Molecular characterization of HDAC8 deletions in individuals with atypical Cornelia de Lange syndrome

Abstract

Cornelia de Lange syndrome (CdLS) is a rare neurodevelopmental syndrome for which mutations in five causative genes that encode (SMC1A, SMC3, RAD21) or regulate (NIPBL, HDAC8) the cohesin complex, account for ~70% of cases. Herein we report on four female Subjects who were found to carry novel intragenic deletions in HDAC8. In one case, the deletion was found in mosaic state and it was determined to be present in ~38% of blood lymphocytes and in nearly all cells of a buccal sample. All deletions, for which parental blood samples were available, were shown to have arisen de novo. X-chromosome inactivation studies demonstrated marked skewing, suggesting strong selection against the mutated HDAC8 allele. Based on an investigation of the deletion breakpoints, we hypothesize that microhomology-mediated replicative mechanisms may be implicated in the formation of some of these rearrangements. This study broadens the mutational spectrum of HDAC8, provides the first description of a causative HDAC8 somatic mutation and increases the knowledge on possible mutational mechanisms underlying copy number variations in HDAC8. Moreover our findings highlight the clinical utility of considering copy number analysis in HDAC8 as well as the analysis on DNA from more than one tissue as an indispensable part of the routine molecular diagnosis of individuals with CdLS or CdLS-overlapping features.

Impact of DNA source on genetic variant detection from human whole-genome sequencing data

“…In clinical diagnostics, additional factors may influence the choice of DNA source. For instance, certain neurodevelopmental and neurological disorders have causative variants specific to, or more evident in, certain sample types, such as ectodermal-derived tissues (which include buccal cells) 40–42. When detecting somatic mutations in patients with leukaemia, blood cannot be used as a matched normal sample.…”

BETting on a Transcriptional Deficit as the Main Cause for Cornelia de Lange Syndrome

“…Mutations in other genes have also been reported (reviewed in (Kline et al, 2018), Table 1): mutations in SMC1A have been identified in an estimated 5% of individuals with CdLS, usually associated to a non-classical phenotype (Musio et al, 2006;Borck et al, 2007;Deardorff et al, 2007;Ansari et al, 2014;Huisman et al, 2017); a SMC3 variant has been found in an individual with atypical CdLS (Deardorff et al, 2007) and others have been associated to individuals with some overlapping phenotypical features but not fulfilling the diagnostic criteria of non-classic CdLS (Ansari et al, 2014;Gil-Rodriguez et al, 2015); RAD21 variants have been found in a small percentage of non-classic CdLS cases ((Deardorff et al, 2012b) and reviewed in (Cheng et al, 2020)); HDAC8 variants have been also reported, with a typically heterogeneous non-classic phenotype, but also with some classic CdLS cases (Deardorff et al, 2012a;Harakalova et al, 2012;Ansari et al, 2014;Feng et al, 2014;Kaiser et al, 2014;Parenti et al, 2016;Helgeson et al, 2018;Jezela-Stanek et al, 2019); BRD4 mutations have been associated with few cases of non-classic CdLS (Olley et al, 2018;Alesi et al, 2019); and other gene variants have been identified, mainly by exome sequencing, associated with individuals with limited clinical CdLS features, like variants of EP300 (Woods et al, 2014;Cucco et al, 2020), AFF4 (Izumi et al, 2015), KMT2A (Yuan et al, 2015;Parenti et al, 2017;Aoi et al, 2019), NAA10 (Saunier et al, 2016), TAF6 (Yuan et al, 2015), ANKRD11 (Ansari et al, 2014;Parenti et al, 2016;…”

A Novel Intragenic Duplication in the HDAC8 Gene Underlying a Case of Cornelia de Lange Syndrome

“…The majority of known disease-causing changes in HDAC8 are SNVs, including nonsense, missense, or splice site variants [ 6 , 7 , 20 , 21 , 22 , 23 , 24 , 25 ]. Nevertheless, recently, several cases of changes involving larger regions of HDAC8 have been reported in individuals with CdLS, especially intragenic deletions ranging from single to multiple exons [ 6 , 12 ]. Interestingly, the presence of two to three pairs of microhomology at the breakpoints was found in these cases [ 12 ].…”

“…Therefore, the international guidelines recommend multiplex ligation-dependent probe amplification (MLPA) approaches when panels and Sanger sequencing cannot detect any variant in this gene [ 1 ], but commercial MLPA assays only cover the NIPBL gene. Since next-generation sequencing panels have been implemented, structural variants involving other causal genes such as SMC1A [ 11 ], HDAC8 [ 12 ], and RAD21 [ 13 ] have been described in some individuals with CdLS. These cases indicate that pathogenic CNVs in CdLS-related genes may be more common than previously thought.…”