There has been one previous report of a cohort of patients with variants in Chromodomain Helicase DNA-binding 3 ( CHD3 ), now recognized as Snijders Blok-Campeau syndrome. However, with only three previously-reported patients with variants outside the ATPase/helicase domain, it was unclear if variants outside of this domain caused a clinically similar phenotype. We have analyzed 24 new patients with CHD3 variants, including nine outside the ATPase/helicase domain. All patients were detected with unbiased molecular genetic methods. There is not a significant difference in the clinical or facial features of patients with variants in or outside this domain. These additional patients further expand the clinical and molecular data associated with CHD3 variants. Importantly we conclude that there is not a significant difference in the phenotypic features of patients with various molecular disruptions, including whole gene deletions and duplications, and missense variants outside the ATPase/helicase domain. This data will aid both clinical geneticists and molecular geneticists in the diagnosis of this emerging syndrome.
R628* (x 5) R322* (x 4) K1396Rfs*3 C146* G681Vfs*11 K734Sfs*24 R481*(x 3) G1018Dfs*2 R528Efs*4 R218* (x 3) Q141Rfs*7 L209Pfs*3 R313* N573Sfs*11 S1157* S1200Ifs*5 (x3) R62Efs*22
The study aimed at widening the clinical and genetic spectrum of ASXL3‐related syndrome, a neurodevelopmental disorder, caused by truncating variants in the ASXL3 gene. In this international collaborative study, we have undertaken a detailed clinical and molecular analysis of 45 previously unpublished individuals with ASXL3‐related syndrome, as well as a review of all previously published individuals. We have reviewed the rather limited functional characterization of pathogenic variants in ASXL3 and discuss current understanding of the consequences of the different ASXL3 variants. In this comprehensive analysis of ASXL3‐related syndrome, we define its natural history and clinical evolution occurring with age. We report familial ASXL3 pathogenic variants, characterize the phenotype in mildly affected individuals and discuss nonpenetrance. We also discuss the role of missense variants in ASXL3. We delineate a variable but consistent phenotype. The most characteristic features are neurodevelopmental delay with consistently limited speech, significant neuro‐behavioral issues, hypotonia, and feeding difficulties. Distinctive features include downslanting palpebral fissures, hypertelorism, tubular nose with a prominent nasal bridge, and low‐hanging columella. The presented data will inform clinical management of individuals with ASXL3‐related syndrome and improve interpretation of new ASXL3 sequence variants.
IntroductionDown syndrome (DS) is the most frequent genetic cause of intellectual disability. Despite the fact that more than 50 years have passed since the discovery of its genetic aberrations, the exact pathogenesis of the DS phenotype has remained largely unexplained. It was recently hypothesized that the DS pathogenesis involves complex (epi)genetic, molecular and cellular determinants. To date, many reports have addressed epigenetic aberrations associated with DS at different developmental stages/ages and tissue types, but to our best knowledge not in DS newborns. This study aimed to investigate genome-wide methylation patterns in DS newborns compared to non-trisomic newborns.MethodWe analyzed blood samples obtained from ten newborns with DS and five age-matched non-trisomic newborns. Epigenetic profiles were obtained from extracted DNA using the Illumina Infinium 450K array. Since aberrant blood cell distribution is known to be present in DS, we applied two distinct models: with and without correction for estimated blood cell distribution.ResultsDifferentially methylated position (DMP) analysis of the uncorrected model detected 19525 significant hits (51,2% hypomethylated). In the corrected model, we found 121953 significant DMPs (49,8% hypomethylated). Independent of the used model we observed a chromosome 21 dosage effect. Moreover, we detected 46 and 145 differentially methylated regions in the uncorrected and corrected model respectively, both showing hypomethylation overrepresentation. Replication analyses of DMPs and DMRs found by Bacalini et al. (2015) showed a large overlap.ConclusionIn this study, we found methylation profile differences between DS newborns and controls reflecting a systematically affected epigenetic profile. The observed chromosome 21 dosage effect suggests the involvement of affected essential regulatory factors/regions or altered expression of chromatin modeling enzymes located on chromosome 21. Additional research is necessary to substantiate these hypotheses.
Interstitial deletions encompassing the 3q26.2 region are rare. Only one case-report was published this far describing a patient with an interstitial deletion of 3q26.2 (involving the MDS1-EVI1 complex (MECOM)) and congenital thrombocytopenia. In this report we describe a case of a neonate with congenital thrombocytopenia and a constitutional 4.52 Mb deletion of 3q26.2q26.31 including TERC and the first 2 exons of MECOM, involving MDS1 but not EVI1. The deletion was demonstrated by array-CGH on lymphocytes. Our report confirms that congenital thrombocytopenia can be due to a constitutional deletion of 3q26.2 involving MECOM. We suggest that in case of unexplained neonatal thrombocytopenia, with even just slight facial dysmorphism, DNA microarray on peripheral blood should be considered early in the diagnostic work-up.
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