Long-Read Sequencing is Required for Precision Diagnosis of Incontinentia Pigmenti

TL;DR

Long-read sequencing is essential for diagnosing Incontinentia Pigmenti when standard tests fail due to a pseudogene.

Contribution

Demonstrates the necessity of long-read sequencing for accurate diagnosis of IP in cases with negative clinical testing.

Findings

Long-read sequencing identified causal variants in seven individuals with IP who had negative clinical test results.

Methylation analysis explained disease severity and identified a mosaic variant in an atypical case.

Skewed X-chromosome inactivation was confirmed in an XXY individual using methylation analysis.

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 testing in whom long-read sequencing identified causal variants. 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.

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