Figure 2. Breakpoint characterization of recurrent 3q13.2q13.31 deletions
(A) Representative Sanger sequencing trace of the breakpoint region of patient 1. The patient's breakpoint sequence is presented between the proximal and distal chromosome 3 reference sequences. The informative cis-morphisims that define the breakpoint uncertainty region are highlighted in yellow. (B) Schematic representation of the breakpoints of 8 patients that were available for further studies. The uncertainty region for each patient is depicted in grey. The structures of the HERV-H elements that contain the breakpoints of the patients are shown below as grey rectangles. All genomic coordinates are shown below in the GRCh37/hg19 assembly. (C) Structures of the 3q13.2q13.31 HERV elements compared to the consensus HERV-H sequence from RepBase. Gaps in the consensus represent insertions in the 3q13.2q13.31 HERVs. Gaps in the 3q13.2q13.31 HERVs represent deletions compared to the consensus. The color of the HERV elements denotes identity at that position when aligned with the other HERV over a 50 base pair window. Blue represents 0% sequence identity (i.e. caused by a 50 bp or larger insertion or deletion present in one 3q13.2q13.31 HERV but not the other) while orange represents perfect identity. The region of the cross-over in each patient is presented as an X with the size of the X representing the uncertainty bounded by informative cis-morphisms. The purple X represents the breakpoints in patients 2 and 7 that occur between the same two cis-morphisms.
Figure 3
Figure 3. Facial features of individuals with 3q13.2q13.31 deletions
(A) Patient 1 at 5 years of age. (B-C) Patient 2 at 3 years of age. (D-E) Patient 3 at 2.5 years (D) and 10 years of age (E). (F) Patient 4 at 3 years of age. (G-H) Patient 5 at 16 months of age. (I-J) Patient 8 at 10 years of age. (K-L) Patient 9 at 5 years of age. Characteristic facial features include bulbous nasal tip, broad or depressed nasal bridge, prominent lower lip, and characteristically shaped eyes with mildly down-slanting palpebral fissures and mild epicanthal folds.
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