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Deep familial phenotyping and genotyping to resolve phenotypic variability of inherited pathogenic genetic variants KU Leuven

Jeroen Breckpot
Department of Human Genetics
The high burden of de novo pathogenic genetic variants in sporadic patients with rare developmental disorders (DD) has led to a de novo paradigm in genetic research and diagnostics. Genetic variants inherited from an unaffected parent are typically disregarded in variant interpretation pipelines. However, we are confronted with a growing list of rare inherited variants, that are enriched in patient versus control cohorts. Mechanisms underlying ...

Segmental duplication structural variation as the cause for the 22q11DS phenotypic variability KU Leuven

Joris Vermeesch
Department of Human Genetics

The 22q11 deletion syndrome (22q11DS), also known as the DiGeorge syndrome or Velo-Cardio-Facial syndrome, is the most common microdeletion syndrome, with a prevalence of 1 in 4000 births. The 22q11 deletion is caused by non-allelic homologous recombination between segmental duplications, causing a 3MB deletion in 90% of patients. Typical phenotypes include congenital heart defects, learning difficulties, characteristic facial features, and ...

Charting the genomic sequence of the 22q11 low copy repeats by cross-platform sequencing to unravel the causes of the phenotypic variability of the 22q11.2 deletion syndrome. KU Leuven

Joris Vermeesch
Department of Human Genetics, Laboratory for Cytogenetics and Genome Research
The 22q11.2 deletion syndrome (22q11.2DS) is a congenital malformation and neuropsychiatric disorder caused by non-allelic homologous recombination events. With an estimated incidence of 1 in 4000 live births, the 22q11.2 deletion syndrome is the most common chromosomal microdeletion disorder in humans. The mechanism behind this disorder involves the four sets of low copy repeats (LCR22) that are dispersed in the 22q11.2 region. Standard ...

Mapping the role of the low copy repeats in the phenotypic variability of the 22q11 Deletion Syndrome KU Leuven

Joris Vermeesch
Department of Human Genetics

The 22q11 deletion syndrome (22q11DS) is the most common
genomic disorder, with a prevalence of 1 in 3000 births. The reason
for this high incidence remains an enigma. The presence and
degrees of severity of most phenotypic features are highly variable
across patients and it remains unknown why some patients acquire
neuropsychiatric features and others do not. The deletion is caused
by non-allelic homologous ...

Identification of modifier genes underlying the phenotypic variability in the U+2018Brittle Bone DiseaseU+2019, using zebrafish models and patient-derived induced pluripotent stem cells Ghent University

Paul Coucke
Department of Biomolecular Medicine

We postulate that U+2018modifier genesU+2019 are responsible for the variable disease severity in Osteogenesis Imperfecta (OI), by altering the manifestations of the major mutated gene. We aim to identify the modifier genes contributing to the intra-familial phenotypic variability in OI, using zebrafish models and human induced pluripotent stem cells. These U+2018modifiersU+2019 represent promising targets for intervening in disease ...

Monogenic autoinflammatory disorders: streamlining the identification and validation of novel variants and exploring the phenotypic variability of disease. KU Leuven

Adrian Liston
Adaptive Immunology

Monogenic autoinflammatory disorders (AIDs) are a group of rare conditions caused by inappropriate activation or lack of regulation of the innate immune system. There has been an increase in the number of AIDs described in the past decade, providing insight into different innate immune pathways in both health and disease. These diagnoses have been made with the use of next generation sequencing, namely whole exome and now whole genome ...

Study of the role of genetic variation in the phenotypic variability and response to treatment in patients with Marfan Syndrome Ghent University

Bart Loeys
Department of Pediatrics and medical genetics

Marfan syndrome is an autosomal dominant disease characterized by multisystemic involvement including ectopia lentis, skeletal overgrowth and aortic root dilatation. Althought the genetic basis for the disease has been identified as the FBN1 gene, the molecular basis for its wide inter- and intrafamilial variability has not been identified. This study studies the influence of single nucleotide polymophisms in the genes encoding in this ...

Discovery of genetic modifiers of the phenotypical cardiovascular variability in Marfan syndrome to pave the road to individualized treatment protocols. University of Antwerp

Bart Loeys
Medical Genetics (MEDGEN)
Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder with pleiotropic ocular, skeletal and cardiovascular manifestations. Morbidity and mortality are mostly determined by aortic root aneurysm, dissection and rupture. Although mutations in FBN1, coding for fibrillin-1, are the sole genetic MFS cause, there is a poor correlation between the MFS phenotype and the nature or location of the FBN1 variant. Wide intra- and ...