Diane Beysen

Universitair Ziekenhuis Antwerpen | UZA · Department of Pediatrics

De novo heterozygous variants in RNU4‐2, a component of the major spliceosome, were recently found to cause a novel neurodevelopmental disorder. Preliminary evidence suggests that this newly discovered syndrome is one of the most common monogenic causes of neurodevelopmental disorders. It is characterised by developmental delay and intellectual dis...

Aromatic l-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive neurometabolic disorder caused by biallelic pathogenic variants in the DDC gene; approximately 140 patients have been described worldwide. AADC deficiency is characterised by a combined deficiency of dopamine, serotonin, adrenaline and noradrenaline causing a highly...

Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant datab...

Objectives To evaluate the effect of French Maritime Pine Bark Extract (PBE; Pycnogenol®) on immune, oxidative stress and neurochemical biomarkers in paediatric Attention-Deficit Hyperactivity Disorder (ADHD) as compared to methylphenidate (MPH) and placebo. Results Paediatric ADHD patients (n = 88, 70 % male, mean age 10.1 years) were randomised...

Objectives Determine the effect of French Maritime Pine Bark Extract (PBE; Pycnogenol®) on Attention-Deficit Hyperactivity Disorder (ADHD) behaviour and co-morbid physical/psychiatric symptoms, compared to placebo and the medicine MPH, and to assess its tolerability. Behaviour (measured by the ADHD-Rating Scale (ADHD-RS) and Social-Emotional Questi...

Familial primary desminopathies are usually autosomal dominantly inherited and present at the age of 20 to 40 years with progressive muscle weakness and atrophy, cardiomyopathy and cardiac arrhythmias. Cardiac features may precede the muscular weakness. Here, we report the rare case of two siblings presenting with a desminopathy at pediatric age, d...

Pathogenic missense variants in GRIN2A and GRIN2B may result in gain or loss of function (GoF/LoF) of the N-methyl-D-aspartate receptor (NMDAR). This observation gave rise to the hypothesis of successfully treating GRIN-related disorders due to LoF variants with co-agonists of the NMDAR. In this respect, we describe a retrospectively collected seri...

Cerebral palsy (CP) is a non-progressive neurodevelopmental disorder characterized by motor impairments, often accompanied by co-morbidities such as intellectual disability, epilepsy, visual and hearing impairment and speech and language deficits. Despite the established role of hypoxic–ischemic injury in some CP cases, several studies suggest that...

In pleiotropic diseases, multiple organ systems are affected causing a variety of clinical manifestations. Here, we report a pleiotropic disorder with a unique constellation of neurological, endocrine, exocrine, and haematological findings that is caused by biallelic MADD variants. MADD, the mitogen-activated protein kinase (MAPK) activating death...

NEDD4L encodes an ubiquitin ligase which is expressed in the cortex and ventricular zone of the fetal brain. Missense variants in NEDD4L have been reported in nine patients with periventricular nodular heterotopia (PNH), polymicrogyria, cleft palate, and syndactyly. All reported variants are located in the HECT domain, causing deregulation of signa...

Mutations in the chromatin regulator gene BRPF1 were recently associated with the Intellectual Developmental Disorder With Dysmorphic Facies And Ptosis (IDDDFP). Up till now, clinical data of 22 patients are reported. Besides intellectual disability (ID), ptosis and blepharophimosis are frequent findings, with refraction problems, amblyopia and str...

Introduction/Background The ACTIVLIM questionnaire was developed to measure global activity performance of neuromuscular patients (NMPs). It also has the potential to assess real life improvement resulting from new coming therapies. For this purpose, long term follow-up data are mandatory. Such data are currently absent from the literature. The aim...

We describe seven patients with KDM6A (located on Xp11.3 and encodes UTX) mutations, a rare cause of Kabuki syndrome (KS2, MIM 300867) and report, for the first time, germ-line missense and splice-site mutations in the gene. We demonstrate that less than 5% cases of Kabuki syndrome are due to KDM6A mutations. Our work shows that similar to the comm...

Schematic representation of the genomic architecture of the remaining regulatory and FOXL2 encompassing deletions. For the remaining deletions, both breakpoint regions joined by the deletion are shown. A breakpoint region is displayed as the combination of two colored, solid lines together representing a 150 bp DNA sequence. The proximal breakpoint...

Multiple sequence alignments. Sequences of 150 bp surrounding the junctions of each deletion were aligned to the proximal and distal reference sequences using ClustalW. The proximal and distal reference sequences are shown in blue and green respectively. The junction sequences are depicted in the colour of the reference sequence they align with. Mi...

The genomic location and gene content of the FOXL2 encompassing and regulatory deletions. (PDF)

aCGH profile of complex deletion F visualized in arrayCGHbase. At the top, for reference, chromosome 3 is represented with a red rectangle indicating the location of the displayed array profile. At the bottom, the genomic position is shown in more detail. The red (loss), green (gain) and black (no change) dots represent log2-ratios of individual ol...

The presence of microhomology and the most likely molecular mechanism in previous studies. (PDF)

Overview of sequence motifs. (PDF)

Sequences of non-B DNA conformations. (PDF)

Genomic disorders are often caused by recurrent copy number variations (CNVs), with nonallelic homologous recombination (NAHR) as the underlying mechanism. Recently, several microhomology-mediated repair mechanisms-such as microhomology-mediated end-joining (MMEJ), fork stalling and template switching (FoSTeS), microhomology-mediated break-induced...

Author Summary Long-range genetic control is an inherent feature of genes harbouring a highly complex spatiotemporal expression pattern, requiring a combined action of multiple cis-regulatory elements such as promoters, enhancers, and silencers. Consequently, disruption of the long-range genetic control of a target gene by genomic rearrangements of...

Alignment of PISRT1 homologues based on BLAST searches and 5′ RACE. Goat mRNA sequence AF404302 was used for BLASTN searches against human and mouse genomes. The homologous regions were localized on human contig NT_005612.15 at position 45445646–45447509 and on the mouse contig NT_039476.7 at position 18278112–18279127. These retrieved sequences, t...

3C analysis of the human FOXL2 locus in EBV, KGN and F2 cells. Schematic representation of the FOXL2 locus. In the top line, genes located in this region are depicted by coloured boxes. The second line indicates the SROs of the downstream deletion (dashed line on the left) and the initial SRO of upstream deletions (red dashed line on the right resp...

Variants identified by sequence analysis of CNCs. (0.04 MB DOC)

Reported extragenic deletions in human genetic disorders. (0.11 MB DOC)

The FOXL2 gene is one of 10 forkhead genes, the mutations of which lead to human developmental disorders, often with ocular manifestations. Mutations in FOXL2 are known to cause blepharophimosis syndrome (BPES), an autosomal dominant eyelid malformation associated (type I) or not (type II) with ovarian dysfunction, leading to premature ovarian fail...

Blepharophimosis syndrome (BPES) is caused by loss-of-function mutations in the single-exon forkhead transcription factor gene FOXL2 and by genomic rearrangements of the FOXL2 locus. Here, we focus on 92 new intragenic FOXL2 mutations, 34 of which are novel. Specifically, we found 10 nonsense mutations (11%), 13 missense mutations (14%), 40 deletio...

Mutations of the FOXL2 gene have been shown to cause blepharophimosis syndrome (BPES), characterized by an eyelid malformation associated with premature ovarian failure or not. Recently, polyalanine expansions and truncating FOXL2 mutations have been shown to lead to protein mislocalization, aggregation and altered transactivation. Here, we study t...

"Autosomal dominant retinitis pigmentosa" (adRP) refers to a genetically heterogeneous group of retinal dystrophies, in which 54% of all cases can be attributed to 17 disease loci. Here, we describe the localization and identification of the photoreceptor cell-specific nuclear receptor gene NR2E3 as a novel disease locus and gene for adRP. A hetero...

The blepharophimosis syndrome (BPES) is an autosomal dominant developmental disorder in which craniofacial/eyelid malformations are associated (type I) or not (type II) with premature ovarian failure (POF). Mutations in the FOXL2 gene, encoding a forkhead transcription factor, are responsible for both types of BPES. Heterozygous polyalanine expansi...

The expression pattern of many developmental genes is regulated at different levels. Usually, basal gene expression is controlled by the core promoter, located immediately upstream of the ORF. However, spatiotemporally and quantitatively correct gene expression is often controlled by long-range cis-acting regulatory elements as distant as 1.1 Mb (V...

Recently the molecular basis of the blepharophimosis-ptosis-epicanthus inversus-syndrome (BPES), an autosomal dominant developmental disorder of the eyelids and ovary, was elucidated. This syndromic form of premature ovarian failure (POF) is caused by mutations in the gene encoding the forkhead transcription factor FOXL2. In this manuscript we revi...

Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES; MIM# 110100) is an autosomal dominant genetic condition in which an eyelid malformation is associated (type I) or not associated (type II) with premature ovarian failure (POF). In 2001, mutations in the FOXL2 gene, encoding a forkhead transcription factor, were shown to cause both BPES typ...

Blepharophimosis syndrome (BPES), an autosomal dominant syndrome in which an eyelid malformation is associated (type I) or not (type II) with premature ovarian failure (POF), has recently been ascribed to mutations in FOXL2, a putative forkhead transcription factor gene. We previously reported 22 FOXL2 mutations and suggested a preliminary genotype...

Neurofibromatosis type 1 (NF1) is one of the most common autosomal dominant disorders and is caused by mutations in the NF1 gene. Mutation detection is complex due to the large size of the NF1 gene, the presence of pseudogenes and the great variety of possible lesions. Although there is no evidence for locus heterogeneity in NF1, mutation detection...

Neurofibromatosis type 1 (NF1) is one of the most common autosomal dominant disorders and is caused by mutations in the NF1 gene. Mutation detection is complex due to the large size of the NF1 gene, the presence of pseudogenes and the great variety of possible lesions. Although there is no evidence for locus heterogeneity in NF1, mutation detection...

Neurofibromatosis type 1 (NF1) is one of the most common autosomal dominant disorders and is caused by mutations in the NF1 gene. Mutation detection is complex due to the large size of the NF1 gene, the presence of pseudogenes and the great variety of possible lesions. Although there is no evidence for locus heterogeneity in NF1, mutation detection...

Neurofibromatosis type 1 (NF1) is one of the most common autosomal dominant disorders and is caused by mutations in the NF1 gene. Mutation detection is complex due to the large size of the NF1 gene, the presence of pseudogenes and the great variety of possible lesions. Although there is no evidence for locus heterogeneity in NF1, mutation detection...