Developmental and temporal characteristics of clonal sperm mosaicism

Yang, Xiaoxu; Breuss, Martin; Xu, Xin; Antaki, Danny; James, Kiely N.; Stanley, Valentina; Ball, Laurel; George, Renee D.; Wirth, Sara; Cao, Bangwei; Nguyen, An; McEvoy‐Venneri, Jennifer; Chai, Guoliang; Nahas, Shareef; Kraan, Lucitia Van Der; Ding, Yan; Sebat, Jonathan; Gleeson, Joseph G.

doi:10.1016/j.cell.2021.07.024

Cited by 31 publications

(69 citation statements)

References 98 publications

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“…These mutations were present at AFs between 0.003 and 0.247 (mean: 0.047; standard deviation: 0.055), with those of lower AF typically restricted to sperm (‘ Sperm’ ) and those of higher AF typically found in both sperm and blood or saliva (‘ Shared’ ) (Figure 1c, and Figure 1- figure supplement 1). Their number and distribution were largely consistent with other unbiased analyses performed previously 10,13 . Of note, similar to our prior observations 13 , the sperm donor F01 (36 years of age) had an excessive number of soma-specific mutations (‘ Soma’ ) at lower AFs, evidencing early clonal hematopoiesis 10,13 (Figure 1- figure supplement 1).…”

Section: Resultssupporting

confidence: 89%

“…Their number and distribution were largely consistent with other unbiased analyses performed previously 10,13 . Of note, similar to our prior observations 13 , the sperm donor F01 (36 years of age) had an excessive number of soma-specific mutations (‘ Soma’ ) at lower AFs, evidencing early clonal hematopoiesis 10,13 (Figure 1- figure supplement 1).…”

Section: Resultssupporting

confidence: 89%

“…A single massive parallel amplicon sequencing (MPAS) panel was used for both detections of mutations in parental tissues and in preimplantation blastocysts. WGS: whole genome sequencing; 300×MSMF: variant calling pipeline on 300× WGS data using MuTect2, Strelka2, and MosaicForecast 13 . (b) Number of MPAS-validated gonadal mosaic mutations for each sperm donor, distinguished by color into sperm-specific (‘ Sperm’ , green) and tissue-shared (‘ Shared’ , brown) mutations.…”

Section: Resultsmentioning

confidence: 99%

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Sperm mosaicism predicts transmission of de novo mutations to human blastocysts

Breuss

Yang

Stanley

et al. 2022

Preprint

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De novo mutations underlie individually rare but collectively common pediatric congenital disorders. Some of these mutations can also be detected in tissues and from cells in a parent, where their abundance and tissue distribution can be measured. We previously reported that a subset of these mutations is detectable in sperm from the father, predicted to impact the health of offspring. Here, in three independent couples undergoing in vitro fertilization, we first assessed male gonadal mosaicism, then assessed the transmission of the mutations to their preimplantation blastocysts. We found an overall predictable transmission but slight under-transmission of mutations to blastocysts based upon measured mutational abundance in sperm, and we replicated this conclusion in an independent family-based cohort. Therefore, unbiased preimplantation genetic testing for gonadal mosaicism may represent a feasible approach to reduce the transmission of potentially harmful de novo mutations, which could help to reduce their impact on miscarriage and pediatric disease.

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Section: Resultssupporting

confidence: 89%

Section: Resultssupporting

confidence: 89%

Section: Resultsmentioning

confidence: 99%

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Sperm mosaicism predicts transmission of de novo mutations to human blastocysts

Breuss

Yang

Stanley

et al. 2022

Preprint

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“…Firstly, ICSI patients might harbour mutations predisposing to infertility, including also in SRY gene [ 6 ]. Secondly, as mean age of ICSI-fathers is >40 years, there is an APA-associated risk of DNMs and monogenic disorders (MDs) in the offspring [ 7 – 9 ]. The presented case confirms necessity of in-depth screening along with basic karyotyping analysis in parents referred to ART procedures.…”

Section: Discussionmentioning

confidence: 99%

Prenatal diagnosis of a 46,XY karyotype female fetus with an SRY-associated gonadal dysgenesis, conceived through an intracytoplasmic sperm injection: a case report

Zhytnik

Peters

Tilk

et al. 2022

BMC Pregnancy Childbirth

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Background Permanent progression of paternal age and development of reproductive medicine lead to increase in number of children conceived with assisted reproductive techniques (ART). Although it is uncertain if ARTs have direct influence on offspring health, advanced paternal age, associated comorbidities and reduced fertility possess significant risks of genetic disorders to the offspring. With a broad implementation of a non-invasive prenatal testing (NIPT), more cases of genetic disorders, including sex discordance are revealed. Among biological causes of sex discordance are disorders of sexual development, majority of which are associated with the SRY gene. Case presentation We report a case of a non-invasive prenatal testing and ultrasound sex discordance in a 46,XY karyotype female fetus with an SRY pathogenic variant, who was conceived through an intracytoplasmic sperm injection (ICSI) due to severe oligozoospermia of the father. Advanced mean age of ICSI patients is associated with risk of de novo mutations and monogenic disorders in the offspring. Additionally, ICSI patients have higher risk to harbour infertility-predisposing mutations, including mutations in the SRY gene. These familial and de novo genetic factors predispose ICSI-conceived children to congenital malformations and might negatively affect reproductive health of ICSI-patients’ offspring. Conclusions Oligozoospermic patients planning assisted reproduction are warranted to undergo genetic counselling and testing for possible inherited and mosaic mutations, and risk factors for de novo mutations.

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“…There are numerous examples of mosaic variants limited to affected tissues, including Proteus syndrome ( Lindhurst et al 2011 ), PIK3CA -related overgrowth syndrome ( Mirzaa et al 2016 ), hemimegalencephaly ( Lee et al 2012 ), and vascular malformations ( Luks et al 2015 ) among others. Germline mosaicism is a special consideration of mosaicism that may be tissue-restricted ( Yang et al 2021 ). In this study, a mosaic parent was identified in 3.4% of families with a genetic diagnosis, a rate similar to several other studies ( Myers et al 2018 ; Møller et al 2019 ), but a parent with mosaicism restricted to the germline would be missed.…”

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confidence: 99%

Mosaicism in clinical genetics

Mefford

2021

Cold Spring Harb Mol Case Stud

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Genetic mosaicism is the state in which there are two or more different sets of cells in a single individual because of one or more postzygotic mutations, and its importance in clinical genetics has long been recognized (Hall, Am J Hum Genet43: 355 [1988]). In this Perspective, a paper in this special issue on mosaicism from Cook et al. (Cold Spring Harb Mol Case Studies7: a006125 [2021]) is discussed.

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Developmental and temporal characteristics of clonal sperm mosaicism

Cited by 31 publications

References 98 publications

Sperm mosaicism predicts transmission of de novo mutations to human blastocysts

Sperm mosaicism predicts transmission of de novo mutations to human blastocysts

Prenatal diagnosis of a 46,XY karyotype female fetus with an SRY-associated gonadal dysgenesis, conceived through an intracytoplasmic sperm injection: a case report

Mosaicism in clinical genetics

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