2023 ACMG Annual Clinical Genetics Meeting Digital Edition: Poster Gallery-A novel case of a female carrier of a Fragile X full expansion with methylation on the normal allele

Pdf Summary

This case presentation discusses a two-year-old female with motor and speech delays who is the daughter of a Fragile X carrier. The patient exhibits autistic features and was tested for Fragile X. PCR testing suggests she has a normal allele and a full mutation allele, but Southern blot analysis only detects a methylated allele. The patient's mother is a carrier with mosaicism for a full expansion allele and a premutation allele, while the father has an intermediate allele. Other tests, including next-generation sequencing, karyotyping, and microarray testing, showed normal results.<br /><br />Fragile X Syndrome (FXS) is the most common form of inheritable intellectual disability, often associated with autism, distinctive facial features, and macroorchidism. FXS is caused by unstable CGG repeats in the FMR1 gene. Alleles are classified based on repeat size, with normal alleles having 5-44 CGG repeats, intermediate alleles having 45-54 CGG repeats, premutation alleles having 55-200 CGG repeats, and full mutation alleles having over 200 CGG repeats. The full mutation is associated with hypermethylation of the FMR1 promoter region and the classical Fragile X phenotype.<br /><br />FMR1 is normally silenced by DNA methylation, histone modifications, and interactions with nuclear proteins. The CpG islands upstream of the FMR1 promoter are methylated, but a boundary of unmethylated DNA prevents methylation from spreading into the promoter. Several nuclear proteins and histone modifications contribute to transcriptional regulation and a heterochromatin state of the full mutation allele.<br /><br />In summary, this case presents a female carrier of a Fragile X full expansion allele with apparent methylation of the normal allele. The patient exhibits motor and speech delays, autistic features, and a known maternal history of Fragile X carrier status. The genetic testing and analysis reveal a complex molecular mechanism involving DNA methylation, histone modifications, and nuclear protein interactions that contribute to the Fragile X phenotype. Further evaluation and follow-up will be needed to fully understand the implications of these findings for the patient's diagnosis and management.

Asset Subtitle

Presenting Author - Odelya Kaufman, MD, PhD; Co-Author - Amy Woroch, MS, CGC; Co-Author - Aslihan Dincer, PhD; Co-Author - Reymundo Lozano, MD, MS; Co-Author - Eric E. Schadt, PhD;

Meta Tag

Epigenetics

Methylation

Triplet and Other Repeats

X-Inactivation/X-Linked Disease

Co-Author Amy Woroch, MS, CGC

Co-Author Aslihan Dincer, PhD

Co-Author Reymundo Lozano, MD, MS

Co-Author Eric E. Schadt, PhD

Presenting Author Odelya Kaufman, MD, PhD

Keywords

Fragile X Syndrome

intellectual disability

autism

macroorchidism

CGG repeats

FMR1 gene

methylation

histone modifications

nuclear proteins

diagnosis and management