Sperm mosaicism: implications for genomic diversity and disease

Breuss, Martin W.; Yang, Xiaoxu; Gleeson, Joseph G.

doi:10.1016/j.tig.2021.05.007

Cited by 16 publications

(21 citation statements)

References 84 publications

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“…We investigated sperm in a genetically heterogeneous cohort and found one parent (3%) with isolated germline mosaicism in sperm. Susceptibility to mutagenesis during the spermatogenesis as well as timing of mutations during paternal embryogenesis may affect the abundance of mutations in germline and somatic tissues, and the overall recurrence risk (Breuss et al, 2020(Breuss et al, , 2021Jónsson et al, 2018). Larger studies of sperm mosaicism in different genetic disorders need to be performed to delineate the recurrence risk in specific conditions.…”

Section: Discussionmentioning

confidence: 99%

“…Considering the level of sperm mosaicism in the father with the ITPR1 variant (20%), compared to the father with the EHMT1 variant (1%), the recurrence risk appears higher in the ITPR1 family. Yet, the recurrence risk to future offspring depends on several factors, such as the timing of mutation and mutation type (Breuss et al, 2020, 2021; Jónsson et al, 2018). Breuss et al (2021) divide sperm mosaicism into different types depending on timing of the mutations, each associated with a different recurrence risk.…”

Section: Discussionmentioning

confidence: 99%

“…Yet, the recurrence risk to future offspring depends on several factors, such as the timing of mutation and mutation type (Breuss et al, 2020, 2021; Jónsson et al, 2018). Breuss et al (2021) divide sperm mosaicism into different types depending on timing of the mutations, each associated with a different recurrence risk. According to this classification, we hypothesize that the ITPR1 variant in the father in our cohort is a type IIIa mutation, since it was found in blood as well sperm and therefore might have originated during embryogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…Due to technical difficulties of obtaining oocytes for analysis, we are limited to study germline mosaicism in males only, making the actual rate of germline mosaicism and true recurrence risk difficult to conclude. Nevertheless, sperm analysis adds important information regarding parental mosaicism since 80% of de novo variants arise on the paternal haplotype (Acuna‐Hidalgo et al, 2016; Breuss et al, 2021; Kong et al, 2012; Rahbari et al, 2016). For future studies, it would also be interesting to collect samples from tissues representing all the three different germ layers during embryonic development, in order to understand when the mutational event has occurred and further deciphering the mechanisms of mosaicism.…”

Section: Discussionmentioning

confidence: 99%

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Detection of germline mosaicism in fathers of children with intellectual disability syndromes caused by de novo variants

Frisk

Wachtmeister

Laurell

et al. 2022

Molec Gen & Gen Med

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Background De novo variants are a common cause to rare intellectual disability syndromes, associated with low recurrence risk. However, when such variants occur pre‐zygotically in parental germ cells, the recurrence risk might be higher. Still, the recurrence risk estimates are mainly based on empirical data and the prevalence of germline mosaicism is often unknown. Methods To establish the prevalence of mosaicism in parents of children with intellectual disability syndromes caused by de novo variants, we performed droplet digital PCR on DNA extracted from blood (43 trios), and sperm (31 fathers). Results We detected low‐level mosaicism in sperm‐derived DNA but not in blood in the father of a child with Kleefstra syndrome caused by an EHMT1 variant. Additionally, we found a higher level of paternal mosaicism in sperm compared to blood in the father of a child with Gillespie syndrome caused by an ITPR1 variant. Conclusion By employing droplet digital PCR, we detected paternal germline mosaicism in two intellectual disability syndromes. In both cases, the mosaicism level was higher in sperm than blood, indicating that analysis of blood alone may underestimate germline mosaicism. Therefore, sperm analysis can be clinically useful to establish the recurrence risk for parents and improve genetic counselling.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Detection of germline mosaicism in fathers of children with intellectual disability syndromes caused by de novo variants

Frisk

Wachtmeister

Laurell

et al. 2022

Molec Gen & Gen Med

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“…In these cases, gonadal mosaic mutations (comprising gonad-specific and gonosomal) have the potential to transmit to offspring. These will appear as a considerable portion of de novo mutations and may result in miscarriage or a congenital or complex disease-often without phenotypes in the parents 8,9 .…”

Section: Introductionmentioning

confidence: 99%

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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Genomic Mosaicism of the Brain: Origin, Impact, and Utility

Graham,

Schlachetzki,

Yang

et al. 2023

Neurosci. Bull.

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Genomic mosaicism describes the phenomenon where some but not all cells within a tissue harbor unique genetic mutations. Traditionally, research focused on the impact of genomic mosaicism on clinical phenotype—motivated by its involvement in cancers and overgrowth syndromes. More recently, we increasingly shifted towards the plethora of neutral mosaic variants that can act as recorders of cellular lineage and environmental exposures. Here, we summarize the current state of the field of genomic mosaicism research with a special emphasis on our current understanding of this phenomenon in brain development and homeostasis. Although the field of genomic mosaicism has a rich history, technological advances in the last decade have changed our approaches and greatly improved our knowledge. We will provide current definitions and an overview of contemporary detection approaches for genomic mosaicism. Finally, we will discuss the impact and utility of genomic mosaicism.

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Sperm mosaicism: implications for genomic diversity and disease

Cited by 16 publications

References 84 publications

Detection of germline mosaicism in fathers of children with intellectual disability syndromes caused by de novo variants

Detection of germline mosaicism in fathers of children with intellectual disability syndromes caused by de novo variants

Sperm mosaicism predicts transmission of de novo mutations to human blastocysts

Genomic Mosaicism of the Brain: Origin, Impact, and Utility

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