Dataset Information

Temple-Baraitser Syndrome and Zimmermann-Laband Syndrome: one clinical entity?

ABSTRACT: KCNH1 encodes a voltage-gated potassium channel that is predominantly expressed in the central nervous system. Mutations in this gene were recently found to be responsible for Temple-Baraitser Syndrome (TMBTS) and Zimmermann-Laband syndrome (ZLS).Here, we report a new case of TMBTS diagnosed in a Lebanese child. Whole genome sequencing was carried out on DNA samples of the proband and his parents to identify mutations associated with this disease. Sanger sequencing was performed to confirm the presence of detected variants.Whole genome sequencing revealed three missense mutations in TMBTS patient: c.1042G?>?A in KCNH1, c.2131 T?>?C in STK36, and c.726C?>?A in ZNF517. According to all predictors, mutation in KCNH1 is damaging de novo mutation that results in substitution of Glycine by Arginine, i.e., p.(Gly348Arg). This mutation was already reported in a patient with ZLS that could affect the connecting loop between helices S4-S5 of KCNH1 with a gain of function effect.Our findings demonstrate that KCNH1 mutations cause TMBTS and expand the mutational spectrum of KCNH1 in TMBTS. In addition, all cases of TMBTS were reviewed and compared to ZLS. We suggest that the two syndromes are a continuum and that the variability in the phenotypes is the result of the involvement of genetic modifiers.

SUBMITTER: Megarbane A

PROVIDER: S-EPMC4901505 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Temple-Baraitser Syndrome and Zimmermann-Laband Syndrome: one clinical entity?

Mégarbané André A Al-Ali Rashid R Choucair Nancy N Lek Monko M Wang Ena E Ladjimi Moncef M Rose Catherine M CM Hobeika Remy R Macary Yvette Y Temanni Ramzi R Jithesh Puthen V PV Chouchane Aouatef A Sastry Konduru S KS Thomas Remy R Tomei Sara S Liu Wei W Marincola Francesco M FM MacArthur Daniel D Chouchane Lotfi L

BMC medical genetics 20160610 1

<h4>Background</h4>KCNH1 encodes a voltage-gated potassium channel that is predominantly expressed in the central nervous system. Mutations in this gene were recently found to be responsible for Temple-Baraitser Syndrome (TMBTS) and Zimmermann-Laband syndrome (ZLS).<h4>Methods</h4>Here, we report a new case of TMBTS diagnosed in a Lebanese child. Whole genome sequencing was carried out on DNA samples of the proband and his parents to identify mutations associated with this disease. Sanger sequen ...[more]

PMID: 27282200

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Project description:BACKGROUND:Imprinting disorders (IDs) show overlapping phenotypes, particularly in Silver-Russell syndrome (SRS), Temple syndrome (TS14), and Prader-Willi syndrome (PWS). These three IDs include fetal and postnatal growth failure, feeding difficulty, and muscular hypotonia as major clinical features. However, the mechanism that causes overlapping phenotypes has not been clarified. To investigate the presence or absence of methylation signatures associated with overlapping phenotypes, we performed genome-wide methylation analysis (GWMA). RESULTS:GWMA was carried out on 36 patients with three IDs (SRS [n?=?16], TS14 [n?=?7], PWS [n?=?13]) and 11 child controls using HumanMethylation450 BeadChip including 475,000 CpG sites across the human genome. To reveal an aberrantly methylated region shared by SRS, TS14, and PWS groups, we compared genome-wide methylation data of the three groups with those of control subjects. All the identified regions were known as SRS-, TS14-, and PWS-related imprinting-associated differentially methylated regions (iDMRs), and there was no hypermethylated or hypomethylated region shared by different ID groups. To examine the methylation pattern shared by SRS, TS14, and PWS groups, we performed clustering analysis based on GWMA data. The result focusing on 620 probes at the 62 known iDMRs (except for SRS-, TS14-, and PWS-related iDMRs) classified patients into two categories: (1) category A, grossly normal methylation patterns mainly consisting of SRS group patients; and (2) category B, broad and mild hypermethylation patterns mainly consisting of TS14 and PWS group patients. However, we found no obvious relationship between these methylation patterns and phenotypes of patients. CONCLUSIONS:GWMA in three IDs found no methylation signatures shared by SRS, TS14, and PWS groups. Although clustering analysis showed similar mild hypermethylation patterns in TS14 and PWS groups, further study is needed to clarify the effect of methylation patterns on the overlapping phenotypes.

Dataset Information

Temple-Baraitser Syndrome and Zimmermann-Laband Syndrome: one clinical entity?

Publications

Temple-Baraitser Syndrome and Zimmermann-Laband Syndrome: one clinical entity?

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