Tissue mosaicism, FMR1 expression and intellectual functioning in males with fragile X syndrome

Emma K. Baker; Marta Arpone; Minh Bui; Claudine M. Kraan; Ling Ling; David Francis; Mathew F. Hunter; Carolyn Rogers; Michael J. Field; Lorena Santa María; Víctor Faundes; Bianca Curotto; Paulina Morales; Cesar Trigo; Isabel Salas; Angelica M. Alliende; David J. Amor; David E. Godler

doi:10.1002/ajmg.a.63027

Tissue mosaicism, FMR1 expression and intellectual functioning in males with fragile X syndrome

Emma K. Baker, Marta Arpone, Minh Bui, Claudine M. Kraan, Ling Ling, David Francis, Mathew F. Hunter, Carolyn Rogers, Michael J. Field, Lorena Santa María, Víctor Faundes, Bianca Curotto, Paulina Morales, Cesar Trigo, Isabel Salas, Angelica M. Alliende, David J. Amor, David E. Godler

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Abstract

Fragile X syndrome (FXS) is caused by hypermethylation of the FMR1 promoter due to the full mutation expansion (full mutation [FM]: CGG ≥ 200 repeats) and silencing of FMR1. Assessment of mosaicism for active-unmethylated alleles has prognostic utility. This study examined relationships between FMR1 methylation in different tissues with FMR1 messenger ribonucleic acid (mRNA) and intellectual functioning in 87 males with FXS (1.89–43.17 years of age). Methylation sensitive Southern blot (mSB) and Methylation Specific-Quantitative Melt Aanalysis (MS-QMA) were used to examine FMR1 methylation. FMR1 mRNA levels in blood showed strong relationships with FMR1 methylation assessed using MS-QMA in blood (n = 68; R² = 0.597; p = 1.4 × 10⁻¹⁰) and buccal epithelial cells (BEC) (n = 62; R² = 0.24; p = 0.003), with these measures also showing relationships with intellectual functioning scores (p < 0.01). However, these relationships were not as strong for mSB, with ~40% of males with only FM alleles that were 100% methylated and non-mosaic by mSB, showing methylation mosaicism by MS-QMA. This was confirmed through presence of detectable levels of FMR1 mRNA in blood. In summary, FMR1 methylation levels in blood and BEC examined by MS-QMA were significantly associated with FMR1 mRNA levels and intellectual functioning in males with FXS. These relationships were not as strong for mSB, which underestimated prevalence of mosaicism.

Original language	English
Pages (from-to)	357-369
Number of pages	13
Journal	American Journal of Medical Genetics. Part A
Volume	191
Issue number	2
Early online date	Nov 2022
DOIs	https://doi.org/10.1002/ajmg.a.63027
Publication status	Published - Feb 2023
Externally published	Yes

Bibliographical note

Copyright the Author(s) 2022. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

Keywords

DNA methylation
epigenetics
FMR1
fragile X syndrome
intellectual disability
mosaicism

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Baker, E. K., Arpone, M., Bui, M., Kraan, C. M., Ling, L., Francis, D., Hunter, M. F., Rogers, C., Field, M. J., María, L. S., Faundes, V., Curotto, B., Morales, P., Trigo, C., Salas, I., Alliende, A. M., Amor, D. J., & Godler, D. E. (2023). Tissue mosaicism, FMR1 expression and intellectual functioning in males with fragile X syndrome. American Journal of Medical Genetics. Part A, 191(2), 357-369. https://doi.org/10.1002/ajmg.a.63027

@article{04b3ada5b47f4d64af1af7d0616f9dd0,

title = "Tissue mosaicism, FMR1 expression and intellectual functioning in males with fragile X syndrome",

abstract = "Fragile X syndrome (FXS) is caused by hypermethylation of the FMR1 promoter due to the full mutation expansion (full mutation [FM]: CGG ≥ 200 repeats) and silencing of FMR1. Assessment of mosaicism for active-unmethylated alleles has prognostic utility. This study examined relationships between FMR1 methylation in different tissues with FMR1 messenger ribonucleic acid (mRNA) and intellectual functioning in 87 males with FXS (1.89–43.17 years of age). Methylation sensitive Southern blot (mSB) and Methylation Specific-Quantitative Melt Aanalysis (MS-QMA) were used to examine FMR1 methylation. FMR1 mRNA levels in blood showed strong relationships with FMR1 methylation assessed using MS-QMA in blood (n = 68; R2 = 0.597; p = 1.4 × 10−10) and buccal epithelial cells (BEC) (n = 62; R2 = 0.24; p = 0.003), with these measures also showing relationships with intellectual functioning scores (p < 0.01). However, these relationships were not as strong for mSB, with ~40% of males with only FM alleles that were 100% methylated and non-mosaic by mSB, showing methylation mosaicism by MS-QMA. This was confirmed through presence of detectable levels of FMR1 mRNA in blood. In summary, FMR1 methylation levels in blood and BEC examined by MS-QMA were significantly associated with FMR1 mRNA levels and intellectual functioning in males with FXS. These relationships were not as strong for mSB, which underestimated prevalence of mosaicism.",

keywords = "DNA methylation, epigenetics, FMR1, fragile X syndrome, intellectual disability, mosaicism",

author = "Baker, {Emma K.} and Marta Arpone and Minh Bui and Kraan, {Claudine M.} and Ling Ling and David Francis and Hunter, {Mathew F.} and Carolyn Rogers and Field, {Michael J.} and Mar{\'i}a, {Lorena Santa} and V{\'i}ctor Faundes and Bianca Curotto and Paulina Morales and Cesar Trigo and Isabel Salas and Alliende, {Angelica M.} and Amor, {David J.} and Godler, {David E.}",

note = "Copyright the Author(s) 2022. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.",

year = "2023",

month = feb,

doi = "10.1002/ajmg.a.63027",

language = "English",

volume = "191",

pages = "357--369",

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

issn = "1552-4825",

publisher = "John Wiley & Sons",

number = "2",

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Baker, EK, Arpone, M, Bui, M, Kraan, CM, Ling, L, Francis, D, Hunter, MF, Rogers, C, Field, MJ, María, LS, Faundes, V, Curotto, B, Morales, P, Trigo, C, Salas, I, Alliende, AM, Amor, DJ & Godler, DE 2023, 'Tissue mosaicism, FMR1 expression and intellectual functioning in males with fragile X syndrome', American Journal of Medical Genetics. Part A, vol. 191, no. 2, pp. 357-369. https://doi.org/10.1002/ajmg.a.63027

TY - JOUR

T1 - Tissue mosaicism, FMR1 expression and intellectual functioning in males with fragile X syndrome

AU - Baker, Emma K.

AU - Arpone, Marta

AU - Bui, Minh

AU - Kraan, Claudine M.

AU - Ling, Ling

AU - Francis, David

AU - Hunter, Mathew F.

AU - Rogers, Carolyn

AU - Field, Michael J.

AU - María, Lorena Santa

AU - Faundes, Víctor

AU - Curotto, Bianca

AU - Morales, Paulina

AU - Trigo, Cesar

AU - Salas, Isabel

AU - Alliende, Angelica M.

AU - Amor, David J.

AU - Godler, David E.

N1 - Copyright the Author(s) 2022. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

PY - 2023/2

Y1 - 2023/2

N2 - Fragile X syndrome (FXS) is caused by hypermethylation of the FMR1 promoter due to the full mutation expansion (full mutation [FM]: CGG ≥ 200 repeats) and silencing of FMR1. Assessment of mosaicism for active-unmethylated alleles has prognostic utility. This study examined relationships between FMR1 methylation in different tissues with FMR1 messenger ribonucleic acid (mRNA) and intellectual functioning in 87 males with FXS (1.89–43.17 years of age). Methylation sensitive Southern blot (mSB) and Methylation Specific-Quantitative Melt Aanalysis (MS-QMA) were used to examine FMR1 methylation. FMR1 mRNA levels in blood showed strong relationships with FMR1 methylation assessed using MS-QMA in blood (n = 68; R2 = 0.597; p = 1.4 × 10−10) and buccal epithelial cells (BEC) (n = 62; R2 = 0.24; p = 0.003), with these measures also showing relationships with intellectual functioning scores (p < 0.01). However, these relationships were not as strong for mSB, with ~40% of males with only FM alleles that were 100% methylated and non-mosaic by mSB, showing methylation mosaicism by MS-QMA. This was confirmed through presence of detectable levels of FMR1 mRNA in blood. In summary, FMR1 methylation levels in blood and BEC examined by MS-QMA were significantly associated with FMR1 mRNA levels and intellectual functioning in males with FXS. These relationships were not as strong for mSB, which underestimated prevalence of mosaicism.

AB - Fragile X syndrome (FXS) is caused by hypermethylation of the FMR1 promoter due to the full mutation expansion (full mutation [FM]: CGG ≥ 200 repeats) and silencing of FMR1. Assessment of mosaicism for active-unmethylated alleles has prognostic utility. This study examined relationships between FMR1 methylation in different tissues with FMR1 messenger ribonucleic acid (mRNA) and intellectual functioning in 87 males with FXS (1.89–43.17 years of age). Methylation sensitive Southern blot (mSB) and Methylation Specific-Quantitative Melt Aanalysis (MS-QMA) were used to examine FMR1 methylation. FMR1 mRNA levels in blood showed strong relationships with FMR1 methylation assessed using MS-QMA in blood (n = 68; R2 = 0.597; p = 1.4 × 10−10) and buccal epithelial cells (BEC) (n = 62; R2 = 0.24; p = 0.003), with these measures also showing relationships with intellectual functioning scores (p < 0.01). However, these relationships were not as strong for mSB, with ~40% of males with only FM alleles that were 100% methylated and non-mosaic by mSB, showing methylation mosaicism by MS-QMA. This was confirmed through presence of detectable levels of FMR1 mRNA in blood. In summary, FMR1 methylation levels in blood and BEC examined by MS-QMA were significantly associated with FMR1 mRNA levels and intellectual functioning in males with FXS. These relationships were not as strong for mSB, which underestimated prevalence of mosaicism.

KW - DNA methylation

KW - epigenetics

KW - FMR1

KW - fragile X syndrome

KW - intellectual disability

KW - mosaicism

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U2 - 10.1002/ajmg.a.63027

DO - 10.1002/ajmg.a.63027

M3 - Article

C2 - 36349505

SN - 1552-4825

VL - 191

SP - 357

EP - 369

JO - American Journal of Medical Genetics. Part A

JF - American Journal of Medical Genetics. Part A

IS - 2

ER -

Tissue mosaicism, FMR1 expression and intellectual functioning in males with fragile X syndrome

Abstract

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Keywords

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