Consensus statement on standards and guidelines for the molecular diagnostics of Alport syndrome: refining the ACMG criteria

Judy Savige; Helen Storey; Elizabeth Watson; Jens Michael Hertz; Constantinos Deltas; Alessandra Renieri; Francesca Mari; Pascale Hilbert; Pavlina Plevova; Peter Byers; Agne Cerkauskaite; Martin Gregory; Rimante Cerkauskiene; Danica Galesic Ljubanovic; Francesca Becherucci; Carmela Errichiello; Laura Massella; Valeria Aiello; Rachel Lennon; Louise Hopkinson; Ania Koziell; Adrian Lungu; Hansjorg Martin Rothe; Julia Hoefele; Miriam Zacchia; Tamara Nikuseva Martic; Asheeta Gupta; Albertien van Eerde; Susie Gear; Samuela Landini; Viviana Palazzo; Laith al-Rabadi; Kathleen Claes; Anniek Corveleyn; Evelien Van Hoof; Micheel van Geel; Maggie Williams; Emma Ashton; Hendica Belge; Elisabeth Ars; Agnieszka Bierzynska; Concetta Gangemi; Beata S. Lipska-Ziętkiewicz

doi:10.1038/s41431-021-00858-1

Consensus statement on standards and guidelines for the molecular diagnostics of Alport syndrome: refining the ACMG criteria

Judy Savige^*, Helen Storey, Elizabeth Watson, Jens Michael Hertz, Constantinos Deltas, Alessandra Renieri, Francesca Mari, Pascale Hilbert, Pavlina Plevova, Peter Byers, Agne Cerkauskaite, Martin Gregory, Rimante Cerkauskiene, Danica Galesic Ljubanovic, Francesca Becherucci, Carmela Errichiello, Laura Massella, Valeria Aiello, Rachel Lennon, Louise HopkinsonAnia Koziell, Adrian Lungu, Hansjorg Martin Rothe, Julia Hoefele, Miriam Zacchia, Tamara Nikuseva Martic, Asheeta Gupta, Albertien van Eerde, Susie Gear, Samuela Landini, Viviana Palazzo, Laith al-Rabadi, Kathleen Claes, Anniek Corveleyn, Evelien Van Hoof, Micheel van Geel, Maggie Williams, Emma Ashton, Hendica Belge, Elisabeth Ars, Agnieszka Bierzynska, Concetta Gangemi, Beata S. Lipska-Ziętkiewicz

^*Corresponding author for this work

Infectious Diseases

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Abstract

The recent Chandos House meeting of the Alport Variant Collaborative extended the indications for screening for pathogenic variants in the COL4A5, COL4A3 and COL4A4 genes beyond the classical Alport phenotype (haematuria, renal failure; family history of haematuria or renal failure) to include persistent proteinuria, steroid-resistant nephrotic syndrome, focal and segmental glomerulosclerosis (FSGS), familial IgA glomerulonephritis and end-stage kidney failure without an obvious cause. The meeting refined the ACMG criteria for variant assessment for the Alport genes (COL4A3–5). It identified ‘mutational hotspots’ (PM1) in the collagen IV α5, α3 and α4 chains including position 1 Glycine residues in the Gly-X-Y repeats in the intermediate collagenous domains; and Cysteine residues in the carboxy non-collagenous domain (PP3). It considered that ‘well-established’ functional assays (PS3, BS3) were still mainly research tools but sequencing and minigene assays were commonly used to confirm splicing variants. It was not possible to define the Minor Allele Frequency (MAF) threshold above which variants were considered Benign (BA1, BS1), because of the different modes of inheritances of Alport syndrome, and the occurrence of hypomorphic variants (often Glycine adjacent to a non-collagenous interruption) and local founder effects. Heterozygous COL4A3 and COL4A4 variants were common ‘incidental’ findings also present in normal reference databases. The recognition and interpretation of hypomorphic variants in the COL4A3–COL4A5 genes remains a challenge.

Original language	English
Pages (from-to)	1186-1197
Number of pages	12
Journal	European Journal of Human Genetics
Volume	29
Issue number	8
DOIs	https://doi.org/10.1038/s41431-021-00858-1
Publication status	Published - Aug 2021

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Savige, J., Storey, H., Watson, E., Hertz, J. M., Deltas, C., Renieri, A., Mari, F., Hilbert, P., Plevova, P., Byers, P., Cerkauskaite, A., Gregory, M., Cerkauskiene, R., Ljubanovic, D. G., Becherucci, F., Errichiello, C., Massella, L., Aiello, V., Lennon, R., ... Lipska-Ziętkiewicz, B. S. (2021). Consensus statement on standards and guidelines for the molecular diagnostics of Alport syndrome: refining the ACMG criteria. European Journal of Human Genetics, 29(8), 1186-1197. https://doi.org/10.1038/s41431-021-00858-1

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title = "Consensus statement on standards and guidelines for the molecular diagnostics of Alport syndrome: refining the ACMG criteria",

abstract = "The recent Chandos House meeting of the Alport Variant Collaborative extended the indications for screening for pathogenic variants in the COL4A5, COL4A3 and COL4A4 genes beyond the classical Alport phenotype (haematuria, renal failure; family history of haematuria or renal failure) to include persistent proteinuria, steroid-resistant nephrotic syndrome, focal and segmental glomerulosclerosis (FSGS), familial IgA glomerulonephritis and end-stage kidney failure without an obvious cause. The meeting refined the ACMG criteria for variant assessment for the Alport genes (COL4A3–5). It identified {\textquoteleft}mutational hotspots{\textquoteright} (PM1) in the collagen IV α5, α3 and α4 chains including position 1 Glycine residues in the Gly-X-Y repeats in the intermediate collagenous domains; and Cysteine residues in the carboxy non-collagenous domain (PP3). It considered that {\textquoteleft}well-established{\textquoteright} functional assays (PS3, BS3) were still mainly research tools but sequencing and minigene assays were commonly used to confirm splicing variants. It was not possible to define the Minor Allele Frequency (MAF) threshold above which variants were considered Benign (BA1, BS1), because of the different modes of inheritances of Alport syndrome, and the occurrence of hypomorphic variants (often Glycine adjacent to a non-collagenous interruption) and local founder effects. Heterozygous COL4A3 and COL4A4 variants were common {\textquoteleft}incidental{\textquoteright} findings also present in normal reference databases. The recognition and interpretation of hypomorphic variants in the COL4A3–COL4A5 genes remains a challenge.",

author = "Judy Savige and Helen Storey and Elizabeth Watson and Hertz, {Jens Michael} and Constantinos Deltas and Alessandra Renieri and Francesca Mari and Pascale Hilbert and Pavlina Plevova and Peter Byers and Agne Cerkauskaite and Martin Gregory and Rimante Cerkauskiene and Ljubanovic, {Danica Galesic} and Francesca Becherucci and Carmela Errichiello and Laura Massella and Valeria Aiello and Rachel Lennon and Louise Hopkinson and Ania Koziell and Adrian Lungu and Rothe, {Hansjorg Martin} and Julia Hoefele and Miriam Zacchia and Martic, {Tamara Nikuseva} and Asheeta Gupta and {van Eerde}, Albertien and Susie Gear and Samuela Landini and Viviana Palazzo and Laith al-Rabadi and Kathleen Claes and Anniek Corveleyn and {Van Hoof}, Evelien and {van Geel}, Micheel and Maggie Williams and Emma Ashton and Hendica Belge and Elisabeth Ars and Agnieszka Bierzynska and Concetta Gangemi and Lipska-Zi{\c e}tkiewicz, {Beata S.}",

year = "2021",

month = aug,

doi = "10.1038/s41431-021-00858-1",

language = "English",

volume = "29",

pages = "1186--1197",

journal = "European Journal of Human Genetics",

issn = "1018-4813",

publisher = "Springer Nature [academic journals on nature.com]",

number = "8",

}

Savige, J, Storey, H, Watson, E, Hertz, JM, Deltas, C, Renieri, A, Mari, F, Hilbert, P, Plevova, P, Byers, P, Cerkauskaite, A, Gregory, M, Cerkauskiene, R, Ljubanovic, DG, Becherucci, F, Errichiello, C, Massella, L, Aiello, V, Lennon, R, Hopkinson, L, Koziell, A, Lungu, A, Rothe, HM, Hoefele, J, Zacchia, M, Martic, TN, Gupta, A, van Eerde, A, Gear, S, Landini, S, Palazzo, V, al-Rabadi, L, Claes, K, Corveleyn, A, Van Hoof, E, van Geel, M, Williams, M, Ashton, E, Belge, H, Ars, E, Bierzynska, A, Gangemi, C & Lipska-Ziętkiewicz, BS 2021, 'Consensus statement on standards and guidelines for the molecular diagnostics of Alport syndrome: refining the ACMG criteria', European Journal of Human Genetics, vol. 29, no. 8, pp. 1186-1197. https://doi.org/10.1038/s41431-021-00858-1

TY - JOUR

T1 - Consensus statement on standards and guidelines for the molecular diagnostics of Alport syndrome

T2 - refining the ACMG criteria

AU - Savige, Judy

AU - Storey, Helen

AU - Watson, Elizabeth

AU - Hertz, Jens Michael

AU - Deltas, Constantinos

AU - Renieri, Alessandra

AU - Mari, Francesca

AU - Hilbert, Pascale

AU - Plevova, Pavlina

AU - Byers, Peter

AU - Cerkauskaite, Agne

AU - Gregory, Martin

AU - Cerkauskiene, Rimante

AU - Ljubanovic, Danica Galesic

AU - Becherucci, Francesca

AU - Errichiello, Carmela

AU - Massella, Laura

AU - Aiello, Valeria

AU - Lennon, Rachel

AU - Hopkinson, Louise

AU - Koziell, Ania

AU - Lungu, Adrian

AU - Rothe, Hansjorg Martin

AU - Hoefele, Julia

AU - Zacchia, Miriam

AU - Martic, Tamara Nikuseva

AU - Gupta, Asheeta

AU - van Eerde, Albertien

AU - Gear, Susie

AU - Landini, Samuela

AU - Palazzo, Viviana

AU - al-Rabadi, Laith

AU - Claes, Kathleen

AU - Corveleyn, Anniek

AU - Van Hoof, Evelien

AU - van Geel, Micheel

AU - Williams, Maggie

AU - Ashton, Emma

AU - Belge, Hendica

AU - Ars, Elisabeth

AU - Bierzynska, Agnieszka

AU - Gangemi, Concetta

AU - Lipska-Ziętkiewicz, Beata S.

PY - 2021/8

Y1 - 2021/8

N2 - The recent Chandos House meeting of the Alport Variant Collaborative extended the indications for screening for pathogenic variants in the COL4A5, COL4A3 and COL4A4 genes beyond the classical Alport phenotype (haematuria, renal failure; family history of haematuria or renal failure) to include persistent proteinuria, steroid-resistant nephrotic syndrome, focal and segmental glomerulosclerosis (FSGS), familial IgA glomerulonephritis and end-stage kidney failure without an obvious cause. The meeting refined the ACMG criteria for variant assessment for the Alport genes (COL4A3–5). It identified ‘mutational hotspots’ (PM1) in the collagen IV α5, α3 and α4 chains including position 1 Glycine residues in the Gly-X-Y repeats in the intermediate collagenous domains; and Cysteine residues in the carboxy non-collagenous domain (PP3). It considered that ‘well-established’ functional assays (PS3, BS3) were still mainly research tools but sequencing and minigene assays were commonly used to confirm splicing variants. It was not possible to define the Minor Allele Frequency (MAF) threshold above which variants were considered Benign (BA1, BS1), because of the different modes of inheritances of Alport syndrome, and the occurrence of hypomorphic variants (often Glycine adjacent to a non-collagenous interruption) and local founder effects. Heterozygous COL4A3 and COL4A4 variants were common ‘incidental’ findings also present in normal reference databases. The recognition and interpretation of hypomorphic variants in the COL4A3–COL4A5 genes remains a challenge.

AB - The recent Chandos House meeting of the Alport Variant Collaborative extended the indications for screening for pathogenic variants in the COL4A5, COL4A3 and COL4A4 genes beyond the classical Alport phenotype (haematuria, renal failure; family history of haematuria or renal failure) to include persistent proteinuria, steroid-resistant nephrotic syndrome, focal and segmental glomerulosclerosis (FSGS), familial IgA glomerulonephritis and end-stage kidney failure without an obvious cause. The meeting refined the ACMG criteria for variant assessment for the Alport genes (COL4A3–5). It identified ‘mutational hotspots’ (PM1) in the collagen IV α5, α3 and α4 chains including position 1 Glycine residues in the Gly-X-Y repeats in the intermediate collagenous domains; and Cysteine residues in the carboxy non-collagenous domain (PP3). It considered that ‘well-established’ functional assays (PS3, BS3) were still mainly research tools but sequencing and minigene assays were commonly used to confirm splicing variants. It was not possible to define the Minor Allele Frequency (MAF) threshold above which variants were considered Benign (BA1, BS1), because of the different modes of inheritances of Alport syndrome, and the occurrence of hypomorphic variants (often Glycine adjacent to a non-collagenous interruption) and local founder effects. Heterozygous COL4A3 and COL4A4 variants were common ‘incidental’ findings also present in normal reference databases. The recognition and interpretation of hypomorphic variants in the COL4A3–COL4A5 genes remains a challenge.

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DO - 10.1038/s41431-021-00858-1

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EP - 1197

JO - European Journal of Human Genetics

JF - European Journal of Human Genetics

IS - 8

ER -

Consensus statement on standards and guidelines for the molecular diagnostics of Alport syndrome: refining the ACMG criteria

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