Genomic Landscape of Branchio-Oto-Renal Syndrome through Whole-Genome Sequencing: A Single Rare Disease Center Experience in South Korea
Abstract
:1. Introduction
2. Results
2.1. Cohort Description and Clinical Phenotypes
2.2. Stepwise Molecular Diagnostic Yield
2.3. Genomic Landscape
3. Discussion
No | PMID | Writer and References | Year | Molecular Diagnostic Yield | Cohort Information | Method | EYA1 | SIX1 | SIX5 | ANKRD11 | SV Annotation |
---|---|---|---|---|---|---|---|---|---|---|---|
1 | 9361030 | Sonia Abdelhak et al. [39] | 1997 | 44% (16/36 families) | 36 families clinically diagnosed with BOR syndrome | PCR direct exon sequencing Southern blot | 16 | - | - | - | 1 EYA1 deletion from intron X to exon 16 1 EYA1 deletion from exon 9 to intron IX 1 EYA1 Alu insertion |
2 | 10991693 | Sarah Rickard et al. [32] | 2000 | 61% (11/18 families) | 18 families with probable BOR syndrome | PCR direct exon sequencing SSCP analysis | 11 | - | - | - | - |
3 | 15146463 | Eugene H. Chang et al. [10] | 2004 | 17% (19/106 families) | 106 families with two or more BOR features | SSCP analysis Bidirectional exon sequencing Semi-quantitative fluorescent multiplex PCR | 19 | - | - | - | 2 entire EYA1 deletions 1 EYA1 deletion from exon 10 to exon 12 |
4 | 16491411 | Michiyo Okada et al. [40] | 2006 | 33% (5/15 families) | 15 families with BOR syndrome or BOR-related conditions | PCR direct sequencing RT-PCR | 5 | - | - | - | - |
5 | 17637804 | Kirsten Marie Sanggaard et al. [37] | 2007 | 83% (5/6 families) | 6 families clinically diagnosed with BOR syndrome | Marker analysis Linkage analysis MLPA PCR direct exon sequencing | 4 | 1 | - | - | - |
6 | 17357085 | Bethan E. Hoskins et al. [13] | 2007 | 5% (5/95 families) | 95 families who met BOR criteria but without EYA1 or SIX1 mutations | PCR direct exon sequencing | - | - | 5 | - | - |
7 | 18330911 | Amit Kochhar et al. [33] | 2008 | 4% (10/247 families) | 247 families with BOR syndrome | DHPLC Bidirectional exon sequencing PCR direct exon sequencing | - | 10 | - | - | - |
8 | 18220287 | Dana J. Orten et al. [27] | 2008 | 30% (76/248 families) | 248 families with at least one of the major BOR criteria | PCR direct exon sequencing DHPLC | 76 | - | - | - | - |
9 | 19206155 | Tracy L. Stockley et al. [41] | 2009 | 82% (14/17 families) | 17 families with a clinical suspicion of BOR syndrome | Bidirectional exon sequencing MLPA | 14 | - | - | - | 1 entire EYA1 deletion 1 EYA1 deletion of exon 9 1 EYA1 deletion from exon 9 to exon 10 |
10 | 21280147 | Krug et al. [17] | 2011 | 46% (45/124 families) | 124 families with BOR syndrome | Whole-exome sequencing Multiplex PCR MLPA | 42 | 3 | - | - | - |
11 | 22447252 | Shin-Hao Wang et al. [42] | 2012 | 16% (2/12 families) | 12 families who fulfilled the criteria for BOR syndrome | Direct sequencing of EYA1/SIX1 Quantitative PCR | 2 | - | - | - | - |
12 | 23840632 | Mee Hyun Song et al. [38] | 2013 | 71% (5/7 families) | 7 families with hearing loss and one or more typical features of BOR syndrome | PCR direct exon sequencing MLPA | 5 | - | - | - | 1 entire EYA1 deletion |
13 | 23851940 | Patrick D. Brophy et al. [43] | 2013 | 14% (5/32 families) | 32 BOR probands negative for coding sequence and splice site mutations in known BOR-causing genes | Array-based CGH Long-range PCR | 5 | - | - | - | 1 EYA1 deletion from intron 17 to exon 18 and entire 3′ UTR 4 entire EYA1 deletions |
14 | 28583505 | Kyle D. Klingbeil et al. [44] | 2017 | 60% (6/10 families) | 10 families clinically diagnosed with BOR syndrome | Whole-exome sequencing Sanger sequencing | 6 | - | - | - | 2 entire EYA1 deletions |
15 | 29500469 | Ai Unzaki et al. [45] | 2018 | 72% (26/36 families) | 36 families clinically diagnosed with BOR syndrome | Direct exon sequencing MLPA Array-based CGH NGS | 22 | 1 | - | - | 1 EYA1 deletion from exon 10 to exon 18 1 EYA1 deletion from exon 2 to exon 3 1 EYA1 deletion from exon 2 to exon 12 1 EYA1 exon 12 deletion 2 EYA1 exon 17 deletions |
16 | 31427586 | Michie Ideura et al. [26] | 2019 | 32% (19/59 families) | 59 families clinically diagnosed with BOR/BO syndrome | NGS Array-based CGH | 18 | 1 | - | - | 1 entire EYA1 deletion |
This study | S. H. Cho et al. | 2024 | 91% (21/23 families) | 23 families with a clinical suspicion of BOR syndrome | MLPA Whole-exome sequencing Whole-genome sequencing | 12 | 8 | - | 1 | 1 EYA1 complex genomic rearrangement 1 EYA1 cryptic inversion 1 entire EYA1 deletion |
4. Materials and Methods
4.1. Participants and Clinical Assessment
4.2. Conventional Genetic Pipeline
4.3. Whole-Genome Sequencing and Bioinformatic Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Family | Sex/Age | Diagnostic Approach * | Gene | Variant [NM/NP No.] | Zygosity/ Inheritance | ACMG Classification # | Affected Domain | Branchial Anomalies | Preauricular Pits | Hearing Loss | Renal Anomalies | EAC Anomalies | Middle Ear Anomalies | Inner Ear Anomalies | Typical/ Atypical |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
BOR01 | F/15 | WES | EYA1 | c.1319G>A;p.Arg440Gln [NM_000503.6/NP_000494.2] | Het/ de novo | Pathogenic | ED | O | O | MHL | O | X | O | O | Typical |
BOR02 | F/22 | WGS | EYA1 | Complex genomic rearrangement g.[71211857_712282326inv;712111857_71215145del] | Het/AD | Pathogenic | N/D | O | O | MHL | X | X | O | O | Typical |
F/56 | WGS | EYA1 | Complex genomic rearrangement g.[71211857_712282326inv;712111857_71215145del] | Het/AD | Pathogenic | N/D | X | O | MHL | X | O | O | X | Atypical | |
M/32 | WGS | EYA1 | Complex genomic rearrangement g.[71211857_712282326inv;712111857_71215145del] | Het/AD | Pathogenic | N/D | O | O | SNHL | O | X | X | O | Typical | |
F/29 | WGS | EYA1 | Complex genomic rearrangement g.[71211857_712282326inv;712111857_71215145del] | Het/AD | Pathogenic | N/D | O | O | SNHL | X | X | X | O | Typical | |
BOR03 | M/31 | WES | EYA1 | c.1623_1626dup:p.Gln543AsnfsTer90 [NM_000503.6/NP_000494.2] | Het/ de novo | Pathogenic | ED | O | O | SNHL | X | X | X | O | Typical |
BOR04 | F/0 | WES | EYA1 | c.1598-2A>C:p.? [NM_000503.6/NP_000494.2] | Het/AD | Pathogenic | N/D | O | O | MHL | X | O | O | X | Typical |
F/30 | WES | EYA1 | c.1598-2A>C:p.? [NM_000503.6/NP_000494.2] | Het/AD | Pathogenic | N/D | O | O | MHL | X | X | O | X | Typical | |
BOR05 | F/4 | WGS | EYA1 | Cryptic inversion c.49-7047[NC_000008.11:g.71448124]inv | Het/AD | Pathogenic | N/D | O | O | SNHL | X | O | X | O | Typical |
F/33 | WGS | EYA1 | Cryptic inversion c.49-7047[NC_000008.11:g.71448124]inv | Het/AD | Pathogenic | N/D | O | X | MHL | X | X | O | X | Typical | |
BOR06 | F/8 | WES | EYA1 | c.1081C>T:p.Arg361Ter [NM_000503.6/NP_000494.2] | Het/AD | Pathogenic | ED | O | O | MHL | X | O | O | O | Typical |
M/8 | WES | EYA1 | c.1081C>T:p.Arg361Ter [NM_000503.6/NP_000494.2] | Het/AD | Pathogenic | ED | O | O | MHL | X | X | O | O | Typical | |
BOR07 | M/17 | WES | EYA1 | c.1220G>A:p.Arg407Gln [NM_000503.6/NP_000494.2] | Het / de novo | Pathogenic | ED | O | O | MHL | O | O | O | O | Typical |
BOR08 | M/6 | WES | EYA1 | c.1276G>A:p.Gly426Ser [NM_000503.6/NP_000494.2] | Het/AD | Likely Pathogenic | ED | O | O | MHL | O | O | O | X | Typical |
M/9 | WES | EYA1 | c.1276G>A:p.Gly426Ser [NM_000503.6/NP_000494.2] | Het/AD | Likely Pathogenic | ED | O | O | X | X | X | X | X | Atypical | |
BOR09 | F/12 | MLPA | EYA1 | Deletion | Het/AD | Pathogenic | N/D | O | O | MHL | X | O | O | O | Typical |
BOR10 | M/7 | WES | EYA1 | c.1081C>T:p.Arg361Ter [NM_000503.6/NP_000494.2] | Het/AD | Pathogenic | ED | X | O | MHL | O | O | O | O | Typical |
BOR11 | F/7 | WES | EYA1 | c.1715G>A:p.Trp572Ter [NM_000503.6/NP_000494.2] | Het/AD | Likely Pathogenic | ED | O | O | MHL | X | X | O | O | Typical |
F/12 | WES | EYA1 | c.1715G>A:p.Trp572Ter [NM_000503.6/NP_000494.2] | Het/AD | Likely Pathogenic | ED | O | O | MHL | X | X | O | X | Typical | |
BOR12 | M/31 | WES | EYA1 | c.802C>T:p.Gln268Ter [NM_000503.6/NP_000494.2] | Het/AD | Likely Pathogenic | ED | O | O | MHL | X | X | O | X | Typical |
M/28 | WES | EYA1 | c.802C>T:p.Gln268Ter [NM_000503.6/NP_000494.2] | Het/AD | Likely Pathogenic | ED | O | O | MHL | X | X | O | X | Typical | |
M/64 | WES | EYA1 | c.802C>T:p.Gln268Ter [NM_000503.6/NP_000494.2] | Het/AD | Likely Pathogenic | ED | O | O | SNHL | X | X | X | O | Typical | |
F/56 | WES | EYA1 | c.802C>T:p.Gln268Ter [NM_000503.6/NP_000494.2] | Het/AD | Likely Pathogenic | ED | O | O | MHL | X | X | O | O | Typical | |
F/49 | WES | EYA1 | c.802C>T:p.Gln268Ter [NM_000503.6/NP_000494.2] | Het/AD | Likely Pathogenic | ED | O | O | MHL | X | X | O | X | Typical | |
F/20 | WES | EYA1 | c.802C>T:p.Gln268Ter [NM_000503.6/NP_000494.2] | Het/AD | Likely Pathogenic | ED | O | O | MHL | X | X | O | X | Typical | |
BOR13 | F/31 | WES | SIX1 | c.501G>C:p.Gln167His [NM_005982.4/NP_005973.1] | Het/AD | Likely Pathogenic | HD | O | X | SNHL | X | X | X | X | Atypical |
F/60 | WES | SIX1 | c.501G>C:p.Gln167His [NM_005982.4/NP_005973.1] | Het/AD | Likely Pathogenic | HD | X | X | SNHL | X | X | X | X | Atypical | |
F/30 | WES | SIX1 | c.501G>C:p.Gln167His [NM_005982.4/NP_005973.1] | Het/AD | Likely Pathogenic | HD | X | X | SNHL | X | X | X | X | Atypical | |
BOR14 | F/10 | WES | SIX1 | c.386_391del:p.Tyr129_Cys130del [NM_005982.4/NP_005973.1] | Het/AD | Pathogenic | HD | X | O | SNHL | X | X | X | X | Atypical |
F/40 | WES | SIX1 | c.386_391del:p.Tyr129_Cys130del [NM_005982.4/NP_005973.1] | Het/AD | Pathogenic | HD | X | O | SNHL | X | X | X | X | Atypical | |
BOR15 | F/11 | WES | SIX1 | c.397_399del:p.Glu133del [NM_005982.4/NP_005973.1] | Het/ de novo | Likely Pathogenic | HD | X | O | SNHL | X | X | X | O | Atypical |
BOR16 | M/76 | WES | SIX1 | c.21del:p.Phe7LeufsTer82 [NM_005982.4/NP_005973.1] | Het/AD | Pathogenic | SD | X | O | SNHL | X | X | X | X | Atypical |
BOR17 | M/10 | WES | SIX1 | c.386A>C:p.Tyr129Ser [NM_005982.4/NP_005973.1] | Het/AD | Likely Pathogenic | HD | X | X | SNHL | X | X | X | X | Atypical |
M/44 | WES | SIX1 | c.386A>C:p.Tyr129Ser [NM_005982.4/NP_005973.1] | Het/AD | Likely Pathogenic | HD | X | X | MHL | X | X | O | X | Atypical | |
BOR18 | M/22 | WES | SIX1 | c.176A>C:p.His59Pro [NM_005982.4/NP_005973.1] | Het/AD | Likely Pathogenic | SD | X | O | SNHL | X | X | X | X | Atypical |
BOR19 | M/16 | WES | SIX1 | c.513G>T:p.Trp171Cys [NM_005982.4/NP_005973.1] | Het/ de novo | Pathogenic | HD | O | O | CHL | X | X | X | X | Typical |
BOR20 | M/1 | WES | SIX1 | c.376_378del:p.Glu126del [NM_005982.4/NP_005973.1] | Het/AD | Likely Pathogenic | HD | X | O | SNHL | X | X | X | X | Atypical |
M/1 | WES | SIX1 | c.376_378del:p.Glu126del [NM_005982.4/NP_005973.1] | Het/AD | Likely Pathogenic | HD | X | X | SNHL | X | X | X | X | Atypical | |
BOR21 | F/1 | WES | ANKRD11 | c.2409_2412del:p.Glu805ArgfsTer57 [NM_013275.6/NP_037407.4] | Het/AD | Pathogenic | Linker region | O | O | SNHL | X | X | X | X | Typical |
BOR22 | M/13 | WGS | Negative | - | - | - | - | O | O | MHL | O | X | O | O | Typical |
BOR23 | F/51 | WES | Negative | - | - | - | - | X | O | MHL | X | X | O | X | N/D |
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Cho, S.H.; Jeong, S.H.; Choi, W.H.; Lee, S.-Y. Genomic Landscape of Branchio-Oto-Renal Syndrome through Whole-Genome Sequencing: A Single Rare Disease Center Experience in South Korea. Int. J. Mol. Sci. 2024, 25, 8149. https://doi.org/10.3390/ijms25158149
Cho SH, Jeong SH, Choi WH, Lee S-Y. Genomic Landscape of Branchio-Oto-Renal Syndrome through Whole-Genome Sequencing: A Single Rare Disease Center Experience in South Korea. International Journal of Molecular Sciences. 2024; 25(15):8149. https://doi.org/10.3390/ijms25158149
Chicago/Turabian StyleCho, Sung Ho, Sung Ho Jeong, Won Hoon Choi, and Sang-Yeon Lee. 2024. "Genomic Landscape of Branchio-Oto-Renal Syndrome through Whole-Genome Sequencing: A Single Rare Disease Center Experience in South Korea" International Journal of Molecular Sciences 25, no. 15: 8149. https://doi.org/10.3390/ijms25158149