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Decrypting Variants of Uncertain Significance in Long-QT Syndrome

Award Number: R01HL122010
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2014
PERIOD OF PERFORMANCE END DATE: 07/31/2026

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Decrypting Variants of Uncertain Significance in Long-QT Syndrome - SUMMARY Clinical genetic testing has become standard-of-care for many diseases including the congenital long-QT syndrome (LQTS). However, interpreting genetic test results is often confounded by the discovery of ‘variants of uncertain significance’ (VUS) for which there are insufficient data to determine whether a particular variant is pathogenic or benign. The goal of this project is to use a novel paradigm for distinguishing pathogenic from benign variants in LQTS with a focus on KCNQ1, the most common cause of LQTS. During the prior periods of support, we implemented high throughput strategies to determine the functional consequences of ~180 KCNQ1 variants, the functional consequences of all known disease-associated KCNE1 variants, and assessed the stability, structure, and cell surface expression of several dozen KCNQ1 variants. We then integrated data on KCNQ1 structure, function and sequence conservation with machine learning tools to build a gene-specific algorithm in a web-based format to predict the likelihood that specific KCNQ1 variants are deleterious. In the next funding period, we propose to continue this powerful and productive multidisciplinary paradigm to extend our research. We used our machine learning approach incorporating an artificial neural network model to predict the functional consequences of 136 KCNQ1 VUS from ClinVar. In Aim 1, we will experimentally evaluate these predictions by determining functional consequences of the variants using automated patch clamp recording. In separate experiments, we will perform deep mutational scanning (DMS) of major regions of KCNQ1 (pore and voltage-sensing domains, C-terminus) to identify all possible single nucleotide variants that cause impaired trafficking of the channel to the plasma membrane. In Aim 2, we will use our quantitative flow cytometry-based method to evaluate cell surface expression of disease-associated KCNQ1 variants in regions of the channel (pore domain, C-terminus) that not been fully investigated for trafficking, and to determine if dysfunctional KCNE1 variants interfere with KCNQ1 trafficking. We will also employ biophysical methods (nano-differential scanning fluorimetry, cellular thermal shift assay) to evaluate the stability of trafficking- impaired KCNQ1 variants in the context of purified channel protein consisting of the voltage-sensor and pore domains. In Aim 3, we will evolve our machine learning algorithm as a deep neural network and enhance algorithm performance by using structural channel models built with a custom version of AlphaFold2.0, computed free energy, and outputs from molecular dynamics simulations of KCNQ1-KCNE1 channels. Our study will yield a large and unprecedented database of functional, structural, and biochemical properties of hundreds of KCNQ1 and KCNE1 variants, along with an advanced, data-trained computational prediction algorithm capable of accurately discriminating deleterious from benign variants. These results will contribute to improving genetic test interpretation and medical decision-making for LQTS.


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: 2025 ( Subtotal = $0 )
2025	2022	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cardiovascular Diseases Research	002	9	1/12/2025	COMPETING CONTINUATION	$284,539
2025	2021	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cardiovascular Diseases Research	001	8	1/12/2025	SUPPLEMENT FOR EXPANSION	-$31,592
2025	2021	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cardiovascular Diseases Research	000	8	1/12/2025	NON-COMPETING CONTINUATION	-$252,947
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $1,259,589 )
2024	2024	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cardiovascular Diseases Research	000	11	8/9/2024	NON-COMPETING CONTINUATION	$1,259,589
														Subtotal = $1,259,589

Issue Date FY: 2023 ( Subtotal = $1,287,423 )
2023	2023	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cardiovascular Diseases Research	000	10	7/25/2023	NON-COMPETING CONTINUATION	$1,287,423
														Subtotal = $1,287,423

Issue Date FY: 2022 ( Subtotal = $1,304,424 )
2022	2022	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cardiovascular Diseases Research	000	9	7/22/2022	COMPETING CONTINUATION	$1,304,424
														Subtotal = $1,304,424

Issue Date FY: 2021 ( Subtotal = $1,297,249 )
2021	2021	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cardiovascular Diseases Research	000	8	7/29/2021	NON-COMPETING CONTINUATION	$1,265,657
2021	2021	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cardiovascular Diseases Research	001	8	8/3/2021	SUPPLEMENT FOR EXPANSION	$31,592
														Subtotal = $1,297,249

Issue Date FY: 2020 ( Subtotal = $1,394,093 )
2020	2020	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cardiovascular Diseases Research	000	6	1/14/2020	SUPPLEMENT FOR EXPANSION	$44,229
2020	2020	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cardiovascular Diseases Research	001	7	7/13/2020	NON-COMPETING CONTINUATION	$1,349,864
														Subtotal = $1,394,093

Issue Date FY: 2019 ( Subtotal = $1,282,186 )
2019	2019	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cardiovascular Diseases Research	004	6	7/29/2019	NON-COMPETING CONTINUATION	$1,282,186
2019	2018	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cardiovascular Diseases Research	003	5	1/23/2019	COMPETING CONTINUATION	$16,365
2019	2018	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cardiovascular Diseases Research	001	5	12/11/2018	COMPETING CONTINUATION	$40,931
2019	2017	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cardiovascular Diseases Research	000	4	12/11/2018	NON-COMPETING CONTINUATION	-$40,931
2019	2017	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cardiovascular Diseases Research	002	4	1/23/2019	NON-COMPETING CONTINUATION	-$16,365
														Subtotal = $1,282,186

Issue Date FY: 2018 ( Subtotal = $1,304,594 )
2018	2018	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cardiovascular Diseases Research	001	5	8/21/2018	COMPETING CONTINUATION	$0
2018	2018	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cardiovascular Diseases Research	000	5	7/26/2018	COMPETING CONTINUATION	$1,304,594
														Subtotal = $1,304,594

Issue Date FY: 2017 ( Subtotal = $1,280,593 )
2017	2017	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cardiovascular Diseases Research	000	4	7/24/2017	NON-COMPETING CONTINUATION	$1,280,593
														Subtotal = $1,280,593

Issue Date FY: 2016 ( Subtotal = $1,277,210 )
2016	2016	NORTHWESTERN UNIVERSITY	633 CLARK STREET	EVANSTON	IL	60208	COOK	USA	Cardiovascular Diseases Research	000	3	7/8/2016	NON-COMPETING CONTINUATION	$1,277,210
														Subtotal = $1,277,210

Issue Date FY: 2015 ( Subtotal = $1,254,784 )
2015	2015	NORTHWESTERN UNIVERSITY	633 CLARK STREET	EVANSTON	IL	60208	COOK	USA	Cardiovascular Diseases Research	000	2	7/16/2015	NON-COMPETING CONTINUATION	$1,254,784
														Subtotal = $1,254,784

Issue Date FY: 2014 ( Subtotal = $1,308,724 )
2014	2014	NORTHWESTERN UNIVERSITY	633 CLARK STREET	EVANSTON	IL	60208	COOK	USA	Cardiovascular Diseases Research	000	1	7/15/2014	NEW	$1,308,724
														Subtotal = $1,308,724

Grand Total All Awards = $14,250,869

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Decrypting Variants of Uncertain Significance in Long-QT Syndrome

Award Number: R01HL122010

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2014

PERIOD OF PERFORMANCE END DATE: 07/31/2026

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