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Table 1 Breakpoint positions and sequence features of the 17 atypical NF1 deletions

From: SVA retrotransposon insertion-associated deletion represents a novel mutational mechanism underlying large genomic copy number changes with non-recurrent breakpoints

Patient

Breakpoint locationsa

Deletion size (bp)

Microhomology (bp)b

Insertion at breakpoint

SNCsc

Mosaic

Proximal (distal) breakpoint location

SINEs located at proximal and distal breakpointsd[homology]e

Postulated mutational mechanismf

08D2261

29,102,848 (30,079,302)

976,455

−

–

–

Yes

SUZ12P (between RAB11FIP4 and COPRS)

–

NHEJ

100206

29,065,415 (30,016,354)

950,940

–

–

+

Yes

SUZ12P (between RAB11FIP4 and COPRS)

–

NHEJ/ RBM

D1008345

29,094,424 (30,218,204)

1,123,781

1

–

–

No

SUZ12P (UTP6)

–

NHEJ

D05.2678

28,142,439 (34,112,082)

5,969,644

1

–

–

No

SSH2 (MMP28)

–

NHEJ

R84329

29,074,557 (30,223,384)

1,148,828

1

TGTCCCCTCTG

+

Yes

SUZ12P (UTP6)

–

NHEJ/RBM

70969

29,092,903 (30,175,393)

1,082,491

1

GGCCAGGTT

–

No

SUZ12P (between RAB11FIP4 and COPRS)

–

NHEJ/RBM

619

28,946,218 (31,954,580)

3,008,363

2

GTAGCAGAAT

–

No

NF1REPa (ASIC2)

–

NHEJ/RBM

61541

29,082,032 (30,187,273)

1,105,242

2

–

+

Yes

SUZ12P (between COPRS and UTP6)

–

NHEJ/RBM

2535

29,101,686 (30,250,762)

1,149,077

2

–

–

No

SUZ12P (between UTP6 and SUZ12)

–

NHEJ

R48018

29,084,006 (30,241,383)

1,157,378

2

–

–

No

SUZ12P (between UTP6 and SUZ12)

–

NHEJ

Ak-47055

29,082,023 (30,243,011)

1,160,989

4

–

–

Yes

SUZ12P (between UTP6 and SUZ12)

–

NHEJ

D06.1047

29,264,225 (29,783,515)

519,291

6

–

–

Yes

ADAP2 (RAB11FIP4)

–

MMEJ/RBM

659g

28,948,946 (30,345,260)

1,396,315

20

–

–

Yes

NF1REPa (NF1REPc)

AluY (AluSp) [84% in 135 bp]

Alu-mediated NAHR/MMEJ/RBM

1106

29,001,813 (29,765,892)

764,080

24

–

+

No

NF1REPa (RAB11FIP4)

AluSz6 (FLAM_C) [79% in 112 bp]

Alu-mediated NAHR/MMEJ/RBM

D0801587

27,726,501 (29,729,864)

2,003,364

52

–

–

Yes

TAOK1 (RAB11FIP4)

AluY (AluY) [89% in 301 bp]

Alu-mediated NAHR/MMEJ/RBM

DA-77/grandmother

29,100,005 (30,101,550)

1,001,546

2

SVA_F1 element

–

Yesh

SUZ12P (between RAB11FIP4 and COPRS)

–

SVA insertion

ASB4-55

29,103,071 (29,969,839)

866,769

–

SVA_F element

–

Yes

SUZ12P (between RAB11FIP4 and COPRS)

–

SVA insertion

  1. aIndicated are the genomic positions of the centromeric breakpoints and, in parentheses, the positions of the telomeric breakpoints (hg19). The indicated genomic positions correspond to the nucleotides immediately before and immediately after the deleted DNA sequence. Where microhomology (100% sequence identity) was present at the deletion breakpoints, the position of the centromeric breakpoint was defined as the last nucleotide adjacent to the region of microhomology whilst the position of the telomeric breakpoint was defined as the first nucleotide adjacent to the region of microhomology.
  2. bIndicated are the numbers of nucleotides exhibiting microhomology at the corresponding breakpoints. Microhomology was defined as one or more perfectly matching basepairs.
  3. cPlus signs indicate single nucleotide changes (SNCs) identified within the breakpoint-flanking regions (±75 bp) of the patients but absent from the reference sequence of the human genome (hg19). Where an SNC was identified within the breakpoint-flanking sequence, a replication-based mechanism (RBM) was considered to have been responsible for causing the SNC as well as the large NF1 deletion. Dashes indicate that SNCs were not detected in the respective breakpoint-flanking sequences.
  4. dSINEs and LINEs spanning the breakpoints were identified by means of the Repeat Masker track of the UCSC Genome Browser (date: 04.11.2013). Indicated are the Alu elements that were located at both breakpoints and in direct orientation with respect to each other. Dashes denote that directly oriented SINEs or LINEs located at both breakpoints and harboring the respective deletion breakpoints at homologous positions were not identified.
  5. eIndicated is the homology between the Alu elements as well as the length of the Alu sequences exhibiting the indicated homology.
  6. fNHEJ, non-homologous end joining; MMEJ, microhomology-mediated end joining; Alu-mediated NAHR,Alu-mediated nonallelic homologous end joining; RBM, replication-based mechanisms such as fork stalling and template-switching (FoSTeS) and microhomology-mediated break-induced replication (MMBIR). SVA insertion, SVA insertion-associated deletion.
  7. The deletions in patients 100206 and 61541 may have been mediated by either NHEJ or RBM. In both patients, SNCs were detected in breakpoint-flanking regions suggestive of the involvement of a low-fidelity DNA polymerase and a RBM. However, the involvement of NHEJ in the occurrence of these deletions cannot be excluded. In addition, the deletions identified in patients R84239, 70969 and 619 may have been caused by either NHEJ or RBM. The microinsertions identified at the breakpoints exhibit homology to sequences closely flanking the breakpoints and hence could have been caused by multiple template switching events indicative of a replication-based mechanism. However, we cannot exclude the possibility that the microinsertions occurred at random and that the deletions were mediated by NHEJ.
  8. The deletion identified in patient D06.1047 may have been mediated by MMEJ since microhomology > 5 bp is indicative of MMEJ [29]. However, microhomology has also been observed at rearrangement breakpoints mediated by a replication-based mechanism and hence the deletion in this patient could also have been caused by an RBM.
  9. In the case of patients 659, 1106 and D0801587, several mechanisms (Alu-mediated NAHR, MMEJ or RBM) could have caused the respective deletions. We observed directly oriented Alu elements at the deletion breakpoints of all three patients. Hence, the deletions may have been caused by Alu-mediated NAHR. Alternatively, the deletions could have been caused by MMEJ or RBM since microhomologies of 20 to 52 bp were observed at the breakpoints.
  10. gThe centromeric deletion breakpoint in patient 659 is located within intron 7 of the LRRC37Bpseudogene in NF1-REPa whereas the telomeric breakpoint is located within intron 2 of the functional LRRC37B gene located in NF1-REPc. The breakpoints of the deletion in patient 659 do not overlap with the nonallelic homologous recombination (NAHR) hotspots of type-1 NF1 deletions, termed PRS1 and PRS2. Hence, this atypical NF1 deletion is not considered to exhibit recurrent breakpoints located within regions of extended sequence homology.
  11. hThe grandmother of patient DA-77 exhibits somatic mosaicism since she possesses cells harboring the deletion alongside normal cells. Her granddaughter, patient DA-77, harbors the deletion in all of her cells.
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Genome Biology

ISSN: 1474-760X

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