Funded projects

The Solve-RD brokerage service aims to fund 50 projects (so called Seeding Grants) to functionally validate newly discovered disease genes. Below you'll find a list of all funded projects.

Sara Wells | Lisenka Vissers & Tjitske Kleefstra (ERN-ITHACA)

By combining de novo calls identified by different algorithms and prioritizing candidate genes for intellectual disability, the groups of Lisenka Vissers and Tjitske Kleefstra at the Radboudumc, Nijmegen, the Netherlands identified five different de novo missense variants and one de novo truncating variant in a protein coding gene in patients with mild to moderate intellectual disability and additional medical problems such as obesity, cerebral palsy or seizures. By searching the Solve-RD cohort and using GeneMatcher exchange tools, they identified additional patients from unrelated families with overlapping phenotypes and mutations in the same gene. The Solve-RD RDMM-Europe Seeding Grant will support a validation study by introducing a human variant into the mouse genome performed by Sara Wells and her group at the Mary Lyon Centre, MRC Harwell Institute, UK.

Sara Wells is the director of the Mary Lyon Centre that works in synergy with academic institutions as well as large global programmes such as the International Mouse Phenotyping Consortium (IMPC) in order to provide expertise in mouse genetics and resources such as innovative and transformative phenotyping platforms that deliver relevant, translatable and reproducible data.

Start date: September 2021

Sandra Cooper | Ana Töpf and Volker Straub (ERN-EURO NMD)

The group of Ana Töpf and Volker Straub at the John Walton Muscular Dystrophy Research Centre in Newcastle upon Tyne, UK have identified novel recessive gene variants in three individuals from two families that showed myopathy with severe cardiac involvement. With a disease onset in the second decade of life, the patients showed remarkably similar, rapidly progressing proximal upper and lower muscle weakness and developed a severe cardiomyopathy resulting in early death. A Solve-RD RDMM-Europe Seeding Grant was awarded to Sandra Cooper and her group at the Sydney Children’s Hospitals Network, University of Sydney, Australia. Due to her expertise and previous research, Sandra is an excellent candidate to investigate the causative implication of the gene. The group will analyse muscles samples of their huge biobank and biopsies from the patients and will apply pre-mRNA splicing studies and Western blot. Furthermore, they will conduct rescue experiments in CRISPR/Cas9 KO cells of the given gene.

Start date: September 2021

Sahar Isa Da’as | Antonio Vitobello (ERN-ITHACA)

By exome and Sanger sequencing, the group of Antonio Vitobello at the CHU Dijon identified a de novo variant in a gene implicated in the regulation of natural killer cell effector functions. The variant was identified in a cohort of three unrelated patients with severe malformation phenotypes described as Cornelia de Lange-like syndrome. The Solve-RD RDMM-Europe Seeding Grant will support a validation study in a knock-in zebrafish line proposed by Sahar Isa Da’as at the Sidra Medical and Research Centre, Doha, Qatar. Sahar Isa Da’as and her group will use the zebrafish model to analyze effects of the variant on skeletal and nervous system development and locomotor activity. Sahar Isa Da’as leads the Functional Genomics Core Facility at Sidra Medicine and has extensive expertise with modeling of human disease in zebrafish.

Start date: September 2021

Zhenghe Wang | Stefan Aretz (ERN-GENTURIS)

Analysing leukocyte WES data, the group of Stefan Aretz at the University Hospital Bonn identified three different germline missense variants of a tumour suppressor gene in five patients from three families with Serrated Polyposis Syndrome, a colorectal cancer predisposition. The implicated protein is part of a family of signalling molecules that regulate different cellular processes such as cell growth and differentiation. The patients were diagnosed with several serrated polyps through the whole colon with a size of ~10mm.

The Solve-RD RDMM-Europe Seeding Grant will support a validation study in knockout mice performed by Zhenghe Wang and his group at the Case Western Reserve University, Cleveland, USA. The applicant is a cancer biologist with perfect expertise to model colorectal cancers in knockout mice.

Start date: July 2021

Thomas Boulin | Alessandra Renieri (ERN-ITHACA)

Solve-RD partner Alessandra Renieri and her team (University of Siena, Italy) recently identified a de novo mutation of a highly conserved gene in a patient with intellectual disability and autism spectrum disorders. The respective gene product is crucial for cell signalling, especially in the neural and motor system. Interestingly, additional variants of the same gene were found in unrelated patients with similar phenotypes.

The molecular relationship between these gene variants and the disease will be investigated by Thomas Boulin (Institut NeuroMyoGène, Lyon, France), supported by Solve-RD Seeding Grant funding. Thomas will make use of CRISPR/Cas9-based genome editing technologies to engineer and validate the patient variants in the invertebrate model Caenorhabditis elegans.

Start date: April 2021

R. Grace Zhai | Rebecca Schüle (ERN-RND)

Rebecca Schüle (Center of Neurology, Tübingen, Germany) recently identified a rare missense variant in the Solve-RD cohort of patients with hereditary spastic paraplegia (HSP), a group of inherited disorders that are characterized by progressive weakness and spasticity of the legs. By collaborative analysis of phenotypic and genetic data in the Solve-RD project and via the GENESIS platform (collaborator Stephan Züchner) they have been able to confirm the impact of the variant in additional patients with similar phenotypes.

Grace Zhai (Miller School of Medicine, University of Miami, USA) will receive Seeding Grant funding by Solve-RD to support the investigation of the respective gene variant in respect to its pathological phenotype. Morphological, pathological and developmental studies will be conducted by using loss-of-function and transgenic approaches in Drosophila melanogaster with the aim to establish the functional causality of this new candidate gene in HSP.

Start date: April 2021

Julie Brill | Manuela Morleo (ERN-ITHACA)

Solve RD partner Manuela Morleo from Telethon Institute of Genetics and Medicine, Naples, Italy has discovered previously unknown de novo variants of a gene in six patients with severe neurodevelopmental disorders. Interestingly, loss of function mutations in two known interactors of the respective gene product have been described to result in clinical manifestations with largely overlapping phenotypes.

Via the Canadian RDMM registry we have found Julie Brill from The Hospital for Sick Children (SickKids) in Toronto, Canada as model researcher with expertise for the given gene to answer the causative implication of the new variants in the disease. Julie will introduce variants in the Drosophila orthologue gene in S2 cells, tissues and flies. She proposed a very straightforward approach with high potential to yield clear results on the pathomechanism of the new variants.

Start date: April 2021

Alessandro Sessa | Siddharth Banka (ERN-ITHACA)

The group of Siddharth Banka at the Manchester Centre for Genomic Medicine identified missense variants in a gene involved in the epigenetic machinery in several unrelated patients with neurodevelopmental disorders. The patients presented intellectual disability, learning and behavioural difficulties, facial dysmorphism and occasional heart defects.

Exome sequencing revealed that all patients carry rare missense variants in the novel candidate gene. The Solve-RD RDMM-Europe Seeding Grant will support a validation study in iPSCs performed by Alessandro Sessa and his group at the IRCCS Ospedale San Raffaele, Milano, Italy. The applicant has extensive research experience with stem cells and the analysis of the molecular basis of neurological disorders. One focus of his work is to study how epigenetic factors impact pathological conditions in humans.

Start date: April 2021

Jamile Hazan | Giovanni Stevanin (ERN-RND)

By exome analysis Giovanni Stevanin and his colleagues at INSERM-ICM in Paris identified rare homozygous missense variants in a new candidate gene in three patients of a consanguineous family with symptoms of a specific type of hereditary spastic paraplegia (HSP) and mild mental retardation and learning problems.

The Solve-RD RDMM-Europe Seeding Grant will allow the generation of a Zebrafish model by Jamile Hazan and her group at Sorbonne University (Paris). The successful applicant has extensive experience with the examination of the physiopathology of HSP in vertebrate models and has already done preliminary work to clarify the function of the new candidate gene.

Start date: February 2021

Bart Dermaut & Elke Bogaert | Antonio Vitobello (ERN-ITHACA)

The group of Antonio Vitobello at the University Hospital Dijon-Bourgogne identified novel gene variants in several patients with symptoms like developmental delay, skeletal abnormalities, heart defects and motoric and intellectual impairments. The symptoms are different in severity, but featured in similar patient phenotypes. Most variants emerged by de novo mutations of a gene which is involved in the regulation of posttranscriptional mechanisms.

The Solve-RD RDMM-Europe Seeding Grant will allow to study the impact of the variants in a Drosophila model by the team of Bart Dermaut and Elke Bogaert at Ghent University in Belgium. The group has vast experience in studying flies for Alzheimer's and several other neurological disorders. In addition Drosophila is the best suited model organism for the approach as the respective gene is highly conserved between fly and human.

Start date: January 2021

Pertti Panula | Bjarne Udd (ERN-EURO NMD)

The group of Bjarne Udd at the Folkhälsan Research Center (University of Helsinki) / Tampere Neuromuscular Center, Finland identified a novel disease gene in patients with adult onset distal myopathy. Solve-RD RDMM-Europe Seeding Grant funding will now allow the generation of a Zebrafish model by the group of Pertti Panula at the University of Helsinki. Zebrafish (Danio rerio) is preferred as model organism as it has an ortholog of the gene of interest. The lab of Pertti Panula has extensive experience with genetically modified zebrafish models and quantitative analysis to identify motor, sensory and social anomalies.

Start date: November 2020

Gaurav K. Varshney | Siddharth Banka (ERN-ITHACA)

The group of Siddharth Banka at the Manchester Centre for Genomic Medicine identified novel missense gene variants in several unrelated patients with neurodevelopmental disorders. The patients presented moderate to severe intellectual disability, developmental delay, behavioural problems and in addition occasional congenital malformations. Exome sequencing revealed that all patients carry rare missense variants in a novel candidate gene.

The Solve-RD RDMM-Europe Seeding grant will allow the generation of a Zebrafish model by Gaurav K. Varshney and his group at the Oklahoma Medical Research Foundation. The applicant has extensive experience with clinical collaborations, and his primary focus is the use of zebrafish and gene editing technologies to study human disease models.

Start date: October 2020

Howard Lipshitz | Antonio Vitobello (ERN-ITHACA)

The group of Antonio Vitobello from CHU Dijon identified a novel gene variant in two unrelated patients with polymalformative syndrome. The patients both present with developmental delay and multiple malformations and exome sequencing revealed that both patients carry the same rare missense variant in a gene that has not been associated with human disease so far.

To answer it´s causative implication in the disease the Solve-RD RDMM-Europe Seeding Grant will allow the generation of a Drosophila melanogaster model by Howard Lipshitz and his group at the Department of Molecular Genetics, University of Toronto, Canada. The applicant has extensive experience and a proven track record in the functional validation of human genes in Drosophila. This is the first Solve-RD Seeding Grant awarded to a scientist identified via our partner network RDMM in Canada.

Start date: September 2020

Michela Ori | Antonio Vitobello (ERN-ITHACA)

The group of Antonio Vitobello and Estelle Colin from CHU Dijon identified novel gene variants in patients with facial dysmorphism. Loss-of-function mutations of the respective candidate gene have previously been described as causative in a rare genetic disorder characterized by developmental delay and intellectual disability.

The Seeding Grant will allow the generation of Zebrafish and Xenopus mutants by Michela Ori and her group at the Department of Biology, University of Pisa, Italy to model the dysmorphic phenotype. Michela has extensive experience in molecular embrology and has previously used Xenopus and Zebrafish animal models to study craniofacial development.

Start date: August 2020

Ype Elgersma | Laurence Faivre (ERN-ITHACA)

Solve-RD partner Laurence Faivre from CHU Dijon and colleagues discovered a novel de novo missense variant in a gene in four individuals affected with a severe neurodevelopmental disorder of unknown cause.
The RDMM-Europe Seeding Grant awarded to Ype Elgersma at Erasmus University Medical Center in Rotterdam will allow to assess the pathogenicity of this rare genetic variant. The project involves expression of the mutant form in developing mouse embryos and in primary neuronal cultures and analysis of the resulting phenotypes. Ype has great expertise in functional genomic screenings to assess the pathogenicity of genetic variants identified in individuals with neurological development disorder.
Start date: August 2020

Conrad Weihl | Ana Töpf (ERN-EURO NMD)

The group of Ana Töpf and Volker Straub at the John Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, Newcastle University identified new vary rare variants of a gene in patients with severe respiratory failure, dyspnoea and spine rigidity. The RDMM-Europe Seeding Grant of 20,000 EUR awarded to Conrad Weihl and his group at the Washington University School of Medicine will enable the functional validation of the disease causing gene in a knockout mouse model. The group has vast experience in working with mouse models of neuromuscular disorders. In addition, biochemical studies will be carried out in knockout myoblasts to unravel putative mechanism of pathogenicity.
Start date: July 2020

Sara Wells | Stephanie Efthymiou (ERN-RND)

The group of Stephanie Efthymiou and her colleagues at the UCL Institute of Neurology identified novel variants of a gene associated with severe neurodevelopmental disorders. Homozygous carriers of the alleles come up with severely delayed psychomotor development. Neurophysiological investigations indicated severe demyelination, axonal neuropathy and loss of cerebral white matter.

The RDMM-Europe seeding grant will facilitate the generation of a mouse model by Sara Wells at the Mary Lyon Centre, MRC Harwell Institute by using CRISPR/Cas9 technology to alter this novel gene. The model will play an important role in understanding the pathological consequences of the novel gene variants. In particular, the mutants will be studied for phenotypic features observed in the patient, such as neurological development, locomotor activity and behaviour. Modelling this human disease will not only help to provide further evidence on this new rare genetic disease and hence to improve diagnostic and management strategies, but will also facilitate assessment of potential treatment possibilities for patients.

Start date: July 2020

Binnaz Yalcin | Lisenka Vissers (ERN-ITHACA)

The group of Lisenka Vissers and her colleagues at Radboud University Medical Centre identified novel variants of a gene associated with complex cortical dysplasia and other brain malformations. Affected patients are clinically characterized by neurodevelopmental delay, intellectual disability and refractory epilepsy.
The RDMM Europe Seeding Grant will facilitate the characterisation of a knock-in mouse model by Binnaz Yalcin and her group at University of Burgundy, Dijon, France as part of Inserm U1231. For the validation of the novel gene variants the mouse model will be characterized by histological and neuroanatomical methods as well as in behavioural tests. By modelling this novel rare human disease we expect to improve diagnosis and future treatment possibilities for affected patients.
Start date: March 2020