Research Ayşe Candayan Niron

Abstract

Many Mendelian diseases have benefited from next-generation sequencing (NGS) technologies for molecular diagnosis and gene discovery. However, the technical limitations of NGS pose a challenge for the identification of mutational mechanisms in genomic regions impenetrable by these technologies. I hypothesize that single nucleotide variants and small indels in NGS inaccessible regions, as well as structural variants, can explain a significant proportion of missing heritability in many diseases. To this end, I propose to explore such intractable genomic regions in Charcot-Marie-Tooth disease, the most common genetic affliction of the peripheral nervous system, to bridge the missing heritability gap in this disease. I will utilize long-read nanopore sequencing in a unique patient cohort to look for potentially disease-causing variants that were missed by previous NGS analyses. I will then adopt genetic and functional in vitro and in vivo approaches to characterize the identified genomic variants and ascertain the associated functional genes that most likely underlie molecular pathology. The findings of my pioneering study will highlight the contribution of new mutational classes in peripheral neurodegeneration, discover causal variants long overlooked by state-of-the-art technologies, and deliver in vivo models that might provide clues for therapeutic approaches for peripheral nerve disorders with common etiology.

Researcher(s)

• Promoter: Jordanova Albena
• Fellow: Candayan Niron Ayşe

Research team(s)

• VIB CMN - Molecular Neurogenomics

Project type(s)

• Research Project

Abstract

Many Mendelian diseases have benefited from next-generation sequencing (NGS) technologies for molecular diagnosis and causal gene discovery. However, the technical limitations of NGS pose a challenge for the identification of mutational mechanisms in genomic regions impenetrable by these technologies. I hypothesize that single nucleotide variants and small indels in NGS inaccessible regions, as well as large structural variants, can explain a significant proportion of missing heritability in many diseases. To this end, I propose to explore such intractable genomic regions in Charcot-Marie-Tooth disease, the most common genetic affliction of the peripheral nervous system, to bridge the heritability gap in this disease. I will utilize long-read nanopore sequencing in a unique patient cohort to look for potentially disease-causing variants that were missed by previous NGS analyses. I will then adopt genetic and functional in vitro and in vivo approaches to characterize the identified genomic variants and ascertain the associated functional genes that most likely underlie molecular pathology. The findings of my pioneering study will highlight the contribution of new mutational classes in peripheral neurodegeneration, discover causal variants long overlooked by state-of-the-art technologies, and deliver in vivo models that might provide clues for therapeutic approaches for peripheral nerve disorders with common etiology.

Researcher(s)

• Promoter: Candayan Niron Ayşe
• Co-promoter: Jordanova Albena

Research team(s)

• VIB CMN - Molecular Neurogenomics

Project type(s)

• Research Project

Abstract

Hereditary ataxias are severe neurodegenerative disorders characterized by progressive loss of coordination in voluntary muscle movement. Due to clinical and genetic heterogeneity, the overall genetic diagnosis rate is between 55-65% suggesting there might be disease-causing genes yet to be identified. Previously, while screening a cohort with early-onset severe neurodegeneration, I identified the SEPTIN11 gene as a novel disease-causing candidate in a family presenting with hereditary ataxia and axonal sensorimotor polyneuropathy. The studies in the literature are suggestive that dysregulation of members of the septin protein family could lead to neurodegeneration, however, this is not sufficient to prove SEPTIN11 pathogenicity in the nervous system. Since the family we reported is the sole family in the literature, the only approach to provide concrete evidence of pathogenicity is to generate an animal model for assessing neurodegeneration in a physiologically relevant context. Building on the genetic evidence and promising preliminary data based on septin knock-out flies and humanized transgenic flies expressing wild-type and mutant human SEPTIN11, I would like to further characterize hallmarks of neurodegeneration potentially led by SEPTIN11 dysregulation. This in-depth analysis will provide indisputable evidence of pathogenicity likely associated with the (mal)functioning of SEPTIN11 in the central and peripheral nervous systems.

Researcher(s)

• Promoter: Candayan Niron Ayşe

Research team(s)

• VIB CMN - Molecular Neurogenomics

Project type(s)

• Research Project

Abstract

Many Mendelian diseases have benefited from next-generation sequencing (NGS) technologies for molecular diagnosis and gene discovery. However, technical limitations of NGS pose a challenge for identification of mutational mechanisms in genomic regions impenetrable by these technologies. I hypothesize that complex genomic rearrangements called structural variants (SVs) in these loci can explain a significant proportion of missing heritability in many diseases. To this end, I propose to explore the involvement of SVs in Charcot-Marie-Tooth disease (CMT), the most common genetic affliction of the peripheral nervous system. I will utilize long-read nanopore sequencing in a unique patient cohort to look for potentially disease-causing SVs. I will then adopt genetic and functional in vitro and in vivo approaches to characterize the identified genomic variants, and ascertain the associated functional genes that most likely underlie molecular pathology. The findings of my pioneering study will highlight the contribution of structural variants in peripheral neurodegeneration, discover non-conventional mutational mechanisms long overlooked by state-of-the-art technologies, and deliver in vivo models that might provide clues for therapeutic approaches for peripheral nerve disorders with common etiology.

Researcher(s)

• Promoter: Jordanova Albena
• Fellow: Candayan Niron Ayşe

Research team(s)

• VIB CMN - Molecular Neurogenomics

Project type(s)

• Research Project