Genomic insights from a deeply phenotyped highly consanguineous neurodevelopmental disorders cohort

Hosneara Akter; Md Atikur Rahaman; Tamannyat Binte Eshaque; Nesrin Mohamed; Amirul Islam; Mehzabin Morshed; Zaha Shahin; Al Muhaimin; Arif Md Foyzullah; Rabeya Akter Mim; Farjana Binta Omar; Md Nahid Hasan; Dharana Satsangi; Nahid Ahmed; Abdullah Al Saba; Nargis Jahan; Md Arif Hossen; Md Ashadujjaman Mondol; Ahammad Sharif Sakib; Rezwana Kabir; Mohammod Shah Jahan Chowdhury; Nusrat Shams; Shireen Afroz; Shayla Imam Kanta; Sarwar Jahan Bhuiyan; Rabi Biswas; Shehzad Hanif; Richa Tambi; Nasna Nassir; Muhammad Mizanur Rahman; Jinjie Duan; Anders D. Børglum; Robed Amin; Mohammed Basiruzzaman; Md Kamruzzaman; Shaoli Sarker; Marc Woodbury-Smith; K. M.Furkan Uddin; A. H.M.Nurun Nabi; Mohammed Uddin

doi:10.1016/j.gim.2024.101282

Genomic insights from a deeply phenotyped highly consanguineous neurodevelopmental disorders cohort

Hosneara Akter, Md Atikur Rahaman, Tamannyat Binte Eshaque, Nesrin Mohamed, Amirul Islam, Mehzabin Morshed, Zaha Shahin, Al Muhaimin, Arif Md Foyzullah, Rabeya Akter Mim, Farjana Binta Omar, Md Nahid Hasan, Dharana Satsangi, Nahid Ahmed, Abdullah Al Saba, Nargis Jahan, Md Arif Hossen, Md Ashadujjaman Mondol, Ahammad Sharif Sakib, Rezwana KabirMohammod Shah Jahan Chowdhury, Nusrat Shams, Shireen Afroz, Shayla Imam Kanta, Sarwar Jahan Bhuiyan, Rabi Biswas, Shehzad Hanif, Richa Tambi, Nasna Nassir, Muhammad Mizanur Rahman, Jinjie Duan, Anders D. Børglum, Robed Amin, Mohammed Basiruzzaman, Md Kamruzzaman, Shaoli Sarker, Marc Woodbury-Smith, K. M.Furkan Uddin, A. H.M.Nurun Nabi, Mohammed Uddin^*

^*Corresponding author af dette arbejde

Institut for Biomedicin - Forskning og uddannelse, Bartholin Bygningen

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

4 Citationer (Scopus)

Abstract

Purpose: The genetic underpinning of neurodevelopmental disorders (NDDs) in diverse ethnic populations, especially those with high rates of consanguinity, remains largely unexplored. Here, we aim to elucidate genomic insight from 576 well-phenotyped and highly consanguineous (16%) NDD cohort. Methods: We used chromosomal microarray (CMA; N:247), exome sequencing (ES; N:127), combined CMA and ES (N:202), and long-read genome sequencing to identify genetic etiology. Deep clinical multivariate data were coupled with genomic variants for stratification analysis. Results: Genetic diagnosis rates were 17% with CMA, 29.92% with ES, and 37.13% with combined CMA and ES. Notably, children of consanguineous parents showed a significantly higher diagnostic yield (P < .01) compared to those from nonconsanguineous parents. Among the ES-identified pathogenic variants, 36.19% (38/105) were novel, implicating 35 unique genes. Long-read sequencing of seizure participants unresolved by combined test identified expanded FMR1 trinucleotide repeats. Additionally, we identified 2 recurrent X-linked variants in the G6PD in 3.65% (12/329) of NDD participants. These variants were absent in large-population control cohorts and cohort comprising neurodevelopmental and neuropsychiatric populations of European descendants, indicating a possible associated risk factor potentially resulting from ancient genetic drift. Conclusion: This study unveils unique clinical and genomic insights from a consanguinity rich Bangladeshi NDD cohort, highlighting a strong association of G6PD with NDD in this population.

Originalsprog	Engelsk
Artikelnummer	101282
Tidsskrift	Genetics in Medicine
Vol/bind	27
Nummer	1
ISSN	1098-3600
DOI	https://doi.org/10.1016/j.gim.2024.101282
Status	Udgivet - jan. 2025

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10.1016/j.gim.2024.101282Licens: CC BY

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Akter, H., Rahaman, M. A., Eshaque, T. B., Mohamed, N., Islam, A., Morshed, M., Shahin, Z., Muhaimin, A., Foyzullah, A. M., Mim, R. A., Omar, F. B., Hasan, M. N., Satsangi, D., Ahmed, N., Al Saba, A., Jahan, N., Hossen, M. A., Mondol, M. A., Sakib, A. S., ... Uddin, M. (2025). Genomic insights from a deeply phenotyped highly consanguineous neurodevelopmental disorders cohort. Genetics in Medicine, 27(1), Artikel 101282. https://doi.org/10.1016/j.gim.2024.101282

@article{4fbaed8f0e154e03838347334773a05c,

title = "Genomic insights from a deeply phenotyped highly consanguineous neurodevelopmental disorders cohort",

abstract = "Purpose: The genetic underpinning of neurodevelopmental disorders (NDDs) in diverse ethnic populations, especially those with high rates of consanguinity, remains largely unexplored. Here, we aim to elucidate genomic insight from 576 well-phenotyped and highly consanguineous (16%) NDD cohort. Methods: We used chromosomal microarray (CMA; N:247), exome sequencing (ES; N:127), combined CMA and ES (N:202), and long-read genome sequencing to identify genetic etiology. Deep clinical multivariate data were coupled with genomic variants for stratification analysis. Results: Genetic diagnosis rates were 17% with CMA, 29.92% with ES, and 37.13% with combined CMA and ES. Notably, children of consanguineous parents showed a significantly higher diagnostic yield (P < .01) compared to those from nonconsanguineous parents. Among the ES-identified pathogenic variants, 36.19% (38/105) were novel, implicating 35 unique genes. Long-read sequencing of seizure participants unresolved by combined test identified expanded FMR1 trinucleotide repeats. Additionally, we identified 2 recurrent X-linked variants in the G6PD in 3.65% (12/329) of NDD participants. These variants were absent in large-population control cohorts and cohort comprising neurodevelopmental and neuropsychiatric populations of European descendants, indicating a possible associated risk factor potentially resulting from ancient genetic drift. Conclusion: This study unveils unique clinical and genomic insights from a consanguinity rich Bangladeshi NDD cohort, highlighting a strong association of G6PD with NDD in this population.",

keywords = "Chromosomal microarray, Exome sequencing, Genetic etiology, Long-read genome sequencing, Neurodevelopmental disorders",

author = "Hosneara Akter and Rahaman, {Md Atikur} and Eshaque, {Tamannyat Binte} and Nesrin Mohamed and Amirul Islam and Mehzabin Morshed and Zaha Shahin and Al Muhaimin and Foyzullah, {Arif Md} and Mim, {Rabeya Akter} and Omar, {Farjana Binta} and Hasan, {Md Nahid} and Dharana Satsangi and Nahid Ahmed and {Al Saba}, Abdullah and Nargis Jahan and Hossen, {Md Arif} and Mondol, {Md Ashadujjaman} and Sakib, {Ahammad Sharif} and Rezwana Kabir and {Jahan Chowdhury}, {Mohammod Shah} and Nusrat Shams and Shireen Afroz and Kanta, {Shayla Imam} and Bhuiyan, {Sarwar Jahan} and Rabi Biswas and Shehzad Hanif and Richa Tambi and Nasna Nassir and Rahman, {Muhammad Mizanur} and Jinjie Duan and {D. B{\o}rglum}, Anders and Robed Amin and Mohammed Basiruzzaman and Md Kamruzzaman and Shaoli Sarker and Marc Woodbury-Smith and Uddin, {K. M.Furkan} and Nabi, {A. H.M.Nurun} and Mohammed Uddin",

year = "2025",

month = jan,

doi = "10.1016/j.gim.2024.101282",

language = "English",

volume = "27",

journal = "Genetics in Medicine",

issn = "1098-3600",

publisher = "Elsevier B.V.",

number = "1",

}

Akter, H, Rahaman, MA, Eshaque, TB, Mohamed, N, Islam, A, Morshed, M, Shahin, Z, Muhaimin, A, Foyzullah, AM, Mim, RA, Omar, FB, Hasan, MN, Satsangi, D, Ahmed, N, Al Saba, A, Jahan, N, Hossen, MA, Mondol, MA, Sakib, AS, Kabir, R, Jahan Chowdhury, MS, Shams, N, Afroz, S, Kanta, SI, Bhuiyan, SJ, Biswas, R, Hanif, S, Tambi, R, Nassir, N, Rahman, MM, Duan, J , D. Børglum, A, Amin, R, Basiruzzaman, M, Kamruzzaman, M, Sarker, S, Woodbury-Smith, M, Uddin, KMF, Nabi, AHMN & Uddin, M 2025, 'Genomic insights from a deeply phenotyped highly consanguineous neurodevelopmental disorders cohort', Genetics in Medicine, bind 27, nr. 1, 101282. https://doi.org/10.1016/j.gim.2024.101282

TY - JOUR

T1 - Genomic insights from a deeply phenotyped highly consanguineous neurodevelopmental disorders cohort

AU - Akter, Hosneara

AU - Rahaman, Md Atikur

AU - Eshaque, Tamannyat Binte

AU - Mohamed, Nesrin

AU - Islam, Amirul

AU - Morshed, Mehzabin

AU - Shahin, Zaha

AU - Muhaimin, Al

AU - Foyzullah, Arif Md

AU - Mim, Rabeya Akter

AU - Omar, Farjana Binta

AU - Hasan, Md Nahid

AU - Satsangi, Dharana

AU - Ahmed, Nahid

AU - Al Saba, Abdullah

AU - Jahan, Nargis

AU - Hossen, Md Arif

AU - Mondol, Md Ashadujjaman

AU - Sakib, Ahammad Sharif

AU - Kabir, Rezwana

AU - Jahan Chowdhury, Mohammod Shah

AU - Shams, Nusrat

AU - Afroz, Shireen

AU - Kanta, Shayla Imam

AU - Bhuiyan, Sarwar Jahan

AU - Biswas, Rabi

AU - Hanif, Shehzad

AU - Tambi, Richa

AU - Nassir, Nasna

AU - Rahman, Muhammad Mizanur

AU - Duan, Jinjie

AU - D. Børglum, Anders

AU - Amin, Robed

AU - Basiruzzaman, Mohammed

AU - Kamruzzaman, Md

AU - Sarker, Shaoli

AU - Woodbury-Smith, Marc

AU - Uddin, K. M.Furkan

AU - Nabi, A. H.M.Nurun

AU - Uddin, Mohammed

PY - 2025/1

Y1 - 2025/1

N2 - Purpose: The genetic underpinning of neurodevelopmental disorders (NDDs) in diverse ethnic populations, especially those with high rates of consanguinity, remains largely unexplored. Here, we aim to elucidate genomic insight from 576 well-phenotyped and highly consanguineous (16%) NDD cohort. Methods: We used chromosomal microarray (CMA; N:247), exome sequencing (ES; N:127), combined CMA and ES (N:202), and long-read genome sequencing to identify genetic etiology. Deep clinical multivariate data were coupled with genomic variants for stratification analysis. Results: Genetic diagnosis rates were 17% with CMA, 29.92% with ES, and 37.13% with combined CMA and ES. Notably, children of consanguineous parents showed a significantly higher diagnostic yield (P < .01) compared to those from nonconsanguineous parents. Among the ES-identified pathogenic variants, 36.19% (38/105) were novel, implicating 35 unique genes. Long-read sequencing of seizure participants unresolved by combined test identified expanded FMR1 trinucleotide repeats. Additionally, we identified 2 recurrent X-linked variants in the G6PD in 3.65% (12/329) of NDD participants. These variants were absent in large-population control cohorts and cohort comprising neurodevelopmental and neuropsychiatric populations of European descendants, indicating a possible associated risk factor potentially resulting from ancient genetic drift. Conclusion: This study unveils unique clinical and genomic insights from a consanguinity rich Bangladeshi NDD cohort, highlighting a strong association of G6PD with NDD in this population.

AB - Purpose: The genetic underpinning of neurodevelopmental disorders (NDDs) in diverse ethnic populations, especially those with high rates of consanguinity, remains largely unexplored. Here, we aim to elucidate genomic insight from 576 well-phenotyped and highly consanguineous (16%) NDD cohort. Methods: We used chromosomal microarray (CMA; N:247), exome sequencing (ES; N:127), combined CMA and ES (N:202), and long-read genome sequencing to identify genetic etiology. Deep clinical multivariate data were coupled with genomic variants for stratification analysis. Results: Genetic diagnosis rates were 17% with CMA, 29.92% with ES, and 37.13% with combined CMA and ES. Notably, children of consanguineous parents showed a significantly higher diagnostic yield (P < .01) compared to those from nonconsanguineous parents. Among the ES-identified pathogenic variants, 36.19% (38/105) were novel, implicating 35 unique genes. Long-read sequencing of seizure participants unresolved by combined test identified expanded FMR1 trinucleotide repeats. Additionally, we identified 2 recurrent X-linked variants in the G6PD in 3.65% (12/329) of NDD participants. These variants were absent in large-population control cohorts and cohort comprising neurodevelopmental and neuropsychiatric populations of European descendants, indicating a possible associated risk factor potentially resulting from ancient genetic drift. Conclusion: This study unveils unique clinical and genomic insights from a consanguinity rich Bangladeshi NDD cohort, highlighting a strong association of G6PD with NDD in this population.

KW - Chromosomal microarray

KW - Exome sequencing

KW - Genetic etiology

KW - Long-read genome sequencing

KW - Neurodevelopmental disorders

UR - http://www.scopus.com/inward/record.url?scp=85208115107&partnerID=8YFLogxK

U2 - 10.1016/j.gim.2024.101282

DO - 10.1016/j.gim.2024.101282

M3 - Journal article

C2 - 39342494

AN - SCOPUS:85208115107

SN - 1098-3600

VL - 27

JO - Genetics in Medicine

JF - Genetics in Medicine

IS - 1

M1 - 101282

ER -

Genomic insights from a deeply phenotyped highly consanguineous neurodevelopmental disorders cohort

Abstract

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