The deacetylase enzyme HDAC8 is identified as a crucial regulator of cohesin in humans, and loss-of-function mutations in the HDAC8 gene are found in patients with Cornelia de Lange syndrome. The cohesin complex is important for sister-chromatid cohesion and chromosome segregation, as well as for other chromosomal processes such as gene expression and DNA repair. Cornelia de Lange syndrome (CdLS) is a human developmental disorder associated with significant cognitive deficits and structural birth defects. It is caused by mutations in genes that encode subunits of the cohesin complex or the cohesin regulator NIPL. Here, a deacetylase enzyme, HDAC8, is shown to be a critical regulator of cohesin in human cells, and loss-of-function HDAC8 mutations are found in six patients with CdLS from different families. Cornelia de Lange syndrome (CdLS) is a dominantly inherited congenital malformation disorder, caused by mutations in the cohesin-loading protein NIPBL1,2 for nearly 60% of individuals with classical CdLS3,4,5, and by mutations in the core cohesin components SMC1A (∼5%) and SMC3 (<1%) for a smaller fraction of probands6,7. In humans, the multisubunit complex cohesin is made up of SMC1, SMC3, RAD21 and a STAG protein. These form a ring structure that is proposed to encircle sister chromatids to mediate sister chromatid cohesion8 and also has key roles in gene regulation9. SMC3 is acetylated during S-phase to establish cohesiveness of chromatin-loaded cohesin10,11,12,13, and in yeast, the class I histone deacetylase Hos1 deacetylates SMC3 during anaphase14,15,16. Here we identify HDAC8 as the vertebrate SMC3 deacetylase, as well as loss-of-function HDAC8 mutations in six CdLS probands. Loss of HDAC8 activity results in increased SMC3 acetylation and inefficient dissolution of the ‘used’ cohesin complex released from chromatin in both prophase and anaphase. SMC3 with retained acetylation is loaded onto chromatin, and chromatin immunoprecipitation sequencing analysis demonstrates decreased occupancy of cohesin localization sites that results in a consistent pattern of altered transcription seen in CdLS cell lines with either NIPBL or HDAC8 mutations.

Ciliopathies are an emerging group of disorders, caused by mutations in ciliary genes. One of the most intriguing disease genes associated with ciliopathies is CEP290, in which mutations cause a wide variety of distinct phenotypes, ranging from isolated blindness over Senior‐Loken syndrome (SLS), nephronophthisis (NPHP), Joubert syndrome (related disorders) (JS[RD]), Bardet‐Biedl syndrome (BBS), to the lethal Meckel‐Grüber syndrome (MKS). Despite the identification of over 100 unique CEP290 mutations, no clear genotype–phenotype correlations could yet be established, and consequently the predictive power of a CEP290‐related genotype remains limited. One of the challenges is a better understanding of second‐site modifiers. In this respect, there is a growing interest in the potential modifying effects of variations in genes encoding other members of the ciliary proteome that interact with CEP290. Here, we provide an overview of all CEP290 mutations identified so far, with their associated phenotypes. To this end, we developed CEP290base, a locus‐specific mutation database that links mutations with patients and their phenotypes (medgen.ugent.be/cep290base). Hum Mutat 31:1097–1108, 2010.

Common variable immunodeficiency (CVID) is a primary antibody deficiency characterised by hypogammaglobulinaemia, impaired production of specific antibodies after immunisation and increased susceptibility to infections. CVID shows a considerable phenotypical and genetic heterogeneity. In contrast to many other primary immunodeficiencies, monogenic forms count for only 2–10% of patients with CVID. Genes that have been implicated in monogenic CVID include ICOS, TNFRSF13B (TACI), TNFRSF13C (BAFF-R), TNFSF12 (TWEAK), CD19, CD81, CR2 (CD21), MS4A1 (CD20), TNFRSF7 (CD27), IL21, IL21R, LRBA, CTLA4, PRKCD, PLCG2, NFKB1, NFKB2, PIK3CD, PIK3R1, VAV1, RAC2, BLK, IKZF1 (IKAROS) and IRF2BP2. With the increasing number of disease genes identified in CVID, it has become clear that CVID is an umbrella diagnosis and that many of these genetic defects cause distinct disease entities. Moreover, there is accumulating evidence that at least a subgroup of patients with CVID has a complex rather than a monogenic inheritance. This review aims to discuss current knowledge regarding the molecular genetic basis of CVID with an emphasis on the relationship with the clinical and immunological phenotype.