Solving Undiagnosed Cases and Featuring Other Research Highlights at the Upcoming ACMG 2025 Meeting

After Malia Olson, a genetic counseling graduate student, and her advisor, Erin Baldwin, MS, LCGC, noticed a trend of undiagnosed cases that were eventually solved using a traditional cytogenetics test, Olson began to investigate. She conducted a retrospective study of data from the Undiagnosed Diseases Network (UDN), a research study funded by the National Institutes of Health that uses collective expertise to solve challenging cases, to determine how often undiagnosed cases were later solved using cytogenetic findings.

“To get accepted into the UDN, providers have to make a case that patients have received a reasonable work up without achieving a diagnosis,” Olson said. “When we consider that these participants were diagnosed or could have been diagnosed via karyotyping or chromosomal microarray, which are tests that are readily available clinically, it raises the question of why.”

Olson analyzed data from a diagnosed cohort of participants in the UDN and found that 22 of the 807 diagnoses were determined using cytogenetic findings.

“While 2.7% might not seem significant, this frequency in an undiagnosed population is worth consideration in improving diagnostic outcomes,” Olson said.

Olson also coordinated with medical directors from ARUP Laboratories, which has a robust test menu in cytogenetics and genomic sequencing, to study reports on cytogenetic findings and the sustained value of these test methods.

“It’s still important to consider the role of traditional cytogenetic methods, including karyotype, FISH [fluorescence in situ hybridization], and chromosomal microarray,” Olson said. “These test methodologies can complement next generation sequencing (NGS) methods, including whole exome and whole genome [sequencing] particularly well. From this, clinicians can get a more complete picture of these patients and achieve diagnoses that may not be possible without a multimodal testing approach.”

Olson will present her findings on the continued value of cytogenetics in the era of genomic testing at the upcoming annual meeting for the American College of Medical Genetics and Genomics (ACMG) on Friday, March 21, 2025.

The ACMG Annual Clinical Genetics Meeting provides an opportunity for members of the medical genetics community to share discoveries in genetic disorders, rare diseases, genome sequencing, gene therapies, and best practices. The 2025 meeting will be held in Los Angeles from March 18 to 22.

ARUP medical directors, genetic counselors, and scientists will also share their latest research and discoveries in genetics during the meeting.  

John M. O’Shea, PhD, a laboratory genetics and genomics fellow at ARUP, investigated the diagnostic yield of long-read sequencing in collaboration with additional experts from ARUP and the University of Utah. His study examined a selected cohort of 22 undiagnosed cases from the UDN and the Penelope Program, a University of Utah Health program for solving rare and undiagnosed diseases. Of the five cases analyzed by long-read whole genome sequencing (LRWGS), a de novo deletion in the IRF2BPL gene was identified in one case. This diagnosis would have been difficult to identify using short-read sequencing alone.

Chaofan Zhang, PhD, also a laboratory genetics and genomics fellow at ARUP, worked with additional ARUP experts to examine a complex case of a pediatric patient with multisystem involvement and polysplenia. Trio-based genome sequencing identified a novel de novo KAT6A variant, highlighting the important of genome sequencing in diagnosing rare genetic disorders.

In another project to aid in the diagnosis of rare and undiagnosed genetic disorders, Robert G. Lewis, PhD, a laboratory genetics and genomics fellow at ARUP, collaborated with the Penelope Program and the UDN to analyze 20 cases using RNA sequencing to aid in the diagnostic journeys of the respective patients. In seven of the cases, RNA sequencing played a pivotal role in clarifying pathogenic variants.

More information about these research endeavors will be available at the conference. Visit ARUP Laboratories at booth #625 to learn more about the latest in genetics testing and speak with our experts.

You can review the complete schedule of presentations and posters below.

Presentation

Friday, March 21, 2025, 1:30 p.m.

Platform Session 6: Laboratory Genetics

Petree Hall D, Los Angeles Conference Center

O56. The Value of Cytogenetics in the Age of Genome Sequencing

Malia M. Olson, MS; Erin E. Baldwin, MS, LCGC; Erica F. Andersen, PhD, FACMG; et al.

ARUP Contributors: Erica F. Andersen, PhD, FACMG; Pinar Bayrak-Toydemir, MD, PhD, FACMG; Rong Mao, MD, FACMG

Posters

Thursday, March 20, 2025, 10:30–11:30 a.m.

P603. Laboratory Testing of CFTR Gene in Light of Evolving Professional Guidelines and Standards for Carrier Screening—A Reference Laboratory’s Experience

ARUP Contributors: Yuan Ji, PhD, DABCP, FACMG; Sergio Del Angel, MS, MBA; Holly Bethers, BS; Ha T. Pham, BS; Patti Krautscheid, MS, LCGC; Sara Clark, BS; Sarah Sibio, BS, MBA; Eric Fredrickson, PhD; Sherin Shaaban, MD, PhD, MSci, FACMG; Rong Mao, MD, FACMG

P653. Introns to Insights: The Transformative Power of RNA Sequencing in the Diagnosis of Rare Genetic Disorders

Robert G. Lewis, PhD; Ting Wen, PhD, MBBS; John M. O’Shea, PhD; et al.

ARUP Contributors: Robert G. Lewis, PhD; John M. O’Shea, PhD; Jian M. Zhao, PhD; Alexander Chapin, PhD

P663. A Clinical Laboratory’s Approach to Curating Unexpected Variants in Pharmacogenes

Katie Klingaman, MGC, CGC; Mariska Davids, PhD; Hannah G. Wollenzien, PhD; et al.

ARUP Contributors: Sherin Shaaban, MD, PhD, Msci, FACMG

P785. Premature Termination Codon Variants in CHD1 and SF3B2 in a Complex Pedigree With Phenotypic Variability

Jan Verheijen, PhD; John M. O’Shea, PhD; Steven E. Boyden, PhD; et al.

ARUP Contributors: Jan Verheijen, PhD; John M. O’Shea, PhD; Pinar Bayrak-Toydemir, MD, PhD, FACMG; Rong Mao, MD, FACMG

Friday, March 21, 2025, 10:30–11:30 a.m.

P004. Variant Curation Guideline Specifications for ABCD1 From the ClinGen Peroxisomal Variant Curation Expert Panel

Shruthi Mohan, PhD; Irene De Biase, MD, PhD, FACMG; Tatiana Yuzyuk, PhD, ABMGG; et al.

ARUP Contributors: Irene De Biase, MD, PhD, FACMG; Tatiana Yuzyuk, PhD, ABMGG; Stephanie Francis, MS, LCGC; Rong Mao, MD, FACMG

O56. The Value of Cytogenetics in the Age of Genome Sequencing

Malia M. Olson, MS; Erin E. Baldwin, MS, LCGC; Erica F. Andersen, PhD, FACMG; et al.

ARUP Contributors: Erica F. Andersen, PhD, FACMG; Pinar Bayrak-Toydemir, MD, PhD, FACMG; Rong Mao, MD, FACMG

P574. Long-Chain Fatty Acid Oxidation Disorders: A Review of Newborn Screening Around the Globe for LC-FAOD

Vanessa Rangel Miller, MS, MBCA, CGC; Jennifer Audi, MD; Sara C. Grünert, MD; et al.

ARUP Contributor: Marzia Pasquali, MD, FACMG

P652. Considerations of Variant Interpretation in Galactosemia: Challenges of Creating ACMG Specifications for GALT

Alexa Dickson, PhD; Diane Zastrow, MS, CGC; Robert G. Lewis, PhD; et al.

ARUP Contributors: Robert G. Lewis, PhD; Tatiana Yuzyuk, PhD, ABMGG; Rong Mao, MD, FACMG

P708. Investigating the Diagnostic Yield of Long Read Sequencing in a Selected Cohort of Families With Undiagnosed Disease

John M. O’Shea, PhD; Robert G. Lewis, PhD; Alexandra Rangel, PhD; et al.

ARUP Contributors: John M. O’Shea, PhD; Robert G. Lewis, PhD; Alexandra Rangel, PhD; Brendan O’Fallon, PhD; Andrew Dixon, PhD; Christina Glenzel, BS; Megan Hirschi, BS, MLS(ASCP)^CM; Erica Clyde, MBA, MB(ASCP)^CM; Pinar Bayrak-Toydemir, MD, PhD, FACMG; Rong Mao, MD, FACMG

P784. Novel De Novo KAT6A Variant in a Pediatric Patient With Multisystem Involvement

Chaofan Zhang, PhD; John M. O’Shea, PhD; Erin E. Baldwin, MS, LCGC; et al.

ARUP Contributors: Chaofan Zhang, PhD; John M. O’Shea, PhD; Rong Mao, MD, FACMG; Pinar Bayrak-Toydemir, MD, PhD, FACMG

Kellie Carrigan, kellie.carrigan@aruplab.com