Multiple molecular diagnoses identified through genome sequencing in individuals with suspected rare disease

Genome sequencing is a powerful and comprehensive test that detects multiple variants of different types. The interrogation of variants across the genome enables the identification of multiple molecular diagnoses (MMDs) in a single individual. In this retrospective study, we describe individuals in whom MMDs were associated with the proband's indication for testing (IFT), secondary findings, or incidental findings. An MMD is considered where at least one of the findings is associated with the primary IFT and all variants are classified as either likely pathogenic or pathogenic. Clinical genome sequencing was performed for all individuals as part of the iHope program at the Illumina Laboratory Services between September 2017 and December 2023. The iHope cohort included 1,846 affected individuals, with 872 (47.2%) found to have at least one likely pathogenic or pathogenic variant associated with the primary IFT. Of these, 81 (9.3%) individuals had multiple clinically significant molecular findings, including 76 individuals with reported variants associated with 2 different conditions, and 5 individuals with more than 2 molecular findings. A total of 32 individuals (3.7%) had at least 2 molecular diagnoses related to the primary IFT, while in 49 (5.6%) individuals, the variant(s) reported for the second condition constituted a secondary or incidental finding. Our study highlights that among individuals with a likely pathogenic or pathogenic finding identified through genome sequencing, 9% have MMDs, which may have been missed with different testing methods. Of note, approximately 60% of the 81 individuals with an MMD had a potentially actionable secondary or incidental finding.

Authors

Institutions

Publication Details

Journal
Human Genetics and Genomics Advances
Published
2025-04-08
DOI
https://doi.org/10.1016/j.xhgg.2025.100430
Citations
4
Primary Topic
Genomics and Rare Diseases
Type
article
Field-Weighted Citation Impact
7.27

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

Multiple molecular diagnoses identified through genome sequencing in individuals with suspected rare disease

Mario Cornejo‐Olivas, Mamy Ngole, Donald Basel, Marwan S. Shinawi et al.
4 citations
Human Genetics and Genomics Advances
Genomics and Rare Diseases
7.27
article

Multiple molecular diagnoses identified through genome sequencing in individuals with suspected rare disease

Mario Cornejo‐Olivas, Mamy Ngole, Donald Basel, Marwan S. Shinawi, Akanchha Kesari, Ebenezer Badoe, Todor Arsov, Samuel Agyei Wiafe, Jorge Perez, Milagros M. Dueñas Roque, Ryan J. Taft, Lauren Thompson, Kari Casas, Julie McCarrier, Arturo Serize, Adeline Vanderver, Yvonne Brew, Prince Makay, Aimé Lumaka, Claudia Soler‐Alfonso, Chester Brown, Revathi Rajkumar, Danita Velasco, Abbey Freed, Julio Montoya, Laura Davis‐Keppen, Erin Thorpe, Alison J. Coffey, Gerrye Mubungu, Kerri Bosfield, Diane Masser‐Frye, Fabio Sirchia, Alka Malhotra, Marilyn C. Jones, Keith K. Vaux, Joyce Ashong, Gail H. Vance, Denise Perry, Hildegard Peña Salguero, Alan Taylor, Kate Gibson, Josephine Adjeman, Charles J. Marcuccilli, Ursula Maier, Naomi Adjetey, Enikö K. Pivnick, HelenJ. Mills, Parul Jayakar, Felix Nii Saka Allotey, Martina Kawome, Gioconda Manassero, Marilyn Marbell-Wilson, Sharron Aglobitse
article en
4 citations

Abstract

Genome sequencing is a powerful and comprehensive test that detects multiple variants of different types. The interrogation of variants across the genome enables the identification of multiple molecular diagnoses (MMDs) in a single individual. In this retrospective study, we describe individuals in whom MMDs were associated with the proband's indication for testing (IFT), secondary findings, or incidental findings. An MMD is considered where at least one of the findings is associated with the primary IFT and all variants are classified as either likely pathogenic or pathogenic. Clinical genome sequencing was performed for all individuals as part of the iHope program at the Illumina Laboratory Services between September 2017 and December 2023. The iHope cohort included 1,846 affected individuals, with 872 (47.2%) found to have at least one likely pathogenic or pathogenic variant associated with the primary IFT. Of these, 81 (9.3%) individuals had multiple clinically significant molecular findings, including 76 individuals with reported variants associated with 2 different conditions, and 5 individuals with more than 2 molecular findings. A total of 32 individuals (3.7%) had at least 2 molecular diagnoses related to the primary IFT, while in 49 (5.6%) individuals, the variant(s) reported for the second condition constituted a secondary or incidental finding. Our study highlights that among individuals with a likely pathogenic or pathogenic finding identified through genome sequencing, 9% have MMDs, which may have been missed with different testing methods. Of note, approximately 60% of the 81 individuals with an MMD had a potentially actionable secondary or incidental finding.

Human Genetics and Genomics AdvancesVol. 6(3)
Children's Hospital of Wisconsin (US), Rush University Medical Center (US), Baptist Hospital of Miami (US), Sanford Health (US), Children's Hospital of Los Angeles (US), University of Cape Coast (GH), University of Tennessee Health Science Center (US), Illumina (United States) (US), Medical College of Wisconsin (US), Komfo Anokye Teaching Hospital (GH), Al Jalila Foundation (AE), Sanford USD Medical Center (US), Korle Bu Teaching Hospital (GH), Ho Technical University (GH), Children’s Foundation (GB), Holy Family Hospital (GH), Miami Children's Hospital (US), Texas Children's Hospital (US), Children's Hospital & Medical Center (US), Le Bonheur Children's Hospital (US), Ghana Health Service (GH), Indiana University School of Medicine, Indiana University – Purdue University Indianapolis (US)
Illumina
Openalex Percentile: Top 3%
Genomics and Rare Diseases
7.27
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.