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Variants in CLCN4, which encodes the chloride/hydrogen ion exchanger CIC-4 prominently expressed in brain, were recently described to cause X-linked intellectual disability and epilepsy. We present detailed phenotypic information on 52 individuals from 16 families with CLCN4-related disorder: 5 affected females and 2 affected males with a de novo variant in CLCN4 (6 individuals previously unreported) and 27 affected males, 3 affected females and 15 asymptomatic female carriers from 9 families with inherited CLCN4 variants (4 families previously unreported). Intellectual disability ranged from borderline to profound. Behavioral and psychiatric disorders were common in both child-and adulthood, and included autistic features, mood disorders, obsessive-compulsive behaviors and hetero-and autoaggression. Epilepsy was common, with severity ranging from epileptic encephalopathy to well-controlled seizures. Several affected individuals showed white matter changes on cerebral neuroimaging and progressive neurological symptoms, including movement disorders and spasticity. Heterozygous females can be as severely affected as males. The variability of symptoms in females is not correlated with the X inactivation pattern studied in their blood. The mutation spectrum includes frameshift, missense and splice site variants and one single-exon deletion. All missense variants were predicted to affect CLCN4's function based on in silico tools and either segregated with the phenotype in the family or were de novo. Pathogenicity of all previously unreported missense variants was further supported by electrophysiological studies in Xenopus laevis oocytes. We compare CLCN4-related disorder with conditions related to dysfunction of other members of the CLC family.

Contains fulltext : 183878.pdf (Publisher’s version ) (Open Access)

Contains fulltext : 183878.pdf (Publisher’s version ) (Open Access)

Item does not contain fulltext, Next generation genomic technologies have made a significant contribution to the understanding of the genetic architecture of human neurodevelopmental disorders. Copy number variants (CNVs) play an important role in the genetics of intellectual disability (ID). For many CNVs, and copy number gains in particular, the responsible dosage-sensitive gene(s) have been hard to identify. We have collected 18 different interstitial microduplications and 1 microtriplication of Xq25. There were 15 affected individuals from 6 different families and 13 singleton cases, 28 affected males in total. The critical overlapping region involved the STAG2 gene, which codes for a subunit of the cohesin complex that regulates cohesion of sister chromatids and gene transcription. We demonstrate that STAG2 is the dosage-sensitive gene within these CNVs, as gains of STAG2 mRNA and protein dysregulate disease-relevant neuronal gene networks in cells derived from affected individuals. We also show that STAG2 gains result in increased expression of OPHN1, a known X-chromosome ID gene. Overall, we define a novel cohesinopathy due to copy number gain of Xq25 and STAG2 in particular.

Item does not contain fulltext, Next generation genomic technologies have made a significant contribution to the understanding of the genetic architecture of human neurodevelopmental disorders. Copy number variants (CNVs) play an important role in the genetics of intellectual disability (ID). For many CNVs, and copy number gains in particular, the responsible dosage-sensitive gene(s) have been hard to identify. We have collected 18 different interstitial microduplications and 1 microtriplication of Xq25. There were 15 affected individuals from 6 different families and 13 singleton cases, 28 affected males in total. The critical overlapping region involved the STAG2 gene, which codes for a subunit of the cohesin complex that regulates cohesion of sister chromatids and gene transcription. We demonstrate that STAG2 is the dosage-sensitive gene within these CNVs, as gains of STAG2 mRNA and protein dysregulate disease-relevant neuronal gene networks in cells derived from affected individuals. We also show that STAG2 gains result in increased expression of OPHN1, a known X-chromosome ID gene. Overall, we define a novel cohesinopathy due to copy number gain of Xq25 and STAG2 in particular.

Item does not contain fulltext, We studied two unrelated boys with intellectual disability (ID) and a striking facial resemblance suggestive of a hitherto unappreciated syndrome. Exome sequencing in both families identified identical de novo mutations in PACS1, suggestive of causality. To support these genetic findings and to understand the pathomechanism of the mutation, we studied the protein in vitro and in vivo. Altered PACS1 forms cytoplasmic aggregates in vitro with concomitant increased protein stability and shows impaired binding to an isoform-specific variant of TRPV4, but not the full-length protein. Furthermore, consistent with the human pathology, expression of mutant PACS1 mRNA in zebrafish embryos induces craniofacial defects most likely in a dominant-negative fashion. This phenotype is driven by aberrant specification and migration of SOX10-positive cranial, but not enteric, neural-crest cells. Our findings suggest that PACS1 is necessary for the formation of craniofacial structures and that perturbation of its functions results in a specific syndromic ID phenotype.

Item does not contain fulltext, We studied two unrelated boys with intellectual disability (ID) and a striking facial resemblance suggestive of a hitherto unappreciated syndrome. Exome sequencing in both families identified identical de novo mutations in PACS1, suggestive of causality. To support these genetic findings and to understand the pathomechanism of the mutation, we studied the protein in vitro and in vivo. Altered PACS1 forms cytoplasmic aggregates in vitro with concomitant increased protein stability and shows impaired binding to an isoform-specific variant of TRPV4, but not the full-length protein. Furthermore, consistent with the human pathology, expression of mutant PACS1 mRNA in zebrafish embryos induces craniofacial defects most likely in a dominant-negative fashion. This phenotype is driven by aberrant specification and migration of SOX10-positive cranial, but not enteric, neural-crest cells. Our findings suggest that PACS1 is necessary for the formation of craniofacial structures and that perturbation of its functions results in a specific syndromic ID phenotype.

Item does not contain fulltext, We studied two unrelated boys with intellectual disability (ID) and a striking facial resemblance suggestive of a hitherto unappreciated syndrome. Exome sequencing in both families identified identical de novo mutations in PACS1, suggestive of causality. To support these genetic findings and to understand the pathomechanism of the mutation, we studied the protein in vitro and in vivo. Altered PACS1 forms cytoplasmic aggregates in vitro with concomitant increased protein stability and shows impaired binding to an isoform-specific variant of TRPV4, but not the full-length protein. Furthermore, consistent with the human pathology, expression of mutant PACS1 mRNA in zebrafish embryos induces craniofacial defects most likely in a dominant-negative fashion. This phenotype is driven by aberrant specification and migration of SOX10-positive cranial, but not enteric, neural-crest cells. Our findings suggest that PACS1 is necessary for the formation of craniofacial structures and that perturbation of its functions results in a specific syndromic ID phenotype.

Contains fulltext : 185071.pdf (publisher's version ) (Closed access), Patients with familial hypercholesterolemia (FH) and patients with end-stage renal disease (ESRD) undergoing dialysis suffer from accelerated atherosclerosis. Oxidation of low-density lipoprotein (LDL) cholesterol is crucial in atherogenesis. In the present study, we determined the LDL oxidation level and oxidizability of isolated LDL of 11 male patients with FH, 15 male ESRD patients on hemodialysis, and 15 age-matched male normolipidemic healthy controls. FH patients were without lipid-lowering medication for at least 4 weeks and were reassessed after 2 years of cholesterol-lowering therapy (statins). LDL oxidation level was measured by ELISA using monoclonal antibody 4E6 to oxidized LDL (oxLDL) as the capture antibody and anti-human apoB antibody for detection; results were expressed as percentage oxLDL. In FH patients and in ESRD patients on hemodialysis, both groups having a higher percentage of cardiovascular disease, mean plasma LDL oxidation levels were significantly elevated compared with controls (4.9 +/- 1.3; 3.7 +/- 2.0; 1.7 +/- 0.6%, respectively). Within each group of subjects, LDL oxidation level was not associated with history of cardiovascular disease. Furthermore, in neither group was a significant correlation found between plasma concentration of LDL cholesterol and LDL oxidation level. After cholesterol-lowering therapy, LDL oxidation level in FH patients had not changed significantly and remained elevated compared with controls, despite a reduction of LDL cholesterol by 55% on average. Also, absolute plasma oxLDL concentrations, obtained by multiplying LDL oxidation level with plasma LDL cholesterol concentration, were significantly higher in FH patients before and after cholesterol-lowering therapy and in ESRD patients on hemodialysis than in controls (489 +/- 145; 189 +/- 122; 100 +/- 65; and 59 +/- 27 micro moles/L, respectively). No correlation was found between plasma oxLDL concentration and parameters of LDL oxidizability, LDL fatty acids

Contains fulltext : 185071.pdf (publisher's version ) (Closed access), Patients with familial hypercholesterolemia (FH) and patients with end-stage renal disease (ESRD) undergoing dialysis suffer from accelerated atherosclerosis. Oxidation of low-density lipoprotein (LDL) cholesterol is crucial in atherogenesis. In the present study, we determined the LDL oxidation level and oxidizability of isolated LDL of 11 male patients with FH, 15 male ESRD patients on hemodialysis, and 15 age-matched male normolipidemic healthy controls. FH patients were without lipid-lowering medication for at least 4 weeks and were reassessed after 2 years of cholesterol-lowering therapy (statins). LDL oxidation level was measured by ELISA using monoclonal antibody 4E6 to oxidized LDL (oxLDL) as the capture antibody and anti-human apoB antibody for detection; results were expressed as percentage oxLDL. In FH patients and in ESRD patients on hemodialysis, both groups having a higher percentage of cardiovascular disease, mean plasma LDL oxidation levels were significantly elevated compared with controls (4.9 +/- 1.3; 3.7 +/- 2.0; 1.7 +/- 0.6%, respectively). Within each group of subjects, LDL oxidation level was not associated with history of cardiovascular disease. Furthermore, in neither group was a significant correlation found between plasma concentration of LDL cholesterol and LDL oxidation level. After cholesterol-lowering therapy, LDL oxidation level in FH patients had not changed significantly and remained elevated compared with controls, despite a reduction of LDL cholesterol by 55% on average. Also, absolute plasma oxLDL concentrations, obtained by multiplying LDL oxidation level with plasma LDL cholesterol concentration, were significantly higher in FH patients before and after cholesterol-lowering therapy and in ESRD patients on hemodialysis than in controls (489 +/- 145; 189 +/- 122; 100 +/- 65; and 59 +/- 27 micro moles/L, respectively). No correlation was found between plasma oxLDL concentration and parameters of LDL oxidizability, LDL fatty acids

Contains fulltext : 185071.pdf (publisher's version ) (Closed access), Patients with familial hypercholesterolemia (FH) and patients with end-stage renal disease (ESRD) undergoing dialysis suffer from accelerated atherosclerosis. Oxidation of low-density lipoprotein (LDL) cholesterol is crucial in atherogenesis. In the present study, we determined the LDL oxidation level and oxidizability of isolated LDL of 11 male patients with FH, 15 male ESRD patients on hemodialysis, and 15 age-matched male normolipidemic healthy controls. FH patients were without lipid-lowering medication for at least 4 weeks and were reassessed after 2 years of cholesterol-lowering therapy (statins). LDL oxidation level was measured by ELISA using monoclonal antibody 4E6 to oxidized LDL (oxLDL) as the capture antibody and anti-human apoB antibody for detection; results were expressed as percentage oxLDL. In FH patients and in ESRD patients on hemodialysis, both groups having a higher percentage of cardiovascular disease, mean plasma LDL oxidation levels were significantly elevated compared with controls (4.9 +/- 1.3; 3.7 +/- 2.0; 1.7 +/- 0.6%, respectively). Within each group of subjects, LDL oxidation level was not associated with history of cardiovascular disease. Furthermore, in neither group was a significant correlation found between plasma concentration of LDL cholesterol and LDL oxidation level. After cholesterol-lowering therapy, LDL oxidation level in FH patients had not changed significantly and remained elevated compared with controls, despite a reduction of LDL cholesterol by 55% on average. Also, absolute plasma oxLDL concentrations, obtained by multiplying LDL oxidation level with plasma LDL cholesterol concentration, were significantly higher in FH patients before and after cholesterol-lowering therapy and in ESRD patients on hemodialysis than in controls (489 +/- 145; 189 +/- 122; 100 +/- 65; and 59 +/- 27 micro moles/L, respectively). No correlation was found between plasma oxLDL concentration and parameters of LDL oxidizability, LDL fatty acids

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