Ubiquitin ligases play an important role in the regulation of the immune system. Absence of Itch E3 ubiquitin ligase in mice has been shown to cause severe autoimmune disease. Using autozygosity mapping in a large Amish kindred, we identified a linkage region on chromosome 20 and selected candidate genes for screening. We describe, in ten patients, identification of a mutation resulting in truncation of ITCH. These patients represent the first reported human phenotype associated with ITCH deficiency. These patients not only have multisystem autoimmune disease but also display morphologic and developmental abnormalities. This disorder underscores the importance of ITCH ubiquitin ligase in many cellular processes.

Purpose: Mutations in the CDKL5 gene have been associated with an X-linked dominant early infantile epileptic encephalopathy-2. The clinical presentation is usually of severe encephalopathy with refractory seizures and Rett syndrome (RTT)-like phenotype. We attempted to assess the role of mosaic intragenic copy number variation in CDKL5. Methods: We have used comparative genomic hybridization with a custom-designed clinical oligonucleotide array targeting exons of selected disease and candidate genes, including CDKL5. Results: We have identified mosaic exonic deletions of CDKL5 in one male and two females with developmental delay and medically intractable seizures. These three mosaic changes represent 60% of all deletions detected in 12,000 patients analyzed by array comparative genomic hybridization and involving the exonic portion of CDKL5. Conclusion: We report the first case of an exonic deletion of CDKL5 in a male and emphasize the importance of underappreciated mosaic exonic copy number variation in patients with early-onset seizures and RTT-like features of both genders. Genet T he cyclin-dependent kinase-like 5 (CDKL5) gene (also known as seronine-threonine kinase 9) encodes a protein of 1030 amino acids with highly conserved serine-threonine kinase domain in the N-terminal region and a large C-terminal region involved in either the catalytic activity or the subcellular localization. 1 CDKL5 is particularly expressed in the brain and has homology to the mitogen-activated protein kinase and CDK families. 2 Mutations in CDKL5 (OMIM# 300203) are X-linked dominant and have been described in females with severe neurodevelopmental disorders characterized by early-onset seizures, infantile spasms and severe psychomotor impairments, and Rett Syndrome (RTT)-like phenotypes. 3 The phenotypic resemblance to Rett syndrome is likely related to similar function of the CDKL5 and MeCP2 proteins in the molecular pathways and regional pattern of expression during neurodevelopment. 4,5 Recently, copy number variations (CNVs) involving the CDKL5 gene have been reported in girls with severe epilepsy and a RTT-like phenotype. The increasing availability of array comparative genomic hybridization (CGH) has led to several publications describing different deletions in CDKL5 in females. 6 -9 These data emphasize that deletion CNVs involving CDKL5 are more common than first appreciated, especially in females.CDKL5 mutations have been found very rarely in males, suggesting that nullisomy might be incompatible with life. To date, only two frameshifts and four missense mutations have been reported in males with severe encephalopathy and early-onset intractable epilepsy. 10 -13 In addition, an approximately 2.8-Mb deletion involving CDKL5 and 15 other genes has been reported in a boy with severe encephalopathy, tetralogy of Fallot, and bilateral cataracts. 14 Also, an approximately 136-kb deletion disrupting exons 17-20 of CDKL5 and the RS1 and PPEF1 genes has been described in a male with retinoschisis and epilepsy. 15 We report ...

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