X-exome sequencing identifies a<i>HDAC8</i>variant in a large pedigree with X-linked intellectual disability, truncal obesity, gynaecomastia, hypogonadism and unusual face

Harakaľová, Magdaléna; Boogaard, M.; Sinke, Richard J.; Lieshout, Stef van; Tuil, Marc C van; Duran, Karen; Renkens, Ivo; Terhal, Paulien A; Kovel, Carolien G.F. de; Nijman, Isaäc J; Haelst, Mieke M. van; Knoers, Nine V A M; Haaften, Gijs van; Kloosterman, Wigard P.; Hennekam, Raoul C. M.; Cuppen, Edwin; Amstel, Hans Kristian Ploos van

doi:10.1136/jmedgenet-2012-100921

Cited by 67 publications

(50 citation statements)

References 20 publications

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“…Cohesins similarly play a key role in DNA repair, and defective DNA repair in combination with transcription deregulation further impacts development (Dorsett and Ström, 2012). A link between these syndromes and the cohesin code is further supported by findings that mutations in the vertebrate cohesin de-acetylase HDAC8 are found in a subset of Cornelia de Lange syndrome phenotypes (Deardorff et al, 2012a;Deardorff et al, 2012b;Harakalova et al, 2012). Elucidating the extent to which cohesinopathies and ribosomopathies share underlying molecular mechanisms is likely to provide significant advances to both clinical and basic science research.…”

Section: A Code For All Processesmentioning

confidence: 98%

Cohesin codes – interpreting chromatin architecture and the many facets of cohesin function

Rudra

Skibbens

2013

Journal of Cell Science

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SummarySister chromatid tethering is maintained by cohesin complexes that minimally contain Smc1, Smc3, Mcd1 and Scc3. During S-phase, chromatin-associated cohesins are modified by the Eco1/Ctf7 family of acetyltransferases. Eco1 proteins function during S phase in the context of replicated sister chromatids to convert chromatin-bound cohesins to a tethering-competent state, but also during G2 and M phases in response to double-stranded breaks to promote error-free DNA repair. Cohesins regulate transcription and are essential for ribosome biogenesis and complete chromosome condensation. Little is known, however, regarding the mechanisms through which cohesin functions are directed. Recent findings reveal that Eco1-mediated acetylation of different lysine residues in Smc3 during S phase promote either cohesion or condensation. Phosphorylation and SUMOylation additionally impact cohesin functions. Here, we posit the existence of a cohesin code, analogous to the histone code introduced over a decade ago, and speculate that there is a symphony of posttranslational modifications that direct cohesins to function across a myriad of cellular processes. We also discuss evidence that outdate the notion that cohesion defects are singularly responsible for cohesion-mutant-cell inviability. We conclude by proposing that cohesion establishment is linked to chromatin formation.

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Section: A Code For All Processesmentioning

confidence: 98%

Cohesin codes – interpreting chromatin architecture and the many facets of cohesin function

Rudra

Skibbens

2013

Journal of Cell Science

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“…15 For the standard reference sequence in relation to the variants reported, NCBI Reference Sequences: NM_133433.3 (NIPBL gene), NM_006306.3 (SMC1A), NM_005445.3 (SMC3), NM_006265.2 (RAD21) and NM_018486.2 (HDAC8) should be applied. NIPBL gene variants can be found in the database: Leiden Open Variation Database (LOVD) (http://grenada.lumc.nl/LOVD2/CDLS/ home.php?…”

Section: Mutational Spectrummentioning

confidence: 99%

“…14 HDAC8 mutations have also been found in an X-linked intellectual disability syndrome which overlaps Wilson-Turner syndrome and Börjeson-Forssman-Lehmann syndrome. 15 CdLS has been reported to have some clinical overlap with Fryns syndrome (coarse face, diaphragmatic hernia, cleft palate, distal limb hypoplasia and hypertrichosis), 22 foetal alcohol syndrome (pre-postnatal growth retardation, developmental delay, hirsutism, craniofacial anomalies and cardiac defects), 23 and Coffin-Siris Syndrome (aplasia or hypoplasia of the distal phalanx or nail of the fifth digit, distinctive facial features and moderate-to-severe developmental delay). 24,25 3.1.2 Describe the burden of alternative diagnostic methods to the patient The burden is minimal as clinical features are often sufficient to make a definitive diagnosis.…”

Section: Can a Diagnosis Be Made Other Than Through A Genetic Test?mentioning

confidence: 99%

Clinical utility gene card for: Cornelia de Lange syndrome

et al. 2014

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“…New X-linked disease causing genes such as TARP syndrome, leucoencephalopathy or Xlinked intellectual disability were also discovered (17)(18)(19). Using exome sequencing technique mutations were found in mitochondrial DNA genes such as MRPL3 (mitochondrial cardiomyophathy) or AARS2 (infantile mitochondrial cardiomyophathy) (13,20).…”

Section: Discussionmentioning

confidence: 99%

Next-generation whole-exome sequencing contribution to identification of rare autosomal recessive diseases

Rančelis

Kučinskas²

2013

AML

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A rare disease is any disease that affects a small percentage of the population. In the European Union a disease is defined as rare if it affects less than 1 in 2,000 people. Despite a small percentage of affected people by one disease, the total number of rare diseases is estimated to be around 7,000–8,000, thus, because of their large number they have an impact on many people and even 30 million of European Union citizens may be suffering from them. Research of rare diseases may help to explain their mechanism or to develop more advanced diagnostics. Classical strategies for studies of rare autosomal recessive diseases encounter with additional problems (multiple genetic variants, de novo mutations, extremely rare cases) that make these strategies not enough effective. Next generation whole-exome sequencing (WES) opened a new page in Mendelian disease gene discovery – enabling to study autosomal recessive diseases in a new way. During 3 years of WES usage many novel mutations of autosomal recessive disease genes were discovered.

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X-exome sequencing identifies aHDAC8variant in a large pedigree with X-linked intellectual disability, truncal obesity, gynaecomastia, hypogonadism and unusual face

Cited by 67 publications

References 20 publications

Cohesin codes – interpreting chromatin architecture and the many facets of cohesin function

Cohesin codes – interpreting chromatin architecture and the many facets of cohesin function

Clinical utility gene card for: Cornelia de Lange syndrome

Next-generation whole-exome sequencing contribution to identification of rare autosomal recessive diseases

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