Histone deacetylases (HDACs) are enzymes pivotal for histone modification (i.e. acetylation marks removal), chromatin accessibility and gene expression regulation. Class I HDACs (including HDAC1, 2, ...3, 8) are ubiquitously expressed and they often participate in multi-molecular protein complexes. To date, three neurodevelopmental disorders caused by mutations in genes encoding for HDACs (
HDAC4
,
HDAC6
and
HDAC8
) and thus belonging to the group of chromatinopathies, have been described. We performed whole exome sequencing (WES) for a patient (#249) clinically diagnosed with the chromatinopathy Rubinstein-Taybi syndrome (RSTS) but negative for mutations in RSTS genes, identifying a
de novo
frameshift variant in
HDAC2
gene. We then investigated its molecular effects in lymphoblastoid cell lines (LCLs) derived from the patient compared to LCLs from healthy donors (HD). As the variant was predicted to be likely pathogenetic and to affect the sequence of nuclear localization signal, we performed immunocytochemistry and lysates fractionation, observing a nuclear mis-localization of HDAC2 compared to HD LCLs. In addition, HDAC2 total protein abundance resulted altered in patient, and we found that newly identified variant in
HDAC2
affects also acetylation levels, with significant difference in acetylation pattern among patient #249, HD and RSTS cells and in expression of a known molecular target. Remarkably, RNA-seq performed on #249, HD and RSTS cells shows differentially expressed genes (DEGs) common to #249 and RSTS. Interestingly, our reported patient was clinically diagnosed with RSTS, a chromatinopathy which known causative genes encode for enzymes antagonizing HDACs. These results support the role of
HDAC2
as causative gene for chromatinopathies, strengthening the genotype-phenotype correlations in this relevant group of disorders.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
DYRK1A‐related intellectual disability is a recently described syndrome characterized by microcephaly, global developmental delay, impaired speech development, and distinctive facial features, which ...let to define it as a recognizable syndrome. Here we report four new patients of different ethnicity, broadening the clinical phenotype of the condition and highlighting how ethnic influences in the facial appearance could make it less recognizable.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Introduction: Mendelian disorders of the epigenetic machinery are a growing group of disorders exhibiting several overlapping clinical features that are probably due to common abnormalities at the ...epigenomic level, which lead to downstream convergence at the transcriptomic level. Case presentation: Here, we report a new case of short stature, brachydactyly, intellectual developmental disability, and seizures (SBIDDS) syndrome with a severe ocular phenotype and hypogonadism. Conclusion: Similarities and connections with other mendelian disorders of the epigenetic machinery are highlighted, confirming SBIDDS′ enrolment as a new spoke of the epigenetic machinery wheel.
Abstract Neurofibromatosis 1 is a complex inherited neurocutaneous disease that is often difficult to diagnose early because of its age-dependent presentation. The diagnosis is also extremely ...difficult to communicate to patients and their parents because of the disease's clinical variability, unpredictable evolution, and uncertain prognosis. Since 1988, the year of publication of the last Consensus Conference statement concerning the diagnosis of neurofibromatosis 1, our understanding of the disease has naturally increased and, in addition to the availability of increasingly precise molecular analyses, some new clinical signs have been reported such as anaemic nevi, unidentified bright objects, choroidal hamartomas, and a typical neuropsychological phenotype. We critically review the current diagnostic criteria, and suggest the addition of new signs on the basis of published findings and our own clinical experience. This proposal aims to improve diagnostic power in paediatric age, securing a better and more reliable healthcare transition toward adult age. We finally recommend a new Consensus Conference in order to revise the diagnostic criteria, possibly differentiated by age of presentation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
15.
A multidisciplinary approach in neurofibromatosis 1 Milani, Donatella; Pezzani, Lidia; Tadini, Gianluca ...
Lancet neurology,
2015, January 2015, 2015-Jan, 2015-01-00, 20150101, Volume:
14, Issue:
1
Journal Article
Peer reviewed
Open access
Furthermore, several studies have shown that the established diagnostic criteria are not sensitive enough; some features are not present in infancy, thus leading to a delayed diagnosis with clinical ...and psychological implications for the patients and their families.2 Given the need for improved knowledge and a multidisciplinary approach to NF1 shown by Hirbe and Gutmann,1 we believe that it is time for a new consensus conference where clinicians and molecular biologists with experience in NF1 can draw up a new list of age-related criteria that would allow for earlier diagnosis, better patient care, and the development of new targeted treatments.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
We report a 9‐year‐old girl with hypotonia, severe motor delay, absent speech, and facial dysmorphism who developed acute encephalopathy with severe neurological outcome. Trio‐based whole exome ...sequencing (WES) analysis detected a de novo heterozygous mutation in the BRAF gene leading to the diagnosis of an atypical presentation of cardiofaciocutaneous (CFC) syndrome. This is the second case of CFC syndrome complicated with acute encephalopathy reported in the literature and supports the hypothesis that acute encephalopathy might be one of the complications of the syndrome due to an intrinsic susceptibility to this acute event. The report furthermore highlights the role of WES in providing a fast diagnosis in patients in critical conditions with atypical presentation of rare genetic syndromes.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The study aimed to clinically and molecularly characterize the neurodevelopmental disorder associated with heterozygous de novo variants in CNOT9.
Individuals were clinically examined. Variants were ...identified using exome or genome sequencing. These variants were evaluated using in silico predictions, and their functional relevance was further assessed by molecular models and research in the literature. The variants have been classified according to the criteria of the American College of Medical Genetics.
We report on 7 individuals carrying de novo missense variants in CNOT9, p.(Arg46Gly), p.(Pro131Leu), and p.(Arg227His), and, recurrent in 4 unrelated individuals, p.(Arg292Trp). All affected persons have developmental delay/intellectual disability, with 5 of them showing seizures. Other symptoms include muscular hypotonia, facial dysmorphism, and behavioral abnormalities. Molecular modeling predicted that the variants are damaging and would lead to reduced protein stability or impaired recognition of interaction partners. Functional analyses in previous studies showed a pathogenic effect of p.(Pro131Leu) and p.(Arg227His).
We propose CNOT9 as a novel gene for neurodevelopmental disorder and epilepsy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
