Broadening of cohesinopathies: exome sequencing identifies mutations in ANKRD11 in two patients with Cornelia de Lange‐overlapping phenotype

Abstract

Cornelia de Lange syndrome (CdLS) and KBG syndrome are two distinct developmental pathologies sharing common features such as intellectual disability, psychomotor delay, and some craniofacial and limb abnormalities. Mutations in one of the five genes NIPBL, SMC1A, SMC3, HDAC8 or RAD21, were identified in at least 70% of the patients with CdLS. Consequently, additional causative genes, either unknown or responsible of partially merging entities, possibly account for the remaining 30% of the patients. In contrast, KBG has only been associated with mutations in ANKRD11. By exome sequencing we could identify heterozygous loss-of-function mutations in ANKRD11 in two patients with the clinical diagnosis of CdLS. Both patients show features reminiscent of CdLS such as characteristic facies as well as a small head circumference which is not described for KBG syndrome. Patient A, who carries the mutation in a mosaic state, is a 4-year-old girl with features reminiscent of CdLS. Patient B, a 15-year-old boy, shows a complex phenotype which resembled CdLS during infancy, but has developed to a more KBG overlapping phenotype during childhood. These findings point out the importance of screening ANKRD11 in young CdLS patients who were found to be negative for mutations in the five known CdLS genes.

Novel Mutations and Unreported Clinical Features in KBG Syndrome

“…ANKRD11 represses the transcriptional activation of target genes of nuclear receptors by recruiting deacetylases to different promoters [Zhang et al, 2004]. Both ANKRD11 and cohesin-complex are involved in gene expression regulation, and dysregulation of functionally interconnected sets of genes due to deficiency of the cohesin complex or ANKRD11 may result in overlapping phenotypic features [Parenti et al, 2016].…”

“…Overall, the usefulness of clinical diagnostic criteria was challenged by the identification of ANKRD11 -mutated individuals in large cohorts of patients with developmental disorders who underwent whole-exome sequencing: these individuals often showed less striking clinical features [Low et al, 2016]. Furthermore, it was recognized that some patients (5 to date) with de novo ANKRD11 mutations showed a nonclassical Cornelia de Lange syndrome (CdLS) phenotype [Ansari et al, 2014;Parenti et al, 2016], and gene panels for CdLS were recently developed to include ANKRD11 . A possible explanation of the clinical overlap between KBG and CdLS relies on the functional effect of ANKRD11, which was shown to be a chromatin regulator that controls histone acetylation and gene expression during neural development [Gallagher et al, 2015].…”

Nipbl Interacts with Zfp609 and the Integrator Complex to Regulate Cortical Neuron Migration

“…Indeed, neuronal heterotopias were reported in autopsy data of CdLS patients (Tekin and Bodurtha, 2015). Abnormal localization of E13.5-born neurons in the IZ was also observed in mice carrying a heterozygous mutation in Ankrd11 , a chromatin regulator mutated in rare cases of CdLS (Gallagher et al., 2015, Parenti et al., 2016). Furthermore, our data suggest that Zfp609 and Nipbl act through the Integrator complex to contact the basal transcription machinery and regulate gene expression at the level of RNA pol2 pause release.…”

KBG syndrome involving a single-nucleotide duplication in ANKRD11

“…Minor features of KBG syndrome include cutaneous syndactyly, conductive hearing loss, palatal abnormalities, cryptorchidism, webbed/short neck, strabismus, and congenital heart defects (Brancati et al 2006). There is some phenotypic overlap with Cornelia de Lange syndrome (CdLS), although there is nothing that is necessarily pathognomonic in either disorder (Ansari et al 2014; Parenti et al 2015). More than 100 cases have now been reported (see Fig.…”