# Elucidating the effects of extra chromosome elimination in mosaic aneuploidy syndromes: Pallister-Killian syndrome as a model

> **NIH NIH R21** · CHILDREN'S HOSP OF PHILADELPHIA · 2022 · $280,806

## Abstract

Project Summary/Abstract
The presence of an extra chromosome (trisomy or marker chromosome) is a common cause of congenital
anomalies and developmental disabilities. Approximately 1% of chromosomal abnormalities are mosaic, and
these patients have two cellular populations with and without chromosomal abnormalities. Pallister-Killian
syndrome (PKS) is a common mosaic chromosomal disorder, and this syndrome is caused by the presence of
an extra supernumerary marker chromosome, isochromosome 12p (i(12p), composed of two 12p arms that are
mirror-images). We previously demonstrated that the i(12p) in PKS is formed during meiosis. All PKS zygotes
contain i(12p), but during mitosis, some cells lose the i(12p) through a process known as aneuploid rescue.
Consequently, all patients with PKS demonstrate mosaicism. In mosaic chromosomal disorders, altered gene
dosage is believed to be the primary driver of the clinical phenotype, and the rescued cells without the
chromosome abnormality are thought to be “normal.” Based on this premise, it has been proposed that there
exists a correlation between the mosaic ratio (proportion of the cells possessing chromosomal abnormality in
any given tissue) and the severity of patient’s clinical symptoms, but we previously demonstrated the lack of
such a correlation in PKS. One possible explanation for the lack of correlation is that cells that have lost the
extra chromosome continue to demonstrate functional alterations. By taking advantage of the mosaic nature of
chromosomal abnormality seen in PKS, we assessed if aneuploid-rescued PKS cells retain gene expression
and epigenetic abnormalities without i(12p), and we discovered similar transcriptome and histone modification
profiles between PKS cells with and without the extra 12p. Hence, our data points to an ongoing “memory”
effect of the i(12p) on both the transcriptome and epigenome that are not restored after the elimination of i(12p)
by aneuploid rescue. The long-term goal of this project is to identify treatments to improve the clinical features
associated with PKS and other numerical chromosomal disorders in children. Our preliminary data suggest
that, for the full restoration of cellular functions in PKS, not only elimination of the extra chromosome but also
epigenetic resetting is needed. The overall objective of this study is to investigate the role of i(12p) in the
transcriptional and epigenetic alterations observed in PKS. To achieve our overall objective, we will perform
further genomic analyses through two Specific Aims. In Aim 1, we will investigate gene expression alterations
at the single-cell level using single-cell RNA-sequencing and mosaic PKS skin fibroblast cell lines. In Aim 2, we
will investigate whether induced pluripotent stem cell reprogramming can alleviate transcriptome and
epigenome alterations seen in PKS cells without i(12p). This project has a potential to drive a paradigm shift in
our understanding of the basic pathobiology of mosaic chro...

## Key facts

- **NIH application ID:** 10431449
- **Project number:** 1R21HD108557-01
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** Kosuke Izumi
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $280,806
- **Award type:** 1
- **Project period:** 2022-07-08 → 2023-04-01

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10431449

## Citation

> US National Institutes of Health, RePORTER application 10431449, Elucidating the effects of extra chromosome elimination in mosaic aneuploidy syndromes: Pallister-Killian syndrome as a model (1R21HD108557-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10431449. Licensed CC0.

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