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De novo mutations in children born after medical assisted reproduction

STUDY QUESTION: Are there more de novo mutations (DNMs) present in the genomes of children born through medical assisted reproduction (MAR) compared to spontaneously conceived children? SUMMARY ANSWER: In this pilot study, no statistically significant difference was observed in the number of DNMs ob...

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Autores principales: Smits, R M, Xavier, M J, Oud, M S, Astuti, G D N, Meijerink, A M, de Vries, P F, Holt, G S, Alobaidi, B K S, Batty, L E, Khazeeva, G, Sablauskas, K, Vissers, L E L M, Gilissen, C, Fleischer, K, Braat, D D M, Ramos, L, Veltman, J A
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9156847/
https://www.ncbi.nlm.nih.gov/pubmed/35413117
http://dx.doi.org/10.1093/humrep/deac068
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author Smits, R M
Xavier, M J
Oud, M S
Astuti, G D N
Meijerink, A M
de Vries, P F
Holt, G S
Alobaidi, B K S
Batty, L E
Khazeeva, G
Sablauskas, K
Vissers, L E L M
Gilissen, C
Fleischer, K
Braat, D D M
Ramos, L
Veltman, J A
author_facet Smits, R M
Xavier, M J
Oud, M S
Astuti, G D N
Meijerink, A M
de Vries, P F
Holt, G S
Alobaidi, B K S
Batty, L E
Khazeeva, G
Sablauskas, K
Vissers, L E L M
Gilissen, C
Fleischer, K
Braat, D D M
Ramos, L
Veltman, J A
author_sort Smits, R M
collection PubMed
description STUDY QUESTION: Are there more de novo mutations (DNMs) present in the genomes of children born through medical assisted reproduction (MAR) compared to spontaneously conceived children? SUMMARY ANSWER: In this pilot study, no statistically significant difference was observed in the number of DNMs observed in the genomes of MAR children versus spontaneously conceived children. WHAT IS KNOWN ALREADY: DNMs are known to play a major role in sporadic disorders with reduced fitness such as severe developmental disorders, including intellectual disability and epilepsy. Advanced paternal age is known to place offspring at increased disease risk, amongst others by increasing the number of DNMs in their genome. There are very few studies reporting on the effect of MAR on the number of DNMs in the offspring, especially when male infertility is known to be affecting the potential fathers. With delayed parenthood an ongoing epidemiological trend in the 21st century, there are more children born from fathers of advanced age and more children born through MAR every day. STUDY DESIGN, SIZE, DURATION: This observational pilot study was conducted from January 2015 to March 2019 in the tertiary care centre at Radboud University Medical Center. We included a total of 53 children and their respective parents, forming 49 trios (mother, father and child) and two quartets (mother, father and two siblings). One group of children was born after spontaneous conception (n = 18); a second group of children born after IVF (n = 17) and a third group of children born after ICSI combined with testicular sperm extraction (ICSI-TESE) (n = 18). In this pilot study, we also subdivided each group by paternal age, resulting in a subgroup of children born to younger fathers (<35 years of age at conception) and older fathers (>45 years of age at conception). PARTICIPANTS/MATERIALS, SETTING, METHODS: Whole-genome sequencing (WGS) was performed on all parent-offspring trios to identify DNMs. For 34 of 53 trios/quartets, WGS was performed twice to independently detect and validate the presence of DNMs. Quality of WGS-based DNM calling was independently assessed by targeted Sanger sequencing. MAIN RESULTS AND THE ROLE OF CHANCE: No significant differences were observed in the number of DNMs per child for the different methods of conception, independent of parental age at conception (multi-factorial ANOVA, f(2) = 0.17, P-value = 0.85). As expected, a clear paternal age effect was observed after adjusting for method of conception and maternal age at conception (multiple regression model, t = 5.636, P-value = 8.97 × 10(−7)), with on average 71 DNMs in the genomes of children born to young fathers (<35 years of age) and an average of 94 DNMs in the genomes of children born to older fathers (>45 years of age). LIMITATIONS, REASONS FOR CAUTION: This is a pilot study and other small-scale studies have recently reported contrasting results. Larger unbiased studies are required to confirm or falsify these results. WIDER IMPLICATIONS OF THE FINDINGS: This pilot study did not show an effect for the method of conception on the number of DNMs per genome in offspring. Given the role that DNMs play in disease risk, this negative result is good news for IVF and ICSI-TESE born children, if replicated in a larger cohort. STUDY FUNDING/COMPETING INTEREST(S): This research was funded by the Netherlands Organisation for Scientific Research (918-15-667) and by an Investigator Award in Science from the Wellcome Trust (209451). The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.
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spelling pubmed-91568472022-06-04 De novo mutations in children born after medical assisted reproduction Smits, R M Xavier, M J Oud, M S Astuti, G D N Meijerink, A M de Vries, P F Holt, G S Alobaidi, B K S Batty, L E Khazeeva, G Sablauskas, K Vissers, L E L M Gilissen, C Fleischer, K Braat, D D M Ramos, L Veltman, J A Hum Reprod Original Articles STUDY QUESTION: Are there more de novo mutations (DNMs) present in the genomes of children born through medical assisted reproduction (MAR) compared to spontaneously conceived children? SUMMARY ANSWER: In this pilot study, no statistically significant difference was observed in the number of DNMs observed in the genomes of MAR children versus spontaneously conceived children. WHAT IS KNOWN ALREADY: DNMs are known to play a major role in sporadic disorders with reduced fitness such as severe developmental disorders, including intellectual disability and epilepsy. Advanced paternal age is known to place offspring at increased disease risk, amongst others by increasing the number of DNMs in their genome. There are very few studies reporting on the effect of MAR on the number of DNMs in the offspring, especially when male infertility is known to be affecting the potential fathers. With delayed parenthood an ongoing epidemiological trend in the 21st century, there are more children born from fathers of advanced age and more children born through MAR every day. STUDY DESIGN, SIZE, DURATION: This observational pilot study was conducted from January 2015 to March 2019 in the tertiary care centre at Radboud University Medical Center. We included a total of 53 children and their respective parents, forming 49 trios (mother, father and child) and two quartets (mother, father and two siblings). One group of children was born after spontaneous conception (n = 18); a second group of children born after IVF (n = 17) and a third group of children born after ICSI combined with testicular sperm extraction (ICSI-TESE) (n = 18). In this pilot study, we also subdivided each group by paternal age, resulting in a subgroup of children born to younger fathers (<35 years of age at conception) and older fathers (>45 years of age at conception). PARTICIPANTS/MATERIALS, SETTING, METHODS: Whole-genome sequencing (WGS) was performed on all parent-offspring trios to identify DNMs. For 34 of 53 trios/quartets, WGS was performed twice to independently detect and validate the presence of DNMs. Quality of WGS-based DNM calling was independently assessed by targeted Sanger sequencing. MAIN RESULTS AND THE ROLE OF CHANCE: No significant differences were observed in the number of DNMs per child for the different methods of conception, independent of parental age at conception (multi-factorial ANOVA, f(2) = 0.17, P-value = 0.85). As expected, a clear paternal age effect was observed after adjusting for method of conception and maternal age at conception (multiple regression model, t = 5.636, P-value = 8.97 × 10(−7)), with on average 71 DNMs in the genomes of children born to young fathers (<35 years of age) and an average of 94 DNMs in the genomes of children born to older fathers (>45 years of age). LIMITATIONS, REASONS FOR CAUTION: This is a pilot study and other small-scale studies have recently reported contrasting results. Larger unbiased studies are required to confirm or falsify these results. WIDER IMPLICATIONS OF THE FINDINGS: This pilot study did not show an effect for the method of conception on the number of DNMs per genome in offspring. Given the role that DNMs play in disease risk, this negative result is good news for IVF and ICSI-TESE born children, if replicated in a larger cohort. STUDY FUNDING/COMPETING INTEREST(S): This research was funded by the Netherlands Organisation for Scientific Research (918-15-667) and by an Investigator Award in Science from the Wellcome Trust (209451). The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A. Oxford University Press 2022-04-12 /pmc/articles/PMC9156847/ /pubmed/35413117 http://dx.doi.org/10.1093/humrep/deac068 Text en © The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Smits, R M
Xavier, M J
Oud, M S
Astuti, G D N
Meijerink, A M
de Vries, P F
Holt, G S
Alobaidi, B K S
Batty, L E
Khazeeva, G
Sablauskas, K
Vissers, L E L M
Gilissen, C
Fleischer, K
Braat, D D M
Ramos, L
Veltman, J A
De novo mutations in children born after medical assisted reproduction
title De novo mutations in children born after medical assisted reproduction
title_full De novo mutations in children born after medical assisted reproduction
title_fullStr De novo mutations in children born after medical assisted reproduction
title_full_unstemmed De novo mutations in children born after medical assisted reproduction
title_short De novo mutations in children born after medical assisted reproduction
title_sort de novo mutations in children born after medical assisted reproduction
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9156847/
https://www.ncbi.nlm.nih.gov/pubmed/35413117
http://dx.doi.org/10.1093/humrep/deac068
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