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A Long-read Sequencing Approach for Investigating Repeat Number and DNA Methylation of the D4Z4 Region

Award Number: R03NS116444
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2020
PERIOD OF PERFORMANCE END DATE: 01/31/2023

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A Long-read Sequencing Approach for Investigating Repeat Number and DNA Methylation of the D4Z4 Region - ABSTRACT Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant muscle disorder caused by complex genetic and epigenetic mechanisms. Previous studies showed that transcription de- repression of double homeobox protein 4 (DUX4) due to epigenetic changes in the D4Z4 region causes FSHD. The epigenetic changes are caused by either contraction of the D4Z4 array from 11-150 repeat units in unaffected individuals to 1-10 repeat units in roughly 95% of patients (FSHD1) or mutations in epigenetic regulators of the region (FSHD2). Current genetic testing for FSHD is labor intensive and does not assess DNA methylation status, which has been suggested to be the primary determinant of disease severity in FSHD1. In this application, we propose to use a novel approach, Nanopore long- read sequencing, to determine the copy number and methylation level of D4Z4 region in a single test. Our preliminary data showed that optical mapping can accurately provide sizing for D4Z4 repeat region. In aim 1 of the project, we will first develop a Nanopore long-read sequencing assay to evaluate the D4Z4 arrays on both chromosome 4 and chromosome 10 and built a data analysis workflow for the data. In aim 2, we will use the approach to determine D4Z4 repeat size and DNA methylation status of FSHD DNA samples and DNA samples from unaffected individuals collected from a recent study of early onset FSHD; then determine the correlation between the methylation status and disease onset and severities. Development of a single test that could assess both genetic and epigenetic causes of FSHD will significantly transform the molecular diagnosis of FSHD as well as provide a roadmap for researcher to investigate how genetic and epigenetic variations in subtelomeric region of 4q35 affect FSHD onset and severity.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = -$1,175 )
2024	2021	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	1/9/2024	NON-COMPETING CONTINUATION	-$1,175
														Subtotal = -$1,175

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	10/18/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $89,250 )
2021	2021	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	1/25/2021	NON-COMPETING CONTINUATION	$89,250
														Subtotal = $89,250

Issue Date FY: 2020 ( Subtotal = $89,250 )
2020	2020	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	1/31/2020	NEW	$89,250
														Subtotal = $89,250

Grand Total All Awards = $177,325

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A Long-read Sequencing Approach for Investigating Repeat Number and DNA Methylation of the D4Z4 Region

Award Number: R03NS116444

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 02/01/2020

PERIOD OF PERFORMANCE END DATE: 01/31/2023

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