Short summary

In this international study we want to explore the severity of clinical, cognitive, neuroimaging and molecular outcome of 100 patients and their parents with a copy number variant (deletion or duplication) at the chromosomal region 15q11.2 and clinical related CNVs.

Rationale

Deletions or duplications at chromosome 15q11.2 and clinical related CNVs are frequently detected in patients referred for genetic workup by microarray analysis due to developmental delay, intellectual disability, epilepsy, autism spectrum disorders, ADHD and congenital heart malformations, but it is also found in unaffected relatives. The cause of the great clinical variability in carriers of the deletions is still unknown, but it has been suggested to be explained by additional deleterious genetic changes present in some carriers leading to an (additive) effect in the more severely affected individuals. Currently, very little information exists of the reciprocal 15q11.2 micro duplication.

This PhD project is part of a larger project investigating the dysfunction of the CYFIP1-FMRP complex

The main aims are to:

• Characterize the effect of the 15q11.2 (BP1-BP2) gene dosage on cognitive and behavioral traits.
• Characterize the contribution of additional deleterious variant to the phenotypic variance of the 15q11.2 locus.
• Study biomarkers of the CYFIP1-FMRP complex in patient with genomic rearrangements of this locus.
• For comparison of phenotypes additional clinical related CNVs will be characterized as well.

Some of the main challenges regarding 15q11.2 rearrangements and clinically related CNVs are the variable phenotypic expression and the incomplete penetrance. Inheritance from unaffected parents is common and makes genetic counseling of the families very challenging. The purpose of this study is to understand how this region can cause difficulties for some individuals carrying a certain rearrangement, and save others. With this study we will learn more about the relationship between genetic variations and the risk for symptoms which will potentially lead to more reliable prognosis, interventions and treatment options and better outcomes for patients and families. 

Description of the cohort

The study cohort will consist of carriers of a deletion or duplication at chromosome 15q11.2 and clinical related CNVs and their healthy relatives (parents and eventual siblings) age range 3-70 years. We expect to be able to recruit 20 Danish families for the study (app. 60 participants). In the whole international study the goal is to include 100 families which will make up data and samples from 300 participants.

In addition to this patients with clinical related CNV will be included.

Data and biological material

All participants will be physically examined.

The following data are collected and/or retrieved from medical records: patient and family history, copy number variant, gender, age, birth weight, birth height, head circumference, diagnosis, operations, imaging results, therapy, treatment, smoking, alcohol consumption, motor and language development, behavior, eating habits, sleep, results from prior cognitive assessments, education and schooling.

Questionnaires regarding behavior, cognition and psychiatric conditions.

Blood cells, plasma and fibroblasts (optional) for DNA analysis are stored in a biobank.

In a subgroup of (30) participants a cerebral MRI scan and an EEG (optional) will be performed.

Collaborating researchers and departments

Department of Clinical Gentics, Odense University Hospital

• ilian Bomme Ousager, MD, PhD
• PhD student Aia Elise Jønch, MD

Department of Clinical Genetics, Vejle Hospital

• Anders Bojesen, MD, PhD

The Danish Epilepsy Center, Umbrella organization Filadelfia

• Helle Hjalgrim, MD, PhD

Medical Genetics in the Department of Pediatrics and Research Center, University Hospital of Sainte Justine, Montreal, Quebec, Canada and Service of Medical Genetics, CHUV, Lausanne, Switzerland

• Principal Investigator Sebastien Jacquemont, MD

Department of Neuroscience, UNIL, University of Lausanne, Lausanne, Switzerland

• Professor, Claudia Bagni, PhD

Department of Radiology Odense University Hospital

• Professor Poul Erik Andersen, MD
• Head of the Department of Radiology Jens Karstoft, MD