# Analysis of pathogenic tandem repeat variation in Gabriella Miller Kids First pediatric cohorts

> **NIH NIH R03** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2022 · $169,000

## Abstract

Tandem Repeat Expansions (TREs), most commonly of triplet repeats such as poly(CAG), are now known to
underlie >40 different human diseases. While the most well-known TREs occur in late-onset
neurodegenerative disorders such as hereditary ataxias and Huntington disease, pathogenic TREs have also
been identified in a growing list of congenital disorders. To date, pathogenic expansions of coding or intronic
repeats are known to occur in nine different genes that cause congenital disease. However, despite this ample
evidence that variation in tandem repeat (TR) sequences can act as the causative mutation in a wide variety of
congenital disorders, to our knowledge, there have been no concerted efforts to systematically screen for novel
TREs in cohorts of patients with congenital disease.
 Newly developed bioinformatic approaches that can be applied to analyze Whole Genome Sequencing
(WGS) data now provide an opportunity to fill this knowledge gap. Utilizing the expertise and knowledge that
we have gained working on other disease cohorts, we now propose to apply these approaches to analyze
WGS data from ~3,000 trios generated by Gabriella Miller Kids First Pediatric Research Program. We will use
these data to profile TR variation genome-wide using multiple different algorithmic approaches that are
optimized to identify the full range of pathogenic TR variations, including relatively subtle expansions (increase
of 1-20 TR copies), and much longer TREs (gains of 20 up to several thousand repeat copies), both of which
are known to cause congenital disorders.
 We hypothesize that some cases of AD are caused by rare, highly penetrant pathogenic TREs. Using
novel bioinformatic tools that can identify TREs, we will search for rare TREs that are observed only in AD
samples, or which show significant enrichment in AD cases compared to controls, and thus are likely causative
for AD. Potentially pathogenic TREs will then be validated by PCR or long-read sequencing in available DNA
samples.
 Given that TREs represent an established mutational mechanism that contributes to a variety of
congenital disorders, we propose that the study of TR variation represents a logical step that has a high
likelihood of uncovering novel genetic causes of congenital disorders.

## Key facts

- **NIH application ID:** 10492425
- **Project number:** 5R03HD103782-02
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Andrew James Sharp
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $169,000
- **Award type:** 5
- **Project period:** 2021-09-22 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10492425

## Citation

> US National Institutes of Health, RePORTER application 10492425, Analysis of pathogenic tandem repeat variation in Gabriella Miller Kids First pediatric cohorts (5R03HD103782-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10492425. Licensed CC0.

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