The impact of clinical genome sequencing in a global population with suspected rare genetic disease

Erin Thorpe; Taylor Williams; Chad Shaw; Evgenii Chekalin; Julia Ortega; Keisha Robinson; Jason Button; Marilyn C. Jones; Miguel del Campo; Donald Basel; Julie McCarrier; Laura Davis Keppen; Erin Royer; Romina Foster-Bonds; Milagros M. Duenas-Roque; Nora Urraca; Kerri Bosfield; Chester W. Brown; Holly Lydigsen; Henry J. Mroczkowski; Jewell Ward; Fabio Sirchia; Elisa Giorgio; Keith Vaux; Hildegard Peña Salguero; Aimé Lumaka; Gerrye Mubungu; Prince Makay; Mamy Ngole; Prosper Tshilobo Lukusa; Adeline Vanderver; Kayla Muirhead; Omar Sherbini; Melissa D. Lah; Katelynn Anderson; Jeny Bazalar-Montoya; Richard S. Rodriguez; Mario Cornejo-Olivas; Karina Milla-Neyra; Marwan Shinawi; Pilar Magoulas; Duncan Henry; Kate Gibson; Samuel Wiafe; Parul Jayakar; Daria Salyakina; Diane Masser-Frye; Arturo Serize; Jorge E. Perez; Alan Taylor; Shruti Shenbagam; Ahmad Abou Tayoun; Alka Malhotra; Maren Bennett; Vani Rajan; James Avecilla; Andrew Warren; Max Arseneault; Tasha Kalista; Ali Crawford; Subramanian S. Ajay; Denise L. Perry; John Belmont; Ryan J. Taft

doi:10.1016/j.ajhg.2024.05.006

The impact of clinical genome sequencing in a global population with suspected rare genetic disease

Erin Thorpe, Taylor Williams, Chad Shaw, Evgenii Chekalin, Julia Ortega, Keisha Robinson, Jason Button, Marilyn C. Jones, Miguel del Campo, Donald Basel, Julie McCarrier, Laura Davis Keppen, Erin Royer, Romina Foster-Bonds, Milagros M. Duenas-Roque, Nora Urraca, Kerri Bosfield, Chester W. Brown, Holly Lydigsen, Henry J. MroczkowskiJewell Ward, Fabio Sirchia, Elisa Giorgio, Keith Vaux, Hildegard Peña Salguero, Aimé Lumaka, Gerrye Mubungu, Prince Makay, Mamy Ngole, Prosper Tshilobo Lukusa, Adeline Vanderver, Kayla Muirhead, Omar Sherbini, Melissa D. Lah, Katelynn Anderson, Jeny Bazalar-Montoya, Richard S. Rodriguez, Mario Cornejo-Olivas, Karina Milla-Neyra, Marwan Shinawi, Pilar Magoulas, Duncan Henry, Kate Gibson, Samuel Wiafe, Parul Jayakar, Daria Salyakina, Diane Masser-Frye, Arturo Serize, Jorge E. Perez, Alan Taylor, Shruti Shenbagam, Ahmad Abou Tayoun, Alka Malhotra, Maren Bennett, Vani Rajan, James Avecilla, Andrew Warren, Max Arseneault, Tasha Kalista, Ali Crawford, Subramanian S. Ajay, Denise L. Perry, John Belmont, Ryan J. Taft

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Abstract

There is mounting evidence of the value of clinical genome sequencing (cGS) in individuals with suspected rare genetic disease (RGD), but cGS performance and impact on clinical care in a diverse population drawn from both high-income countries (HICs) and low- and middle-income countries (LMICs) has not been investigated. The iHope program, a philanthropic cGS initiative, established a network of 24 clinical sites in eight countries through which it provided cGS to individuals with signs or symptoms of an RGD and constrained access to molecular testing. A total of 1,004 individuals (median age, 6.5 years; 53.5% male) with diverse ancestral backgrounds (51.8% non-majority European) were assessed from June 2016 to September 2021. The diagnostic yield of cGS was 41.4% (416/1,004), with individuals from LMIC sites 1.7 times more likely to receive a positive test result compared to HIC sites (LMIC 56.5% [195/345] vs. HIC 33.5% [221/659], OR 2.6, 95% CI 1.9–3.4, p < 0.0001). A change in diagnostic evaluation occurred in 76.9% (514/668) of individuals. Change of management, inclusive of specialty referrals, imaging and testing, therapeutic interventions, and palliative care, was reported in 41.4% (285/694) of individuals, which increased to 69.2% (480/694) when genetic counseling and avoidance of additional testing were also included. Individuals from LMIC sites were as likely as their HIC counterparts to experience a change in diagnostic evaluation (OR 6.1, 95% CI 1.1–∞, p = 0.05) and change of management (OR 0.9, 95% CI 0.5–1.3, p = 0.49). Increased access to genomic testing may support diagnostic equity and the reduction of global health care disparities.

Original language	English
Pages (from-to)	1271-1281
Number of pages	11
Journal	American Journal of Human Genetics
Volume	111
Issue number	7
DOIs	https://doi.org/10.1016/j.ajhg.2024.05.006
State	Published - 11 Jul 2024

Keywords

change of management
clinical genome testing
clinical utility
diagnostic equity
genetic testing
low- and middle-income
rare disease
rare genetic disease
whole-genome sequencing

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10.1016/j.ajhg.2024.05.006

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Thorpe, E., Williams, T., Shaw, C., Chekalin, E., Ortega, J., Robinson, K., Button, J., Jones, M. C., Campo, M. D., Basel, D., McCarrier, J., Keppen, L. D., Royer, E., Foster-Bonds, R., Duenas-Roque, M. M., Urraca, N., Bosfield, K., Brown, C. W., Lydigsen, H., ... Taft, R. J. (2024). The impact of clinical genome sequencing in a global population with suspected rare genetic disease. American Journal of Human Genetics, 111(7), 1271-1281. https://doi.org/10.1016/j.ajhg.2024.05.006

@article{a6ec1d42328c48fe95f5110253a2f9cf,

title = "The impact of clinical genome sequencing in a global population with suspected rare genetic disease",

abstract = "There is mounting evidence of the value of clinical genome sequencing (cGS) in individuals with suspected rare genetic disease (RGD), but cGS performance and impact on clinical care in a diverse population drawn from both high-income countries (HICs) and low- and middle-income countries (LMICs) has not been investigated. The iHope program, a philanthropic cGS initiative, established a network of 24 clinical sites in eight countries through which it provided cGS to individuals with signs or symptoms of an RGD and constrained access to molecular testing. A total of 1,004 individuals (median age, 6.5 years; 53.5% male) with diverse ancestral backgrounds (51.8% non-majority European) were assessed from June 2016 to September 2021. The diagnostic yield of cGS was 41.4% (416/1,004), with individuals from LMIC sites 1.7 times more likely to receive a positive test result compared to HIC sites (LMIC 56.5% [195/345] vs. HIC 33.5% [221/659], OR 2.6, 95% CI 1.9–3.4, p < 0.0001). A change in diagnostic evaluation occurred in 76.9% (514/668) of individuals. Change of management, inclusive of specialty referrals, imaging and testing, therapeutic interventions, and palliative care, was reported in 41.4% (285/694) of individuals, which increased to 69.2% (480/694) when genetic counseling and avoidance of additional testing were also included. Individuals from LMIC sites were as likely as their HIC counterparts to experience a change in diagnostic evaluation (OR 6.1, 95% CI 1.1–∞, p = 0.05) and change of management (OR 0.9, 95% CI 0.5–1.3, p = 0.49). Increased access to genomic testing may support diagnostic equity and the reduction of global health care disparities.",

keywords = "change of management, clinical genome testing, clinical utility, diagnostic equity, genetic testing, low- and middle-income, rare disease, rare genetic disease, whole-genome sequencing",

author = "Erin Thorpe and Taylor Williams and Chad Shaw and Evgenii Chekalin and Julia Ortega and Keisha Robinson and Jason Button and Jones, {Marilyn C.} and Campo, {Miguel del} and Donald Basel and Julie McCarrier and Keppen, {Laura Davis} and Erin Royer and Romina Foster-Bonds and Duenas-Roque, {Milagros M.} and Nora Urraca and Kerri Bosfield and Brown, {Chester W.} and Holly Lydigsen and Mroczkowski, {Henry J.} and Jewell Ward and Fabio Sirchia and Elisa Giorgio and Keith Vaux and Salguero, {Hildegard Pe{\~n}a} and Aim{\'e} Lumaka and Gerrye Mubungu and Prince Makay and Mamy Ngole and Lukusa, {Prosper Tshilobo} and Adeline Vanderver and Kayla Muirhead and Omar Sherbini and Lah, {Melissa D.} and Katelynn Anderson and Jeny Bazalar-Montoya and Rodriguez, {Richard S.} and Mario Cornejo-Olivas and Karina Milla-Neyra and Marwan Shinawi and Pilar Magoulas and Duncan Henry and Kate Gibson and Samuel Wiafe and Parul Jayakar and Daria Salyakina and Diane Masser-Frye and Arturo Serize and Perez, {Jorge E.} and Alan Taylor and Shruti Shenbagam and {Abou Tayoun}, Ahmad and Alka Malhotra and Maren Bennett and Vani Rajan and James Avecilla and Andrew Warren and Max Arseneault and Tasha Kalista and Ali Crawford and Ajay, {Subramanian S.} and Perry, {Denise L.} and John Belmont and Taft, {Ryan J.}",

note = "Publisher Copyright: {\textcopyright} 2024 The Authors",

year = "2024",

month = jul,

day = "11",

doi = "10.1016/j.ajhg.2024.05.006",

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Thorpe, E, Williams, T, Shaw, C, Chekalin, E, Ortega, J, Robinson, K, Button, J, Jones, MC, Campo, MD, Basel, D, McCarrier, J, Keppen, LD, Royer, E, Foster-Bonds, R, Duenas-Roque, MM, Urraca, N, Bosfield, K, Brown, CW, Lydigsen, H, Mroczkowski, HJ, Ward, J, Sirchia, F, Giorgio, E, Vaux, K, Salguero, HP, Lumaka, A, Mubungu, G, Makay, P, Ngole, M, Lukusa, PT, Vanderver, A, Muirhead, K, Sherbini, O, Lah, MD, Anderson, K, Bazalar-Montoya, J, Rodriguez, RS, Cornejo-Olivas, M, Milla-Neyra, K, Shinawi, M, Magoulas, P, Henry, D, Gibson, K, Wiafe, S, Jayakar, P, Salyakina, D, Masser-Frye, D, Serize, A, Perez, JE, Taylor, A, Shenbagam, S, Abou Tayoun, A, Malhotra, A, Bennett, M, Rajan, V, Avecilla, J, Warren, A, Arseneault, M, Kalista, T, Crawford, A, Ajay, SS, Perry, DL, Belmont, J & Taft, RJ 2024, 'The impact of clinical genome sequencing in a global population with suspected rare genetic disease', American Journal of Human Genetics, vol. 111, no. 7, pp. 1271-1281. https://doi.org/10.1016/j.ajhg.2024.05.006

TY - JOUR

T1 - The impact of clinical genome sequencing in a global population with suspected rare genetic disease

AU - Thorpe, Erin

AU - Williams, Taylor

AU - Shaw, Chad

AU - Chekalin, Evgenii

AU - Ortega, Julia

AU - Robinson, Keisha

AU - Button, Jason

AU - Jones, Marilyn C.

AU - Campo, Miguel del

AU - Basel, Donald

AU - McCarrier, Julie

AU - Keppen, Laura Davis

AU - Royer, Erin

AU - Foster-Bonds, Romina

AU - Duenas-Roque, Milagros M.

AU - Urraca, Nora

AU - Bosfield, Kerri

AU - Brown, Chester W.

AU - Lydigsen, Holly

AU - Mroczkowski, Henry J.

AU - Ward, Jewell

AU - Sirchia, Fabio

AU - Giorgio, Elisa

AU - Vaux, Keith

AU - Salguero, Hildegard Peña

AU - Lumaka, Aimé

AU - Mubungu, Gerrye

AU - Makay, Prince

AU - Ngole, Mamy

AU - Lukusa, Prosper Tshilobo

AU - Vanderver, Adeline

AU - Muirhead, Kayla

AU - Sherbini, Omar

AU - Lah, Melissa D.

AU - Anderson, Katelynn

AU - Bazalar-Montoya, Jeny

AU - Rodriguez, Richard S.

AU - Cornejo-Olivas, Mario

AU - Milla-Neyra, Karina

AU - Shinawi, Marwan

AU - Magoulas, Pilar

AU - Henry, Duncan

AU - Gibson, Kate

AU - Wiafe, Samuel

AU - Jayakar, Parul

AU - Salyakina, Daria

AU - Masser-Frye, Diane

AU - Serize, Arturo

AU - Perez, Jorge E.

AU - Taylor, Alan

AU - Shenbagam, Shruti

AU - Abou Tayoun, Ahmad

AU - Malhotra, Alka

AU - Bennett, Maren

AU - Rajan, Vani

AU - Avecilla, James

AU - Warren, Andrew

AU - Arseneault, Max

AU - Kalista, Tasha

AU - Crawford, Ali

AU - Ajay, Subramanian S.

AU - Perry, Denise L.

AU - Belmont, John

AU - Taft, Ryan J.

PY - 2024/7/11

Y1 - 2024/7/11

N2 - There is mounting evidence of the value of clinical genome sequencing (cGS) in individuals with suspected rare genetic disease (RGD), but cGS performance and impact on clinical care in a diverse population drawn from both high-income countries (HICs) and low- and middle-income countries (LMICs) has not been investigated. The iHope program, a philanthropic cGS initiative, established a network of 24 clinical sites in eight countries through which it provided cGS to individuals with signs or symptoms of an RGD and constrained access to molecular testing. A total of 1,004 individuals (median age, 6.5 years; 53.5% male) with diverse ancestral backgrounds (51.8% non-majority European) were assessed from June 2016 to September 2021. The diagnostic yield of cGS was 41.4% (416/1,004), with individuals from LMIC sites 1.7 times more likely to receive a positive test result compared to HIC sites (LMIC 56.5% [195/345] vs. HIC 33.5% [221/659], OR 2.6, 95% CI 1.9–3.4, p < 0.0001). A change in diagnostic evaluation occurred in 76.9% (514/668) of individuals. Change of management, inclusive of specialty referrals, imaging and testing, therapeutic interventions, and palliative care, was reported in 41.4% (285/694) of individuals, which increased to 69.2% (480/694) when genetic counseling and avoidance of additional testing were also included. Individuals from LMIC sites were as likely as their HIC counterparts to experience a change in diagnostic evaluation (OR 6.1, 95% CI 1.1–∞, p = 0.05) and change of management (OR 0.9, 95% CI 0.5–1.3, p = 0.49). Increased access to genomic testing may support diagnostic equity and the reduction of global health care disparities.

AB - There is mounting evidence of the value of clinical genome sequencing (cGS) in individuals with suspected rare genetic disease (RGD), but cGS performance and impact on clinical care in a diverse population drawn from both high-income countries (HICs) and low- and middle-income countries (LMICs) has not been investigated. The iHope program, a philanthropic cGS initiative, established a network of 24 clinical sites in eight countries through which it provided cGS to individuals with signs or symptoms of an RGD and constrained access to molecular testing. A total of 1,004 individuals (median age, 6.5 years; 53.5% male) with diverse ancestral backgrounds (51.8% non-majority European) were assessed from June 2016 to September 2021. The diagnostic yield of cGS was 41.4% (416/1,004), with individuals from LMIC sites 1.7 times more likely to receive a positive test result compared to HIC sites (LMIC 56.5% [195/345] vs. HIC 33.5% [221/659], OR 2.6, 95% CI 1.9–3.4, p < 0.0001). A change in diagnostic evaluation occurred in 76.9% (514/668) of individuals. Change of management, inclusive of specialty referrals, imaging and testing, therapeutic interventions, and palliative care, was reported in 41.4% (285/694) of individuals, which increased to 69.2% (480/694) when genetic counseling and avoidance of additional testing were also included. Individuals from LMIC sites were as likely as their HIC counterparts to experience a change in diagnostic evaluation (OR 6.1, 95% CI 1.1–∞, p = 0.05) and change of management (OR 0.9, 95% CI 0.5–1.3, p = 0.49). Increased access to genomic testing may support diagnostic equity and the reduction of global health care disparities.

KW - change of management

KW - clinical genome testing

KW - clinical utility

KW - diagnostic equity

KW - genetic testing

KW - low- and middle-income

KW - rare disease

KW - rare genetic disease

KW - whole-genome sequencing

UR - http://www.scopus.com/inward/record.url?scp=85197069117&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2024.05.006

DO - 10.1016/j.ajhg.2024.05.006

M3 - Artículo

C2 - 38843839

AN - SCOPUS:85197069117

SN - 0002-9297

VL - 111

SP - 1271

EP - 1281

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 7

ER -

The impact of clinical genome sequencing in a global population with suspected rare genetic disease

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