| 1. |
- Rodriguez-Palmero, Agusti, et al.
(author)
-
DLG4-related synaptopathy : a new rare brain disorder
- 2021
-
In: Genetics in Medicine. - : Elsevier BV. - 1098-3600 .- 1530-0366. ; 23:5, s. 888-899
-
Journal article (peer-reviewed)abstract
- PurposePostsynaptic density protein-95 (PSD-95), encoded by DLG4, regulates excitatory synaptic function in the brain. Here we present the clinical and genetic features of 53 patients (42 previously unpublished) with DLG4 variants.MethodsThe clinical and genetic information were collected through GeneMatcher collaboration. All the individuals were investigated by local clinicians and the gene variants were identified by clinical exome/genome sequencing.ResultsThe clinical picture was predominated by early onset global developmental delay, intellectual disability, autism spectrum disorder, and attention deficit–hyperactivity disorder, all of which point to a brain disorder. Marfanoid habitus, which was previously suggested to be a characteristic feature of DLG4-related phenotypes, was found in only nine individuals and despite some overlapping features, a distinct facial dysmorphism could not be established. Of the 45 different DLG4 variants, 39 were predicted to lead to loss of protein function and the majority occurred de novo (four with unknown origin). The six missense variants identified were suggested to lead to structural or functional changes by protein modeling studies.ConclusionThe present study shows that clinical manifestations associated with DLG4 overlap with those found in other neurodevelopmental disorders of synaptic dysfunction; thus, we designate this group of disorders as DLG4-related synaptopathy.
|
|
| 2. |
- Cizmeci, Mehmet N, et al.
(author)
-
Randomized Controlled Early versus Late Ventricular Intervention Study in Posthemorrhagic Ventricular Dilatation : Outcome at 2 Years
- 2020
-
In: Journal of Pediatrics. - : Elsevier BV. - 1097-6833 .- 0022-3476. ; 226, s. 3-35
-
Journal article (peer-reviewed)abstract
- OBJECTIVE: To compare the effect of intervention at low vs high threshold of ventriculomegaly in preterm infants with posthemorrhagic ventricular dilatation on death or severe neurodevelopmental disability.STUDY DESIGN: This multicenter randomized controlled trial reviewed lumbar punctures initiated after either a low threshold (ventricular index of >p97 and anterior horn width of >6 mm) or high threshold (ventricular index of >p97 + 4 mm and anterior horn width of >10 mm). The composite adverse outcome was defined as death or cerebral palsy or Bayley composite cognitive/motor scores <-2 SDs at 24 months corrected age.RESULTS: Outcomes were assessed in 113 of 126 infants. The composite adverse outcome was seen in 20 of 58 infants (35%) in the low threshold group and 28 of 55 (51%) in the high threshold (P = .07). The low threshold intervention was associated with a decreased risk of an adverse outcome after correcting for gestational age, severity of intraventricular hemorrhage, and cerebellar hemorrhage (aOR, 0.24; 95% CI, 0.07-0.87; P = .03). Infants with a favorable outcome had a smaller fronto-occipital horn ratio (crude mean difference, -0.06; 95% CI, -0.09 to -0.03; P < .001) at term-equivalent age. Infants in the low threshold group with a ventriculoperitoneal shunt, had cognitive and motor scores similar to those without (P = .3 for both), whereas in the high threshold group those with a ventriculoperitoneal shunt had significantly lower scores than those without a ventriculoperitoneal shunt (P = .01 and P = .004, respectively).CONCLUSIONS: In a post hoc analysis, earlier intervention was associated with a lower odds of death or severe neurodevelopmental disability in preterm infants with progressive posthemorrhagic ventricular dilatation.TRIAL REGISTRATION: ISRCTN43171322.
|
|
| 3. |
- Fergelot, Patricia, et al.
(author)
-
Phenotype and genotype in 52 patients with Rubinstein–Taybi syndrome caused by EP300 mutations
- 2016
-
In: American Journal of Medical Genetics. Part A. - : Wiley. - 1552-4825 .- 1552-4833. ; 170:12, s. 3069-3082
-
Journal article (peer-reviewed)abstract
- Rubinstein–Taybi syndrome (RSTS) is a developmental disorder characterized by a typical face and distal limbs abnormalities, intellectual disability, and a vast number of other features. Two genes are known to cause RSTS, CREBBP in 60% and EP300 in 8–10% of clinically diagnosed cases. Both paralogs act in chromatin remodeling and encode for transcriptional co-activators interacting with >400 proteins. Up to now 26 individuals with an EP300 mutation have been published. Here, we describe the phenotype and genotype of 42 unpublished RSTS patients carrying EP300 mutations and intragenic deletions and offer an update on another 10 patients. We compare the data to 308 individuals with CREBBP mutations. We demonstrate that EP300 mutations cause a phenotype that typically resembles the classical RSTS phenotype due to CREBBP mutations to a great extent, although most facial signs are less marked with the exception of a low-hanging columella. The limb anomalies are more similar to those in CREBBP mutated individuals except for angulation of thumbs and halluces which is very uncommon in EP300 mutated individuals. The intellectual disability is variable but typically less marked whereas the microcephaly is more common. All types of mutations occur but truncating mutations and small rearrangements are most common (86%). Missense mutations in the HAT domain are associated with a classical RSTS phenotype but otherwise no genotype–phenotype correlation is detected. Pre-eclampsia occurs in 12/52 mothers of EP300 mutated individuals versus in 2/59 mothers of CREBBP mutated individuals, making pregnancy with an EP300 mutated fetus the strongest known predictor for pre-eclampsia.
|
|
| 4. |
- Helsmoortel, Celine, et al.
(author)
-
A SWI/SNF-related autism syndrome caused by de novo mutations in ADNP
- 2014
-
In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 46:4, s. 380-
-
Journal article (peer-reviewed)abstract
- Despite the high heritability of autism spectrum disorders (ASD), characterized by persistent deficits in social communication and interaction and restricted, repetitive patterns of behavior, interests or activities(1), a genetic diagnosis can be established in only a minority of patients. Known genetic causes include chromosomal aberrations, such as the duplication of the 15q11-13 region, and monogenic causes, as in Rett and fragile- X syndromes. The genetic heterogeneity within ASD is striking, with even the most frequent causes responsible for only 1% of cases at the most. Even with the recent developments in nextgeneration sequencing, for the large majority of cases no molecular diagnosis can be established(2-7). Here, we report ten patients with ASD and other shared clinical characteristics, including intellectual disability and facial dysmorphisms caused by a mutation in ADNP, a transcription factor involved in the SWI/ SNF remodeling complex. We estimate this gene to be mutated in at least 0.17% of ASD cases, making it one of the most frequent ASD- associated genes known to date.
|
|
| 5. |
- Kappelle, Paul J. W. H., et al.
(author)
-
Plasma apolipoprotein M responses to statin and fibrate administration in type 2 diabetes mellitus
- 2010
-
In: Atherosclerosis. - : Elsevier BV. - 1879-1484 .- 0021-9150. ; 213:1, s. 247-250
-
Journal article (peer-reviewed)abstract
- Purpose: Plasma apolipoprotein M (apoM) is potentially anti-atherogenic, and has been found to be associated positively with plasma total, LDL and HDL cholesterol in humans. ApoM may, therefore, be intricately related to cholesterol metabolism. Here, we determined whether plasma apoM is affected by statin or fibrate administration in patients with diabetes mellitus. Methods: Fourteen type 2 diabetic patients participated in a placebo-controlled crossover study which included three 8-week treatment periods with simvastatin (40 mg daily), bezafibrate (400 mg daily), and their combination. Results: ApoM was decreased by 7% in response to simvastatin (P < 0.05 from baseline and placebo), and remained unchanged during bezafibrate and combined simvastatin + bezafibrate administration. Plasma apoM concentrations correlated positively with apoB-containing lipoprotein measures at baseline and during placebo (P < 0.02 to P < 0.001), but these relationships were lost during all lipid lowering treatment periods. Conclusions: This study suggests that, even though plasma apoM is lowered by statins, apoM metabolism is to a considerable extent independent of statin-and fibrate-affected pathways involved in cholesterol homeostasis. (C) 2010 Elsevier Ireland Ltd. All rights reserved.
|
|
| 6. |
- Petkov, Petko N., et al.
(author)
-
Discrete Choice Models for Non-Intrusive Quality Assessment
- 2011
-
In: 12th Annual Conference Of The International Speech Communication Association 2011 (INTERSPEECH 2011), Vols 1-5. - : ISCA. - 9781618392701 ; , s. 200-203
-
Conference paper (peer-reviewed)abstract
- Non-intrusive signal quality assessment in general, and its application to speech signal processing, in particular, builds extensively upon statistical regression models. Commonly, the raw preference scores used for fitting these models belong to a categorical scale. Averaging the scores over a number of test subjects results in smooth, close-to-continuous ratings, thus justifying the use of regression as opposed to classification models. A form of marginalization, averaging subjective ratings takes away useful information about the reliability of individual test points. Using a model tailored to the raw data achieves highly competitive performance in terms of conventional performance measures while providing the additional advantage of identifying the usability of individual test points. In this paper, we consider the application of discrete choice models to non-intrusive quality assessment of speech.
|
|
| 7. |
- Thierry, Gaelle, et al.
(author)
-
Molecular characterization of 1q44 microdeletion in 11 patients reveals three candidate genes for intellectual disability and seizures
- 2012
-
In: American Journal of Medical Genetics. Part A. - : Wiley. - 1552-4825 .- 1552-4833. ; 158A:7, s. 1633-1640
-
Journal article (peer-reviewed)abstract
- Patients with a submicroscopic deletion at 1q43q44 present with intellectual disability (ID), microcephaly, craniofacial anomalies, seizures, limb anomalies, and corpus callosum abnormalities. However, the precise relationship between most of deleted genes and the clinical features in these patients still remains unclear. We studied 11 unrelated patients with 1q44 microdeletion. We showed that the deletions occurred de novo in all patients for whom both parents' DNA was available (10/11). All patients presented with moderate to severe ID, seizures and non-specific craniofacial anomalies. By oligoarray-based comparative genomic hybridization (aCGH) covering the 1q44 region at a high resolution, we obtained a critical deleted region containing two coding genesHNRNPU and FAM36Aand one non-coding geneNCRNA00201. All three genes were expressed in different normal human tissues, including in human brain, with highest expression levels in the cerebellum. Mutational screening of the HNRNPU and FAM36A genes in 191 patients with unexplained isolated ID did not reveal any deleterious mutations while the NCRNA00201 non-coding gene was not analyzed. Nine of the 11 patients did not present with microcephaly or corpus callosum abnormalities and carried a small deletion containing HNRNPU, FAM36A, and NCRNA00201 but not AKT3 and ZNF238, two centromeric genes. These results suggest that HNRNPU, FAM36A, and NCRNA00201 are not major genes for microcephaly and corpus callosum abnormalities but are good candidates for ID and seizures.
|
|
| 8. |
- Zhao, David Yuheng, et al.
(author)
-
Online noise estimation using stochastic-gain HMM for speech enhancement
- 2008
-
In: IEEE transactions on speech and audio processing. - 1063-6676 .- 1558-2353. ; 16:4, s. 835-846
-
Journal article (peer-reviewed)abstract
- We propose a noise estimation algorithm for single-channel noise suppression in dynamic noisy environments. A stochastic-gain hidden Markov model (SG-HMM) is used to model the statistics of nonstationary noise with time-varying energy. The noise model is adaptive and the model parameters are estimated online from noisy observations using a recursive estimation algorithm. The parameter estimation is derived for the maximum-likelihood criterion and the algorithm is based on the recursive expectation maximization (EM) framework. The proposed method facilitates continuous adaptation to changes of both noise spectral shapes and noise energy levels, e.g., due to movement of the noise source. Using the estimated noise model, we also develop an estimator of the noise power spectral density (PSD) based on recursive averaging of estimated noise sample spectra. We demonstrate that the proposed scheme achieves more accurate estimates of the noise model and noise PSD, and as part of a speech enhancement system facilitates a lower level of residual noise.
|
|
