# Unrecognized scale and clinical relevance of somatic mosaicism

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2021 · $494,398

## Abstract

ABSTRACT
Nearly all of the genetic material among cells within an organism is identical. However, single-nucleotide
variants (SNVs), copy-number variants (CNVs), and other structural variants continually accumulate as cells
divide during development. This process results in an organism composed of countless cells, each with its own
unique genome. Thus, every human is undoubtedly mosaic. Mosaic mutations can go unnoticed, underlie
genetic disease or normal human variation, and may be transmitted to the next generation as constitutional
variants and cause unexpected intergenerational recurrences of genetic disorders with multiple affected
children born to unaffected parents, contrary to Mendelian expectations. The increasing sensitivity and
resolution of genomic technologies have identified mosaicism for both SNVs and CNVs. Combined somatic
and germline mosaicism has been identified in parents of patients with a number of genetic conditions, thus
raising the possibility that mosaic individuals might be detected by routine blood tests rather than requiring
direct examination of germ cells. Yet despite its considerable impact on human health, systematic population
studies of both germline and somatic mosaicism are lacking. In contrast to recurrent CNVs, usually mediated
by nonallelic homologous recombination during meiosis, nonrecurrent CNVs are thought to arise due to DNA
replication errors, such as microhomology-mediated break-induced replication during mitosis or non-
homologous end joining. Recurrence risks of putatively de novo nonrecurrent CNVs designed to take into
account random chance and mosaicism have been previously estimated to be ~ 0.3%. Our preliminary
published data on 100 unrelated affected families indicate that somatic mosaicism for CNVs is present in ~ 4%
of healthy parents. Currently, the detection rates for CMA and WES are ~ 20% and ~ 25%, respectively, thus in
about half of patients no pathogenic variant is found. We propose that some of these patients may have
mosaic pathogenic variants that are currently undetected using standard algorithms in CMA and WES.
Unrecognized mosaicism could also partially explain variable expressivity and incomplete penetrance. We
hypothesize that a significant number of apparently de novo SNVs and CNVs are not meiotic in origin but arise
during early post-zygotic mitoses and this can be identified either in the affected patients or their healthy
parents. In Aims 1 and 2, we will search for low-level somatic mosaicism in reportedly healthy parents of 500
affected children who have apparent de novo CNVs, indels, or SNVs identified in their affected children. In Aim
2, we will develop a non-invasive prenatal test for detection of recurrent mutations and correlate sperm vs.
somatic mosaicism. In Aim 3, we will study somatic mosaic CNVs, indels, and SNVs in patients in whom no
nonmosaic pathogenic variant has been found in previous clinical or research genetic testing. We will estimate
the currently un...

## Key facts

- **NIH application ID:** 10233990
- **Project number:** 5R01HD087292-05
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** PAWEL STANKIEWICZ
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $494,398
- **Award type:** 5
- **Project period:** 2017-09-13 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10233990

## Citation

> US National Institutes of Health, RePORTER application 10233990, Unrecognized scale and clinical relevance of somatic mosaicism (5R01HD087292-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10233990. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*