Supplemental Material for: Diagnostic odyssey in a patient with Incontinentia Pigmenti elucidated by Optical Genome Mapping: a case report

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Introduction: Incontinentia Pigmenti is a rare neurocutaneous disorder caused by variants in the IKBKG gene, with X-linked dominant inheritance and a high mortality rate in hemizygous males. This disorder has a characteristic natural history comprising four stages (bullous, verrucous, hyperpigmented, and hypopigmented skin lesions); additionally, the phenotypic spectrum is highly variable, and defects in hair, nails, teeth, and other systemic involvements can occur.Molecular confirmation can be performed to detect a common deletion of exons 4 to 10 in approximately 65% of cases, or sequence variants in less than 10% of cases. However, currently over 20% of cases may still yield a negative molecular result.Case Presentation:A female patient was referred due to neurodevelopmental delay, epilepsy, microcephaly, retinal detachment, and cutaneous changes, including diffuse vesiculobullous lesions in the neonatal period evolving in the first year to stable hyperpigmented macules and patches with a blaschkoid distribution. Molecular investigation using different methods, including targetedIKBKGsequencing and short-read whole-genome sequencing,initially ruled out the diagnosis of Incontinentia Pigmenti and revealed a heterozygous pathogenic variant in theCOL7A1gene, suggesting a diagnosis of transient bullous dermolysis of the newborn. However, persistent molecular investigation using optical genome mapping and long-read whole genome sequencing confirmed that she had Incontinentia Pigmenti due to a partial deletion of theIKBKGgene.Conclusion:The case presents the challenges of a diagnostic odyssey and proposes that individuals with Incontinentia Pigmenti reported as negative for the deletion should be reanalyzed using long-read technologies.

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