A number sign (#) is used with this entry because of evidence that Kury-Isidor syndrome (KURIS) is caused by heterozygous mutation in the BAP1 gene (603089) on chromosome 3p21.

Kury-Isidor syndrome (KURIS) is a neurodevelopmental disorder with a highly variable phenotype. It is characterized mainly by mild global developmental delay apparent from infancy or early childhood with walking delayed by a few years and speech delay, often with language deficits. Intellectual development may be mildly delayed, borderline, or even normal; most patients have behavioral problems, including autism. Additional variable systemic features may include poor overall growth, hypotonia, distal skeletal anomalies, seizures, and nonspecific dysmorphic facial features (summary by Kury et al., 2022).

Kury et al. (2022) reported 8 unrelated patients (patients 1-4 and 7-10), ranging from 2 to 16 years of age, who were ascertained through collaborative efforts such as the GeneMatcher Program after exome sequencing identified de novo heterozygous missense variants in the BAP1 gene. Clinical details were limited and the phenotype was highly variable. Most patients presented with mild global developmental delay manifest mainly as delayed walking by a few years and speech delay or speech difficulties. Most also had behavioral abnormalities, including autistic features, sensitivity, and attention deficits. Patient 3 was a 14-year-old girl with more significant behavioral problems, including hyperactivity, tantrums, impulsivity, aggression, and skin picking. Patient 4 was a 6-year-old boy who had speech delay and autism spectrum disorder, but an IQ of 97. Five patients had a history of early seizures that were controlled or resolved. Additional variable features included feeding difficulties with poor overall growth, distal skeletal anomalies, and eye abnormalities, including strabismus, astigmatism, and myopia. Variable nonspecific dysmorphic facial features were sometimes observed: these included frontal bossing, relative macrocephaly, brachycephaly, square-shaped face, coarse facies, long philtrum, low-set simple ears, short nose with anteverted nares, hypertelorism, and downslanting palpebral fissures. Brain imaging, when performed, was normal.

The heterozygous mutations in the BAP1 gene that were identified in patients with KURIS by Kury et al. (2022) occurred de novo.

In 8 unrelated patients (patients 1-4 and 7-10) with KURIS, Kury et al. (2022) identified de novo heterozygous missense mutations in the BAP1 gene (see, e.g., 602089.0011-601089.0014). All the mutations occurred at conserved residues in the catalytic ubiquitin C-terminal hydrolase domain; none were present in the gnomAD database. In vitro functional expression studies in BAP1-null HAP1 cells showed that some of the variants tested (P12T, 603089.0011; C91R, 603089.0013; and H169R, 603089.0014) were unable to rescue BAP1 activity, as measured by increased BAP1 H2AK119ub substrate levels. Rescue with another variant (P12A; 603089.0012) was similar to controls for that particular substrate. All variants tested, including P12A, were unable to rescue the expression of BAP1 target genes TMSB4X (300159) and S100A11 (603114) in a BAP1-null cell line, whereas wildtype BAP1 was able to restore expression of these genes. These data suggested that the BAP1 mutations were unable to compensate H2A deubiquitination of substrates in BAP1-null cells, consistent with a loss-of-function effect. Of note, all the BAP1 variants localized properly to the nucleus in transfected cells. T cells derived from 2 patients carrying the P12T and C91S mutations showed that steady-state levels of ubiquitinated H2A were substantially increased compared to controls, again consistent with a loss-of-function effect for BAP1. CHIP-seq analysis indicated that the variants induced genomewide chromatin state alterations in the 2 patient cell lines; there was also some evidence of proteosome perturbation. Kury et al. (2022) concluded that BAP1 missense variants alter chromatin remodeling through abnormal histone ubiquitination, leading to transcriptional dysregulation of developmental genes. None of the patients developed tumors. The authors noted that BAP1 mutations that predispose to tumor syndrome are truncating or splice-site mutations; the missense mutations identified in patients with KURIS are loss-of-function and may disrupt the deubiquitinase activity without altering other protein-protein interactions. Some of the patients, including 3 additional patients (patients 5, 6, and 11) with variable developmental abnormalities associated with de novo missense BAP1 variants identified in the study, had additional genetic variants of uncertain significance that may have contributed to the phenotype.