# Defining the language phenotype of the FMR1 premutation

> **NIH NIH R21** · UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA · 2020 · $244,237

## Abstract

ABSTRACT
Parent Study. This application is being submitted to PA-18-591 in accordance with NOT-AG-20-008. The
proposed project builds on the parent study (R21DC017804; 2019-2022) to add new questions regarding
aging. The overarching goal of the parent study is to define the language phenotype associated with the FMR1
premutation genotype. The parent study specific aims are to identify aspects of language that distinguish
premutation carriers from controls; investigate the interplay between language and executive aspects of the
FMR1 premutation phenotype; and explore associations with FMR1 gene dysfunction.
Overview. Over 1 million individuals in the US (1:151 females, 1:468 males) carry a premutation allele on the
FMR1 gene. Despite the high prevalence of the FMR1 premutation genotype, its clinical phenotype is poorly
defined. Until recently, it was mistakenly believed that carriers of the FMR1 premutation were “silent carriers”
who suffered no clinical effects besides the risk of passing the mutated gene to their offspring, which could
cause fragile X syndrome. However, it is now clear that premutation carriers experience a range of language,
cognitive, and psychiatric symptoms. Additionally, about 10% of female carriers will develop FXTAS, a late-
onset neurodegenerative disorder that is characterized, in part, by dementia, executive deficits, and cognitive
decline. These clinical manifestations of the premutation are associated with reduced quality of life—both for
the premutation carrier mother as well as for her children with fragile X.
New, emerging evidence suggests premutation carrier mothers may experience premature age-related decline,
where subtle cognitive deficits are evident in the third decade of life and appear to worsen across middle age.
This is significant because it suggests that premutation carrier mothers may experience symptom aggravation
at a time when caregiving burden is at its peak. Yet, there remain large gaps in our understanding of the aging
cognitive phenotype. First, our current understanding is limited to a few reports that were narrowly focused on
specific executive skills without broader characterization of other cognitive domains, such as language.
Additionally, most prior studies have focused on mothers younger than the age of 55, which has resulted in
poor understanding of symptom expression in late midlife and early old age. These knowledge gaps represent
substantial barriers to effective clinical management, as we lack the data needed to understand the long-term
effects of the FMR1 premutation genotype.
Supplement Aims. In other forms of pathological aging, such as in dementia, subtle cognitive-linguistic deficits
are observed early in disease progression, sometimes before impairments in other cognitive skills can be
detected. In this Supplement we will extend this work to the study of premutation carrier mothers through the
characterization of aging cognitive-linguistic deficits. This approach may provide ...

## Key facts

- **NIH application ID:** 10123648
- **Project number:** 3R21DC017804-02S1
- **Recipient organization:** UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
- **Principal Investigator:** Jessica Klusek
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $244,237
- **Award type:** 3
- **Project period:** 2019-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10123648

## Citation

> US National Institutes of Health, RePORTER application 10123648, Defining the language phenotype of the FMR1 premutation (3R21DC017804-02S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10123648. Licensed CC0.

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