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Two patients with intellectual disability, overlapping facial features, and overlapping deletions in 6p25.1p24.3
2013
Clinical Dysmorphology
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The clinical and molecular characterizations of two patients with a 1.4 Mb overlapping deletion in the 6p25.1p24.3 region are reported. In addition to the mild intellectual disability, they shared feeding problems in infancy and several dysmorphic facial features including a prominent forehead, almond-shaped eyes, a short philtrum, and low-set ears with square helices. The overlapping deleted region harbors six genes (RREB1, NRN1, CAGE1, LY86, SSR1, and F13A1), of which NRN1 and RREB1 are
doi:10.1097/mcd.0b013e32835b6e39
pmid:23183317
fatcat:a3tgtb3hafh2zc24qrmwojjeh4
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... ered as candidate genes for the intellectual disability and the overlapping dysmorphism, respectively.
1 in 38 individuals at risk of a dominant medically actionable disease
2018
European Journal of Human Genetics
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Clinical genomic sequencing can identify pathogenic variants unrelated to the initial clinical question, but of medical relevance to the patients and their families. With ongoing discussions on the utility of disclosing or searching for such variants, it is of crucial importance to obtain unbiased insight in the prevalence of these incidental or secondary findings, in order to better weigh potential risks and benefits. Previous studies have reported a broad range of secondary findings ranging
doi:10.1038/s41431-018-0284-2
pmid:30291343
pmcid:PMC6336841
fatcat:vn3ahidzs5fzrouv3ixeywaidy
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... om 1 to 9%, merely attributable to differences in study design, cohorts tested, sequence technology used and genes analyzed. Here, we analyzed WES data of 1640 anonymized healthy Dutch individuals to establish the frequency of medically actionable disease alleles in an outbred population of European descent. Our study shows that 1 in 38 healthy individuals (2.7%) has a (likely) pathogenic variant in one of 59 medically actionable dominant disease genes for which the American College of Medical Genetics and Genomics (ACMG) recommends disclosure. Additionally, we identified 36 individuals (2.2%) to be a carrier of a recessive pathogenic disease allele. Whereas these frequencies of secondary findings are in line with what has been reported in the East-Asian population, the pathogenic variants are differently distributed across the 59 ACMG genes. Our results contribute to the debate on genetic risk factor screening in healthy individuals and the discussion whether the potential benefits of this knowledge and related preventive options, outweigh the risk of the emotional impact of the test result and possible stigmatization.
Mutations in MED12 Cause X-Linked Ohdo Syndrome
2013
American Journal of Human Genetics
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Asterisks denote statistically significant differences compared to WT FLAG-MED12 (Student's t test, *p < 0.05, **p < 0.01). ...
No statistically significant differences in expression levels were observed (Student's t test; p values are given above the bars). ...
doi:10.1016/j.ajhg.2013.01.007
pmid:23395478
pmcid:PMC3591845
fatcat:sntgwsdqu5bdhciwktiky5ldqe
Pierpont syndrome: A collaborative study
2011
American Journal of Medical Genetics. Part A
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Yunis-Varón Syndrome Is Caused by Mutations in FIG4, Encoding a Phosphoinositide Phosphatase
2013
American Journal of Human Genetics
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Protein-interaction do-
main, blue; catalytic domain, yellow;
P loop containing the catalytic CX 5 R(T/S)
motif, orange. ...
Above, YVS; below, CMT4J. 26 Protein-interaction domain, blue; catalytic domain, yellow; P loop containing the catalytic CX 5 R(T/S) motif, orange. ...
doi:10.1016/j.ajhg.2013.03.020
pmid:23623387
pmcid:PMC3644641
fatcat:ycpxvqsajrgw7b6vascszzaygu
DVL1 Frameshift Mutations Clustering in the Penultimate Exon Cause Autosomal-Dominant Robinow Syndrome
2015
American Journal of Human Genetics
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Robinow syndrome is a genetically heterogeneous disorder characterized by mesomelic limb shortening, genital hypoplasia, and distinctive facial features and for which both autosomal-recessive and autosomal-dominant inheritance patterns have been described. Causative variants in the non-canonical signaling gene WNT5A underlie a subset of autosomal-dominant Robinow syndrome (DRS) cases, but most individuals with DRS remain without a molecular diagnosis. We performed whole-exome sequencing in four
doi:10.1016/j.ajhg.2015.02.015
pmid:25817016
pmcid:PMC4385180
fatcat:5wnmpxhgubhyfmuesroqst76pq
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... unrelated DRS-affected individuals without coding mutations in WNT5A and found heterozygous DVL1 exon 14 mutations in three of them. Targeted Sanger sequencing in additional subjects with DRS uncovered DVL1 exon 14 mutations in five individuals, including a pair of monozygotic twins. In total, six distinct frameshift mutations were found in eight subjects, and all were heterozygous truncating variants within the penultimate exon of DVL1. In five families in which samples from unaffected parents were available, the variants were demonstrated to represent de novo mutations. All variant alleles are predicted to result in a premature termination codon within the last exon, escape nonsense-mediated decay (NMD), and most likely generate a C-terminally truncated protein with a distinct À1 reading-frame terminus. Study of the transcripts extracted from affected subjects' leukocytes confirmed expression of both wild-type and variant alleles, supporting the hypothesis that mutant mRNA escapes NMD. Genomic variants identified in our study suggest that truncation of the C-terminal domain of DVL1, a protein hypothesized to have a downstream role in the Wnt-5a non-canonical pathway, is a common cause of DRS.
A SWI/SNF-related autism syndrome caused by de novo mutations in ADNP
2014
Nature Genetics
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Whole-exome sequencing (WES) Patient 1 was detected in a family-based WES study (unpublished data (CH, GV, Filip Van Nieuwerburg, NVdA, RFK)). ...
doi:10.1038/ng.2899
pmid:24531329
pmcid:PMC3990853
fatcat:erv27ocuireelf5clvdffzauby
Homozygous SLC6A17 Mutations Cause Autosomal-Recessive Intellectual Disability with Progressive Tremor, Speech Impairment, and Behavioral Problems
2015
American Journal of Human Genetics
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We report on Dutch and Iranian families with affected individuals who present with moderate to severe intellectual disability and additional phenotypes including progressive tremor, speech impairment, and behavioral problems in certain individuals. A combination of exome sequencing and homozygosity mapping revealed homozygous mutations c.484G>A (p.Gly162Arg) and c.1898C>G (p.Pro633Arg) in SLC6A17. SLC6A17 is predominantly expressed in the brain, encodes a synaptic vesicular transporter of
doi:10.1016/j.ajhg.2015.01.010
pmid:25704603
pmcid:PMC4375531
fatcat:aev43jzmr5ckrntp3b22bv2ijm
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... l amino acids and glutamate, and plays an important role in the regulation of glutamatergic synapses. Prediction programs and 3D modeling suggest that the identified mutations are deleterious to protein function. To directly test the functional consequences, we investigated the neuronal subcellular localization of overexpressed wild-type and mutant variants in mouse primary hippocampal neuronal cells. Wild-type protein was present in soma, axons, dendrites, and dendritic spines. p.Pro633Arg altered SLC6A17 was found in soma and proximal dendrites but did not reach spines. p.Gly162Arg altered SLC6A17 showed a normal subcellular distribution but was associated with an abnormal neuronal morphology mainly characterized by the loss of dendritic spines. In summary, our genetic findings implicate homozygous SLC6A17 mutations in autosomal-recessive intellectual disability, and their pathogenic role is strengthened by genetic evidence and in silico and in vitro functional analyses.
Expanding the phenotypic spectrum of ARID1B-mediated disorders and identification of altered cell-cycle dynamics due to ARID1B haploinsufficiency
2014
Orphanet Journal of Rare Diseases
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The de novo heterozygous ARID1B mutation NM_020732.3(ARID1B):c.294 1C > T (p. ...
T-Test was used to investigate the difference in relative ARID1B expression between samples. Each experiment was independently performed at least three times. ...
doi:10.1186/1750-1172-9-43
pmid:24674232
pmcid:PMC4022252
fatcat:ddjak6tcorffpmiek67q742jly
Disruptive CHD8 Mutations Define a Subtype of Autism Early in Development
2014
Cell
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., not significant; *p < 0.05; **p < 0.001; ***p < 0.0001 (Student's t test). Data are represented as mean ± SEM. See also Figures S4 and S5 . ...
Cortical samples are organized in columns by lobe (f, frontal; p, parietal; t, temporal; o, occipital) and in rows by layer from basal to apical surfaces of the developing neocortex (SG, suprageniculate ...
doi:10.1016/j.cell.2014.06.017
pmid:24998929
pmcid:PMC4136921
fatcat:lcspkktohvdylg4gll7mm3qnre
Mutations in DDHD2, Encoding an Intracellular Phospholipase A1, Cause a Recessive Form of Complex Hereditary Spastic Paraplegia
2012
American Journal of Human Genetics
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(C) Consanguineous family 3 has seven affected individuals and homozygous mutation c.1546C>T (p.Arg516*). ...
This homozygous C-to-T substitution in exon 9 at c.859 introduces a PTC at amino acid position 287 of the protein (family 4, Figure 1D ). ...
doi:10.1016/j.ajhg.2012.10.017
pmid:23176823
pmcid:PMC3516595
fatcat:26b4v6guunehrdw56bolxouwtq
Dominant β-catenin mutations cause intellectual disability with recognizable syndromic features
2014
Journal of Clinical Investigation
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We would like to thank all patients and their relatives for their participation in these studies and Willemijn Wissink-Lindhout, Saskia van der Velde-Visser, Gaby van de Ven-Schobers, and Marga Schepens ...
Tucci), and grants from the Consortium "Stronger on your own feet" (to T. Kleefstra and M.H. Willemsen), the Netherlands Organization for Health Research and Development (ZonMw) (907-00-365 to T. ...
Statistical significance was determined using unpaired Student's t test (GraphPad Prism 5.0). ...
doi:10.1172/jci70372
pmid:24614104
pmcid:PMC3973091
fatcat:mrbvshcojve6tkf5eocuc5ucay
De Novo and Inherited Pathogenic Variants in KDM3B Cause Intellectual Disability, Short Stature, and Facial Dysmorphism
2019
American Journal of Human Genetics
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p.Arg45*
de novo
0
4.08
38
NA
NA
NA
2
c.277G>T
p.Glu93*
maternal
0
4.00
35
NA
NA
NA
3 b
c.277G>T
p.Glu93*
ND
0
4.00
35
NA
NA
NA
4
c.349T>C
p.Trp117Arg
de novo
0
3.35 ...
To determine whether a facial gestalt is present in individuals with a variant in KDM3B, we used a hybrid model recently developed and described by van der Donk et al. 20 This hybrid model combines the ...
doi:10.1016/j.ajhg.2019.02.023
pmid:30929739
pmcid:PMC6451728
fatcat:woon44gpdbfwvcba5hzmlp3bde
Variants inCUL4Bare Associated with Cerebral Malformations
2014
Human Mutation
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For c.1906+1G>T, the MAXENT score was reduced from 8.60 to 0.10 and the NNSPLICE donor site prediction score from 0.92 to zero. ...
Impaired chromatin remodeling, more specifically also increased H3K4 methylation, is a common mechanism underlying ID [van Bokhoven, 2011], for example, in patients with KDM5C variants [Iwase et al., ...
doi:10.1002/humu.22718
pmid:25385192
pmcid:PMC4608231
fatcat:77xtlglz5zclfobxwqxi7w7lum
Mutations Affecting the SAND Domain of DEAF1 Cause Intellectual Disability with Severe Speech Impairment and Behavioral Problems
2015
American Journal of Human Genetics
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Late in the review process, an additional SCN2A mutation (c.1570C > T [p.Arg524*]) leading to a truncating allele was identified in one of the four subjects (individual 3) and was added to Table 1 . ...
doi:10.1016/j.ajhg.2014.12.019
fatcat:ywftfik6yvakdgrrjsykwhvwk4
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