Association of the fragile X premutation with cognitive and behavioral skills in children

Active Project Grant Awarded Last action

Award ID
R01HD102429
Recipient
Awarding agency
Obligated
$5,396,092

Award facts

Completion date 86% complete
Originally
Funding
  • $4,749,674.00 Federal
  • $646,418.00 Non-federal
Place of performance
Flushing, NY 11367, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
The overarching goal of our proposal is to answer the clinically significant question: does a fragile X premutation (PM; an allele of 55-200 CGG repeats in the X-linked FMR1 gene) pose a significant risk to childhood development? Why is this important? At least one in 300 women in the US carries a PM allele. Because most of these alleles are small and not prone to large expansions, nearly half of children born to these women will inherit a PM, whereas fewer than 6% will inherit a full mutation (>200 repeats), the allele that causes fragile X syndrome. PM alleles are known to increase the risk for two late-onset disorders: fragile X associated tremor/ataxia syndrome (FXTAS) and fragile X-associated primary ovarian insufficiency (FXPOI). Adults with a PM allele who do not have FXTAS or FXPOI are still reported to have executive skill and working memory deficits, visuospatial weakness and poor math skills, anxiety, and depression. For children who carry a PM, there is a significant GAP in our knowledge. Some reports find higher rates of developmental delay, attention deficits, autism, and anxiety among children with a PM versus non-carriers, but these reports are limited by ascertainment bias and small sample size. We hypothesize that the toxic effect of a PM can manifest early in life, leading to adverse neurodevelopmental outcomes and we propose to test this rigorously and thoroughly. To address this GAP in knowledge, we have an outstanding opportunity to study a large cohort of children, now age 3 -12 years, who were identified prospectively: specifically, 582 children with a PM and 958 non-carriers, all identified when their carrier mothers underwent prenatal diagnosis for a fragile X mutation. This unique cohort of children has minimal potential for ascertainment bias. In aim 1, parents will complete online questionnaires to describe their child's general health and history of diagnosed neurodevelopmental problems and to detail-using standardized questionnaires-the child's behavior, executive skills, and social relatedness. In aim 2, a subset of school-aged participants who live in the mid-atlantic region will be assessed individually primarily via remote-administered semi-structured interview and neuropsychological measures examining cognitive, academic, social and psychological function. Mothers will also complete questionnaires regarding their own psychological well-being and parenting stress. We will evaluate all phenotypes with respect to SEX, CGG repeat length, and repeat structure to gain insight into the mechanisms and associated risks (aim 3). Our primary hypothesis is that children with a PM have a higher frequencies of neurodevelopmental deficits than non-carrier children, stratified by SEX. The combination of parental report and direct assessment will provide a comprehensive evaluation of cognitive and behavioral skills. This will result in a powerful combination of detailed phenotypic and genetic information that will unambiguously define the risk of adverse childhood development posed by a PM allele.

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Subawards

Subrecipient Amount Awarded
Emory University Dr. Allen is the PI of this sub-contract. She will direct the recruitment for the project and be involved in data analysis and interpretation. After the initial… $165,964
Research Foundation For Mental Hygiene, Inc. Scope of Work: Institute for Basic Research in Developmental Disabilities (IBR) Mohammad Arif, PhD, FACMG, Site PI Dr. Arif, Director of the Molecular… $122,678
Research Triangle Institute Scope of Work for Jessica Ezzell Hunter at RTI International Dr. Hunter will serve as a co-Principal Investigator on this study and as such will collaborate… $88,015
Research Foundation For Mental Hygiene, Inc. Scope of Work: Institute for Basic Research in Developmental Disabilities (IBR) Mohammad Arif, PhD, FACMG, Site PI Dr. Arif, Director of the Molecular… $41,399
Emory University Dr. Allen is the PI of this sub-contract. She will direct the recruitment for the project and be involved in data analysis and interpretation. After the initial… $165,964

Quick answers

Who received award R01HD102429?

R01HD102429 was awarded to Research Foundation Of The City University Of New York by National Institute of Child Health and Human Development (National Institutes of Health) on September 1, 2021.

How much is award R01HD102429 worth?

$5,396,092 has been obligated on R01HD102429: $4,749,674 in federal funding and $646,418 in non-federal funding.

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