Long-read sequencing is required for precision diagnosis of incontinentia pigmenti

Monica H Wojcik; Robin D Clark; Abdallah F Elias; Casie A Genetti; Jill A Madden; Dana Simpson; Linda Golkar; Miranda P G Zalusky; Angela L Miller; Araceli Rodriguez; Joy Goffena; Camille A Dash; Nikhita Damaraju; Sophia B Gibson; Sophie H R Storz; Zachary B Anderson; Jonas A Gustafson; Isabelle Thiffault; Emily G Farrow; Tomi Pastinen; Jasmine Lin; Jennifer T Huang; Alan H Beggs; Pankaj B Agrawal; Genomics Research to Elucidate the Genetics of Rare Diseases (GREGoR) Consortium; David T Miller; Danny E Miller

doi:10.1016/j.xhgg.2025.100468

Long-read sequencing is required for precision diagnosis of incontinentia pigmenti

HGG Adv. 2025 Jun 12;6(3):100468. doi: 10.1016/j.xhgg.2025.100468. Online ahead of print.

Authors

Monica H Wojcik¹, Robin D Clark², Abdallah F Elias³, Casie A Genetti¹, Jill A Madden¹, Dana Simpson⁴, Linda Golkar⁵, Miranda P G Zalusky⁶, Angela L Miller⁶, Araceli Rodriguez², Joy Goffena⁶, Camille A Dash¹, Nikhita Damaraju⁶, Sophia B Gibson⁷, Sophie H R Storz⁶, Zachary B Anderson⁶, Jonas A Gustafson⁸, Isabelle Thiffault⁹, Emily G Farrow⁹, Tomi Pastinen⁹, Jasmine Lin¹, Jennifer T Huang¹⁰, Alan H Beggs¹, Pankaj B Agrawal¹; Genomics Research to Elucidate the Genetics of Rare Diseases (GREGoR) Consortium; David T Miller¹⁰, Danny E Miller¹¹

Affiliations

¹ Boston Children's Hospital and Harvard Medical School, Boston, MA, USA; Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA, USA.
² Division of Clinical Genetics, Loma Linda University Children's Hospital and Loma Linda University School of Medicine, Loma Linda, CA, USA.
³ Department of Medical Genetics, Shodair Children's Hospital, Helena, MT, USA; Division of Biological Sciences, University of Montana, Missoula, MT, USA; Division of Medical Genetics, Department of Pediatrics, University of Utah, Salt Lake City, UT, USA.
⁴ Randall Children's Hospital, Portland, OR, USA.
⁵ Department of Dermatology, Loma Linda University School of Medicine, Loma Linda, CA, USA.
⁶ Division of Genetic Medicine, Department of Pediatrics, University of Washington and Seattle Children's Hospital, Seattle, WA, USA.
⁷ Division of Genetic Medicine, Department of Pediatrics, University of Washington and Seattle Children's Hospital, Seattle, WA, USA; Department of Genome Sciences, University of Washington, Seattle, WA, USA.
⁸ Division of Genetic Medicine, Department of Pediatrics, University of Washington and Seattle Children's Hospital, Seattle, WA, USA; Molecular and Cellular Biology Program, University of Washington, Seattle, WA, USA.
⁹ Children's Mercy Hospital, Kansas City, MO, USA.
¹⁰ Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
¹¹ Division of Genetic Medicine, Department of Pediatrics, University of Washington and Seattle Children's Hospital, Seattle, WA, USA; Department of Genome Sciences, University of Washington, Seattle, WA, USA; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA; Brotman Baty Institute for Precision Medicine, University of Washington, Seattle, WA, USA. Electronic address: dm1@uw.edu.

PMID: 40515401
DOI: 10.1016/j.xhgg.2025.100468

Abstract

Incontinentia pigmenti (IP) is caused by loss-of-function variants in IKBKG, with molecular genetic diagnosis complicated by a pseudogene. We describe seven individuals from three families with IP but negative clinical genetic testing in whom long-read sequencing identified causal variants, including one family with the common exon 4-10 deletion not identified by conventional clinical genetic testing. Concurrent methylation analysis explained disease severity in one individual who died from neurologic complications, identified a mosaic variant in an individual with an atypical presentation, and confirmed skewed X chromosome inactivation in an XXY individual.

Keywords: IKBKG; incontinentia pigmenti; long-read sequencing; methylation; pseudogene; skewed X chromosome inactivation; structural variation.