A BBS1 SVA F retrotransposon insertion is a frequent cause of Bardet-Biedl syndrome

Clarisse Delvallée; Samuel Nicaise; Manuela Antin; Anne Sophie Leuvrey; Elsa Nourisson; Carmen C. Leitch; Georgios Kellaris; Corinne Stoetzel; Véronique Geoffroy; Sophie Scheidecker; Boris Keren; Christel Depienne; Joakim Klar; Niklas Dahl; Jean François Deleuze; Emmanuelle Génin; Richard Redon; Florence Demurger; Koenraad Devriendt; Michèle Mathieu-Dramard; Christine Poitou-Bernert; Sylvie Odent; Nicholas Katsanis; Jean Louis Mandel; Erica E. Davis; Hélène Dollfus; Jean Muller

doi:10.1111/cge.13878

A BBS1 SVA F retrotransposon insertion is a frequent cause of Bardet-Biedl syndrome

Clarisse Delvallée, Samuel Nicaise, Manuela Antin, Anne Sophie Leuvrey, Elsa Nourisson, Carmen C. Leitch, Georgios Kellaris, Corinne Stoetzel, Véronique Geoffroy, Sophie Scheidecker, Boris Keren, Christel Depienne, Joakim Klar, Niklas Dahl, Jean François Deleuze, Emmanuelle Génin, Richard Redon, Florence Demurger, Koenraad Devriendt, Michèle Mathieu-DramardChristine Poitou-Bernert, Sylvie Odent, Nicholas Katsanis, Jean Louis Mandel, Erica E. Davis, Hélène Dollfus, Jean Muller^*

^*Corresponding author for this work

Pediatrics

Research output: Contribution to journal › Article › peer-review

21 Scopus citations

Abstract

Bardet-Biedl syndrome (BBS) is a ciliopathy characterized by retinitis pigmentosa, obesity, polydactyly, cognitive impairment and renal failure. Pathogenic variants in 24 genes account for the molecular basis of >80% of cases. Toward saturated discovery of the mutational basis of the disorder, we carefully explored our cohorts and identified a hominid-specific SINE-R/VNTR/Alu type F (SVA-F) insertion in exon 13 of BBS1 in eight families. In six families, the repeat insertion was found in trans with c.1169 T > G, p.Met390Arg and in two families the insertion was found in addition to other recessive BBS loci. Whole genome sequencing, de novo assembly and SNP array analysis were performed to characterize the genomic event. This insertion is extremely rare in the general population (found in 8 alleles of 8 BBS cases but not in >10 800 control individuals from gnomAD-SV) and due to a founder effect. Its 2435 bp sequence contains hallmarks of LINE1 mediated retrotransposition. Functional studies with patient-derived cell lines confirmed that the BBS1 SVA-F is deleterious as evidenced by a significant depletion of both mRNA and protein levels. Such findings highlight the importance of dedicated bioinformatics pipelines to identify all types of variation.

Original language	English (US)
Pages (from-to)	318-324
Number of pages	7
Journal	Clinical genetics
Volume	99
Issue number	2
DOIs	https://doi.org/10.1111/cge.13878
State	Published - Feb 2021

Keywords

BBS1
Bardet-Biedl syndrome
Mobile element insertion
SVA F
founder effect

ASJC Scopus subject areas

Genetics(clinical)
Genetics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1111/cge.13878

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Delvallée, C., Nicaise, S., Antin, M., Leuvrey, A. S., Nourisson, E., Leitch, C. C., Kellaris, G., Stoetzel, C., Geoffroy, V., Scheidecker, S., Keren, B., Depienne, C., Klar, J., Dahl, N., Deleuze, J. F., Génin, E., Redon, R., Demurger, F., Devriendt, K., ... Muller, J. (2021). A BBS1 SVA F retrotransposon insertion is a frequent cause of Bardet-Biedl syndrome. Clinical genetics, 99(2), 318-324. https://doi.org/10.1111/cge.13878

@article{49359beb2392486db1f37daa5237adbe,

title = "A BBS1 SVA F retrotransposon insertion is a frequent cause of Bardet-Biedl syndrome",

abstract = "Bardet-Biedl syndrome (BBS) is a ciliopathy characterized by retinitis pigmentosa, obesity, polydactyly, cognitive impairment and renal failure. Pathogenic variants in 24 genes account for the molecular basis of >80% of cases. Toward saturated discovery of the mutational basis of the disorder, we carefully explored our cohorts and identified a hominid-specific SINE-R/VNTR/Alu type F (SVA-F) insertion in exon 13 of BBS1 in eight families. In six families, the repeat insertion was found in trans with c.1169 T > G, p.Met390Arg and in two families the insertion was found in addition to other recessive BBS loci. Whole genome sequencing, de novo assembly and SNP array analysis were performed to characterize the genomic event. This insertion is extremely rare in the general population (found in 8 alleles of 8 BBS cases but not in >10 800 control individuals from gnomAD-SV) and due to a founder effect. Its 2435 bp sequence contains hallmarks of LINE1 mediated retrotransposition. Functional studies with patient-derived cell lines confirmed that the BBS1 SVA-F is deleterious as evidenced by a significant depletion of both mRNA and protein levels. Such findings highlight the importance of dedicated bioinformatics pipelines to identify all types of variation.",

keywords = "BBS1, Bardet-Biedl syndrome, Mobile element insertion, SVA F, founder effect",

author = "Clarisse Delvall{\'e}e and Samuel Nicaise and Manuela Antin and Leuvrey, {Anne Sophie} and Elsa Nourisson and Leitch, {Carmen C.} and Georgios Kellaris and Corinne Stoetzel and V{\'e}ronique Geoffroy and Sophie Scheidecker and Boris Keren and Christel Depienne and Joakim Klar and Niklas Dahl and Deleuze, {Jean Fran{\c c}ois} and Emmanuelle G{\'e}nin and Richard Redon and Florence Demurger and Koenraad Devriendt and Mich{\`e}le Mathieu-Dramard and Christine Poitou-Bernert and Sylvie Odent and Nicholas Katsanis and Mandel, {Jean Louis} and Davis, {Erica E.} and H{\'e}l{\`e}ne Dollfus and Jean Muller",

note = "Publisher Copyright: {\textcopyright} 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd",

year = "2021",

month = feb,

doi = "10.1111/cge.13878",

language = "English (US)",

volume = "99",

pages = "318--324",

journal = "Clinical genetics",

issn = "0009-9163",

publisher = "Wiley-Blackwell",

number = "2",

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Delvallée, C, Nicaise, S, Antin, M, Leuvrey, AS, Nourisson, E, Leitch, CC, Kellaris, G, Stoetzel, C, Geoffroy, V, Scheidecker, S, Keren, B, Depienne, C, Klar, J, Dahl, N, Deleuze, JF, Génin, E, Redon, R, Demurger, F, Devriendt, K, Mathieu-Dramard, M, Poitou-Bernert, C, Odent, S, Katsanis, N, Mandel, JL, Davis, EE, Dollfus, H & Muller, J 2021, 'A BBS1 SVA F retrotransposon insertion is a frequent cause of Bardet-Biedl syndrome', Clinical genetics, vol. 99, no. 2, pp. 318-324. https://doi.org/10.1111/cge.13878

TY - JOUR

T1 - A BBS1 SVA F retrotransposon insertion is a frequent cause of Bardet-Biedl syndrome

AU - Delvallée, Clarisse

AU - Nicaise, Samuel

AU - Antin, Manuela

AU - Leuvrey, Anne Sophie

AU - Nourisson, Elsa

AU - Leitch, Carmen C.

AU - Kellaris, Georgios

AU - Stoetzel, Corinne

AU - Geoffroy, Véronique

AU - Scheidecker, Sophie

AU - Keren, Boris

AU - Depienne, Christel

AU - Klar, Joakim

AU - Dahl, Niklas

AU - Deleuze, Jean François

AU - Génin, Emmanuelle

AU - Redon, Richard

AU - Demurger, Florence

AU - Devriendt, Koenraad

AU - Mathieu-Dramard, Michèle

AU - Poitou-Bernert, Christine

AU - Odent, Sylvie

AU - Katsanis, Nicholas

AU - Mandel, Jean Louis

AU - Davis, Erica E.

AU - Dollfus, Hélène

AU - Muller, Jean

PY - 2021/2

Y1 - 2021/2

N2 - Bardet-Biedl syndrome (BBS) is a ciliopathy characterized by retinitis pigmentosa, obesity, polydactyly, cognitive impairment and renal failure. Pathogenic variants in 24 genes account for the molecular basis of >80% of cases. Toward saturated discovery of the mutational basis of the disorder, we carefully explored our cohorts and identified a hominid-specific SINE-R/VNTR/Alu type F (SVA-F) insertion in exon 13 of BBS1 in eight families. In six families, the repeat insertion was found in trans with c.1169 T > G, p.Met390Arg and in two families the insertion was found in addition to other recessive BBS loci. Whole genome sequencing, de novo assembly and SNP array analysis were performed to characterize the genomic event. This insertion is extremely rare in the general population (found in 8 alleles of 8 BBS cases but not in >10 800 control individuals from gnomAD-SV) and due to a founder effect. Its 2435 bp sequence contains hallmarks of LINE1 mediated retrotransposition. Functional studies with patient-derived cell lines confirmed that the BBS1 SVA-F is deleterious as evidenced by a significant depletion of both mRNA and protein levels. Such findings highlight the importance of dedicated bioinformatics pipelines to identify all types of variation.

AB - Bardet-Biedl syndrome (BBS) is a ciliopathy characterized by retinitis pigmentosa, obesity, polydactyly, cognitive impairment and renal failure. Pathogenic variants in 24 genes account for the molecular basis of >80% of cases. Toward saturated discovery of the mutational basis of the disorder, we carefully explored our cohorts and identified a hominid-specific SINE-R/VNTR/Alu type F (SVA-F) insertion in exon 13 of BBS1 in eight families. In six families, the repeat insertion was found in trans with c.1169 T > G, p.Met390Arg and in two families the insertion was found in addition to other recessive BBS loci. Whole genome sequencing, de novo assembly and SNP array analysis were performed to characterize the genomic event. This insertion is extremely rare in the general population (found in 8 alleles of 8 BBS cases but not in >10 800 control individuals from gnomAD-SV) and due to a founder effect. Its 2435 bp sequence contains hallmarks of LINE1 mediated retrotransposition. Functional studies with patient-derived cell lines confirmed that the BBS1 SVA-F is deleterious as evidenced by a significant depletion of both mRNA and protein levels. Such findings highlight the importance of dedicated bioinformatics pipelines to identify all types of variation.

KW - BBS1

KW - Bardet-Biedl syndrome

KW - Mobile element insertion

KW - SVA F

KW - founder effect

UR - http://www.scopus.com/inward/record.url?scp=85096675793&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85096675793&partnerID=8YFLogxK

U2 - 10.1111/cge.13878

DO - 10.1111/cge.13878

M3 - Article

C2 - 33169370

AN - SCOPUS:85096675793

SN - 0009-9163

VL - 99

SP - 318

EP - 324

JO - Clinical genetics

JF - Clinical genetics

IS - 2

ER -

A BBS1 SVA F retrotransposon insertion is a frequent cause of Bardet-Biedl syndrome

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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