Two cases of misinterpretation of molecular results in incontinentia pigmenti, and a PCR-based method to discriminate NEMO/IKK? dene deletion

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Abstract
Familial incontinentia pigmenti (IP) is a rare X‐linked dominant disorder that affects ectodermal tissues. Over 90% of IP carrier females have a recurrent genomic deletion of exons 4–10 of the NEMO (IKBKG‐IKKγ) gene, which encodes a regulatory component of the IkB kinase complex, required to activate the NF‐kB pathway. In IP, mutations in NEMOlead to the complete loss of NF‐kB activation creating a susceptibility to cellular apoptosis in response to TNF‐α. This condition is lethal for males during embryogenesis while females, who are mosaic as a result of X‐inactivation, can survive. Recently, a second nonfunctional copy of the gene, ΔNEMO, was identified, opposite in direction to NEMO in a 35.5‐kb duplicated sequence tract. PCR‐based detection of the NEMO deletion is diagnostic for IP disease. However, we present instances in which ex 4–10 ΔNEMO pseudogene deletion occurs in unaffected parents of two females with clinically characteristic IP. These were missed by the currently standard PCR‐based method, but can be easily discriminated by a new PCR‐based test reported here that permits unambiguous molecular diagnosis and proper familial genetic counseling for IP. Hum Mutat 21:8–11, 2002.