Partially methylated alleles, microdeletion, and tissue mosaicism in a fragile X male with tremor and ataxia at 30 years of age: A case report

Yun Tae Hwang, Solange Mabel Aliaga, Marta Arpone, David Francis, Xin Li, Belinda Chong, Howard Robert Slater, Carolyn Rogers, Lesley Bretherton, Matthew Hunter, Robert Heard, David Eugeny Godler

Research output: Contribution to journalArticleOtherpeer-review

12 Citations (Scopus)

Abstract

CGG repeat expansion >200 within FMR1, termed full mutation (FM), has been associated with promoter methylation, consequent silencing of gene expression and fragile X syndrome (FXS)—a common cause of intellectual disability and co-morbid autism. Unmethylated premutation (55–199 repeats) and FM alleles have been associated with fragile X related tremor/ataxia syndrome (FXTAS), a late onset neurodegenerative disorder. Here we present a 33-year-old male with FXS, with white matter changes and progressive deterioration in gait with cerebellar signs consistent with probable FXTAS; there was no evidence of any other cerebellar pathology. We show that he has tissue mosaicism in blood, saliva, and buccal samples for the size and methylation of his expanded alleles and a de novo, unmethylated microdeletion. This microdeletion involves a ∼80 bp sequence in the FMR1 promoter as well as complete loss of the CGG repeat in a proportion of cells. Despite FMR1 mRNA levels in blood within the normal range, the methylation and CGG sizing results are consistent with the diagnosis of concurrent FXS and probable FXTAS. The demonstrated presence of unmethylated FM alleles would explain the manifestation of milder than expected cognitive and behavioral impairments and early onset of cerebellar ataxia. Our case suggests that individuals with FXS, who manifest symptoms of FXTAS, may benefit from more detailed laboratory testing.

Original languageEnglish
Pages (from-to)3327-3332
Number of pages6
JournalAmerican Journal of Medical Genetics Part A
Volume170
Issue number12
DOIs
Publication statusPublished - 1 Dec 2016
Externally publishedYes

Keywords

  • cerebellar ataxia
  • fragile X related tremor/ataxia syndrome
  • Fragile X syndrome
  • mental retardation
  • methylation
  • molecular biology
  • mosaicism
  • tremor

Cite this

Hwang, Yun Tae ; Aliaga, Solange Mabel ; Arpone, Marta ; Francis, David ; Li, Xin ; Chong, Belinda ; Slater, Howard Robert ; Rogers, Carolyn ; Bretherton, Lesley ; Hunter, Matthew ; Heard, Robert ; Godler, David Eugeny. / Partially methylated alleles, microdeletion, and tissue mosaicism in a fragile X male with tremor and ataxia at 30 years of age : A case report. In: American Journal of Medical Genetics Part A. 2016 ; Vol. 170, No. 12. pp. 3327-3332.
@article{a087f64b747d434999beeb4d9f43aa01,
title = "Partially methylated alleles, microdeletion, and tissue mosaicism in a fragile X male with tremor and ataxia at 30 years of age: A case report",
abstract = "CGG repeat expansion >200 within FMR1, termed full mutation (FM), has been associated with promoter methylation, consequent silencing of gene expression and fragile X syndrome (FXS)—a common cause of intellectual disability and co-morbid autism. Unmethylated premutation (55–199 repeats) and FM alleles have been associated with fragile X related tremor/ataxia syndrome (FXTAS), a late onset neurodegenerative disorder. Here we present a 33-year-old male with FXS, with white matter changes and progressive deterioration in gait with cerebellar signs consistent with probable FXTAS; there was no evidence of any other cerebellar pathology. We show that he has tissue mosaicism in blood, saliva, and buccal samples for the size and methylation of his expanded alleles and a de novo, unmethylated microdeletion. This microdeletion involves a ∼80 bp sequence in the FMR1 promoter as well as complete loss of the CGG repeat in a proportion of cells. Despite FMR1 mRNA levels in blood within the normal range, the methylation and CGG sizing results are consistent with the diagnosis of concurrent FXS and probable FXTAS. The demonstrated presence of unmethylated FM alleles would explain the manifestation of milder than expected cognitive and behavioral impairments and early onset of cerebellar ataxia. Our case suggests that individuals with FXS, who manifest symptoms of FXTAS, may benefit from more detailed laboratory testing.",
keywords = "cerebellar ataxia, fragile X related tremor/ataxia syndrome, Fragile X syndrome, mental retardation, methylation, molecular biology, mosaicism, tremor",
author = "Hwang, {Yun Tae} and Aliaga, {Solange Mabel} and Marta Arpone and David Francis and Xin Li and Belinda Chong and Slater, {Howard Robert} and Carolyn Rogers and Lesley Bretherton and Matthew Hunter and Robert Heard and Godler, {David Eugeny}",
year = "2016",
month = "12",
day = "1",
doi = "10.1002/ajmg.a.37954",
language = "English",
volume = "170",
pages = "3327--3332",
journal = "American Journal of Medical Genetics Part A",
issn = "1552-4825",
publisher = "Wiley-Blackwell",
number = "12",

}

Hwang, YT, Aliaga, SM, Arpone, M, Francis, D, Li, X, Chong, B, Slater, HR, Rogers, C, Bretherton, L, Hunter, M, Heard, R & Godler, DE 2016, 'Partially methylated alleles, microdeletion, and tissue mosaicism in a fragile X male with tremor and ataxia at 30 years of age: A case report', American Journal of Medical Genetics Part A, vol. 170, no. 12, pp. 3327-3332. https://doi.org/10.1002/ajmg.a.37954

Partially methylated alleles, microdeletion, and tissue mosaicism in a fragile X male with tremor and ataxia at 30 years of age : A case report. / Hwang, Yun Tae; Aliaga, Solange Mabel; Arpone, Marta; Francis, David; Li, Xin; Chong, Belinda; Slater, Howard Robert; Rogers, Carolyn; Bretherton, Lesley; Hunter, Matthew; Heard, Robert; Godler, David Eugeny.

In: American Journal of Medical Genetics Part A, Vol. 170, No. 12, 01.12.2016, p. 3327-3332.

Research output: Contribution to journalArticleOtherpeer-review

TY - JOUR

T1 - Partially methylated alleles, microdeletion, and tissue mosaicism in a fragile X male with tremor and ataxia at 30 years of age

T2 - A case report

AU - Hwang, Yun Tae

AU - Aliaga, Solange Mabel

AU - Arpone, Marta

AU - Francis, David

AU - Li, Xin

AU - Chong, Belinda

AU - Slater, Howard Robert

AU - Rogers, Carolyn

AU - Bretherton, Lesley

AU - Hunter, Matthew

AU - Heard, Robert

AU - Godler, David Eugeny

PY - 2016/12/1

Y1 - 2016/12/1

N2 - CGG repeat expansion >200 within FMR1, termed full mutation (FM), has been associated with promoter methylation, consequent silencing of gene expression and fragile X syndrome (FXS)—a common cause of intellectual disability and co-morbid autism. Unmethylated premutation (55–199 repeats) and FM alleles have been associated with fragile X related tremor/ataxia syndrome (FXTAS), a late onset neurodegenerative disorder. Here we present a 33-year-old male with FXS, with white matter changes and progressive deterioration in gait with cerebellar signs consistent with probable FXTAS; there was no evidence of any other cerebellar pathology. We show that he has tissue mosaicism in blood, saliva, and buccal samples for the size and methylation of his expanded alleles and a de novo, unmethylated microdeletion. This microdeletion involves a ∼80 bp sequence in the FMR1 promoter as well as complete loss of the CGG repeat in a proportion of cells. Despite FMR1 mRNA levels in blood within the normal range, the methylation and CGG sizing results are consistent with the diagnosis of concurrent FXS and probable FXTAS. The demonstrated presence of unmethylated FM alleles would explain the manifestation of milder than expected cognitive and behavioral impairments and early onset of cerebellar ataxia. Our case suggests that individuals with FXS, who manifest symptoms of FXTAS, may benefit from more detailed laboratory testing.

AB - CGG repeat expansion >200 within FMR1, termed full mutation (FM), has been associated with promoter methylation, consequent silencing of gene expression and fragile X syndrome (FXS)—a common cause of intellectual disability and co-morbid autism. Unmethylated premutation (55–199 repeats) and FM alleles have been associated with fragile X related tremor/ataxia syndrome (FXTAS), a late onset neurodegenerative disorder. Here we present a 33-year-old male with FXS, with white matter changes and progressive deterioration in gait with cerebellar signs consistent with probable FXTAS; there was no evidence of any other cerebellar pathology. We show that he has tissue mosaicism in blood, saliva, and buccal samples for the size and methylation of his expanded alleles and a de novo, unmethylated microdeletion. This microdeletion involves a ∼80 bp sequence in the FMR1 promoter as well as complete loss of the CGG repeat in a proportion of cells. Despite FMR1 mRNA levels in blood within the normal range, the methylation and CGG sizing results are consistent with the diagnosis of concurrent FXS and probable FXTAS. The demonstrated presence of unmethylated FM alleles would explain the manifestation of milder than expected cognitive and behavioral impairments and early onset of cerebellar ataxia. Our case suggests that individuals with FXS, who manifest symptoms of FXTAS, may benefit from more detailed laboratory testing.

KW - cerebellar ataxia

KW - fragile X related tremor/ataxia syndrome

KW - Fragile X syndrome

KW - mental retardation

KW - methylation

KW - molecular biology

KW - mosaicism

KW - tremor

UR - http://www.scopus.com/inward/record.url?scp=84989303076&partnerID=8YFLogxK

U2 - 10.1002/ajmg.a.37954

DO - 10.1002/ajmg.a.37954

M3 - Article

AN - SCOPUS:84989303076

VL - 170

SP - 3327

EP - 3332

JO - American Journal of Medical Genetics Part A

JF - American Journal of Medical Genetics Part A

SN - 1552-4825

IS - 12

ER -