Reclassification of an FBN1 variant emphasizes the importance of segregation analysis, information sharing, and multidisciplinary teamwork in understanding genetic variants in health and disease

Dorte L. Lildballe; Sara Markholt; Christina Daugaard Lyngholm; Qin Hao; Christina Fagerberg; Dorte Guldbrand Nielsen; Julius Hannibal Svensmark; Birgitte Rode Diness; Pernille A. Gregersen

doi:10.1002/ajmg.a.63795

Reclassification of an FBN1 variant emphasizes the importance of segregation analysis, information sharing, and multidisciplinary teamwork in understanding genetic variants in health and disease

Dorte L. Lildballe^*, Sara Markholt, Christina Daugaard Lyngholm, Qin Hao, Christina Fagerberg, Dorte Guldbrand Nielsen, Julius Hannibal Svensmark, Birgitte Rode Diness, Pernille A. Gregersen

^*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

Abstract

Marfan syndrome (MFS) is a complex connective tissue disorder characterized by considerable clinical variability. The diagnosis of MFS is based on the Ghent criteria, which require the presence of both clinical and genetic features. MFS is primarily caused by pathogenic alterations in FBN1, which encodes the fibrillin-1 protein. Fibrillin-1 comprises multiple domains rich in cysteine residues, with disulfide bonds formed between these residues. It has long been recognized that variants that alter or introduce cysteine residues damage protein function, leading to the development of MFS. In this study, we report a cysteine-introducing variant: FBN1 variant, c.6724C>T (p.[Arg2242Cys]). We have observed this variant in several individuals without MFS, challenging our previous understanding of the underlying mechanism of MFS. This finding emphasizes the importance of revisiting and reevaluating our current knowledge in light of new and unexpected observations. Moreover, our study highlights the significance of incorporating local and national data on allele frequencies, as well as employing multidisciplinary phenotyping approaches, in the classification of genetic variants. By considering a wide range of information, we can enhance the accuracy and reliability of variant classification, ultimately improving the diagnosis and management of individuals with genetic disorders like MFS.

Original language	English
Journal	American Journal of Medical Genetics - Part A
ISSN	1552-4825
DOIs	https://doi.org/10.1002/ajmg.a.63795
Publication status	E-pub ahead of print - 2024

Keywords

clinical genetics
FBN1
fibrillin-1
genetic variant classification
Marfan syndrome

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Lildballe, D. L., Markholt, S., Lyngholm, C. D., Hao, Q., Fagerberg, C., Nielsen, D. G., Svensmark, J. H., Diness, B. R., & Gregersen, P. A. (2024). Reclassification of an FBN1 variant emphasizes the importance of segregation analysis, information sharing, and multidisciplinary teamwork in understanding genetic variants in health and disease. American Journal of Medical Genetics - Part A. Advance online publication. https://doi.org/10.1002/ajmg.a.63795

@article{9cb0b0423d294039aa6cc48fcd2ec61e,

title = "Reclassification of an FBN1 variant emphasizes the importance of segregation analysis, information sharing, and multidisciplinary teamwork in understanding genetic variants in health and disease",

abstract = "Marfan syndrome (MFS) is a complex connective tissue disorder characterized by considerable clinical variability. The diagnosis of MFS is based on the Ghent criteria, which require the presence of both clinical and genetic features. MFS is primarily caused by pathogenic alterations in FBN1, which encodes the fibrillin-1 protein. Fibrillin-1 comprises multiple domains rich in cysteine residues, with disulfide bonds formed between these residues. It has long been recognized that variants that alter or introduce cysteine residues damage protein function, leading to the development of MFS. In this study, we report a cysteine-introducing variant: FBN1 variant, c.6724C>T (p.[Arg2242Cys]). We have observed this variant in several individuals without MFS, challenging our previous understanding of the underlying mechanism of MFS. This finding emphasizes the importance of revisiting and reevaluating our current knowledge in light of new and unexpected observations. Moreover, our study highlights the significance of incorporating local and national data on allele frequencies, as well as employing multidisciplinary phenotyping approaches, in the classification of genetic variants. By considering a wide range of information, we can enhance the accuracy and reliability of variant classification, ultimately improving the diagnosis and management of individuals with genetic disorders like MFS.",

keywords = "clinical genetics, FBN1, fibrillin-1, genetic variant classification, Marfan syndrome",

author = "Lildballe, {Dorte L.} and Sara Markholt and Lyngholm, {Christina Daugaard} and Qin Hao and Christina Fagerberg and Nielsen, {Dorte Guldbrand} and Svensmark, {Julius Hannibal} and Diness, {Birgitte Rode} and Gregersen, {Pernille A.}",

note = "Publisher Copyright: {\textcopyright} 2024 The Author(s). American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.",

year = "2024",

doi = "10.1002/ajmg.a.63795",

language = "English",

journal = "American Journal of Medical Genetics - Part A",

issn = "1552-4825",

publisher = "Wiley",

}

Lildballe, DL , Markholt, S , Lyngholm, CD, Hao, Q, Fagerberg, C, Nielsen, DG, Svensmark, JH, Diness, BR & Gregersen, PA 2024, 'Reclassification of an FBN1 variant emphasizes the importance of segregation analysis, information sharing, and multidisciplinary teamwork in understanding genetic variants in health and disease', American Journal of Medical Genetics - Part A. https://doi.org/10.1002/ajmg.a.63795

Reclassification of an FBN1 variant emphasizes the importance of segregation analysis, information sharing, and multidisciplinary teamwork in understanding genetic variants in health and disease. / Lildballe, Dorte L.; Markholt, Sara ; Lyngholm, Christina Daugaard et al.
In: American Journal of Medical Genetics - Part A, 2024.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Reclassification of an FBN1 variant emphasizes the importance of segregation analysis, information sharing, and multidisciplinary teamwork in understanding genetic variants in health and disease

AU - Lildballe, Dorte L.

AU - Markholt, Sara

AU - Lyngholm, Christina Daugaard

AU - Hao, Qin

AU - Fagerberg, Christina

AU - Nielsen, Dorte Guldbrand

AU - Svensmark, Julius Hannibal

AU - Diness, Birgitte Rode

AU - Gregersen, Pernille A.

PY - 2024

Y1 - 2024

N2 - Marfan syndrome (MFS) is a complex connective tissue disorder characterized by considerable clinical variability. The diagnosis of MFS is based on the Ghent criteria, which require the presence of both clinical and genetic features. MFS is primarily caused by pathogenic alterations in FBN1, which encodes the fibrillin-1 protein. Fibrillin-1 comprises multiple domains rich in cysteine residues, with disulfide bonds formed between these residues. It has long been recognized that variants that alter or introduce cysteine residues damage protein function, leading to the development of MFS. In this study, we report a cysteine-introducing variant: FBN1 variant, c.6724C>T (p.[Arg2242Cys]). We have observed this variant in several individuals without MFS, challenging our previous understanding of the underlying mechanism of MFS. This finding emphasizes the importance of revisiting and reevaluating our current knowledge in light of new and unexpected observations. Moreover, our study highlights the significance of incorporating local and national data on allele frequencies, as well as employing multidisciplinary phenotyping approaches, in the classification of genetic variants. By considering a wide range of information, we can enhance the accuracy and reliability of variant classification, ultimately improving the diagnosis and management of individuals with genetic disorders like MFS.

AB - Marfan syndrome (MFS) is a complex connective tissue disorder characterized by considerable clinical variability. The diagnosis of MFS is based on the Ghent criteria, which require the presence of both clinical and genetic features. MFS is primarily caused by pathogenic alterations in FBN1, which encodes the fibrillin-1 protein. Fibrillin-1 comprises multiple domains rich in cysteine residues, with disulfide bonds formed between these residues. It has long been recognized that variants that alter or introduce cysteine residues damage protein function, leading to the development of MFS. In this study, we report a cysteine-introducing variant: FBN1 variant, c.6724C>T (p.[Arg2242Cys]). We have observed this variant in several individuals without MFS, challenging our previous understanding of the underlying mechanism of MFS. This finding emphasizes the importance of revisiting and reevaluating our current knowledge in light of new and unexpected observations. Moreover, our study highlights the significance of incorporating local and national data on allele frequencies, as well as employing multidisciplinary phenotyping approaches, in the classification of genetic variants. By considering a wide range of information, we can enhance the accuracy and reliability of variant classification, ultimately improving the diagnosis and management of individuals with genetic disorders like MFS.

KW - clinical genetics

KW - FBN1

KW - fibrillin-1

KW - genetic variant classification

KW - Marfan syndrome

UR - http://www.scopus.com/inward/record.url?scp=85196612994&partnerID=8YFLogxK

U2 - 10.1002/ajmg.a.63795

DO - 10.1002/ajmg.a.63795

M3 - Journal article

AN - SCOPUS:85196612994

SN - 1552-4825

JO - American Journal of Medical Genetics - Part A

JF - American Journal of Medical Genetics - Part A

ER -

Reclassification of an FBN1 variant emphasizes the importance of segregation analysis, information sharing, and multidisciplinary teamwork in understanding genetic variants in health and disease

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Keywords

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