Funded projects

The team of Matthis Synofizik (Center of Neurology, Tübingen, Germany) identified a strong heterozygous gene variant segregating with disease in a large family with autosomal-dominant cerebellar ataxia (ATX). The WES datasets of two affected family members available in RD-Connect GPAP were taken as a starting point, complemented by subsequent Sanger segregation in 11 family members in total. Screening of several genomic databases (e.g. RD-Connect, GENESIS) with a total of more than 2000 WES/WGS ATX datasets led to identification of two additional unrelated ATX index cases with the same gene variant as identified in the first family. All three index cases share a uniform phenotype of early onset slowly progressive cerebellar ataxia, remarkably without relevant signs of extra-cerebellar systems affection.

The Solve-RD RDMM-Europe Seeding Grant will support quantitative in vitro assays with purified proteins performed by David Lambright, University of Massachusetts Chan Medical School in Worcester, USA. The biochemical effects of the variants will be interpreted in the context of available structural models, allowing structural and molecular understanding of the functional impact of the variants. This information will further support design and interpretation of subsequent cell-based and/or in vivo experiments to examine specific mechanism-based hypotheses.

Start date: June 2022

Elisa Cali and colleagues at the UCL Queen Square Institute of Neurology described eight affected individuals from five unrelated families with a recurrent segregating homozygous truncating gene variant. All affected presented at birth with microcephaly and respiratory failure requiring intubation and constant ventilation assistance for the rest of their life. Concerning psychomotor development, the impairment was profound with lack of achievement of any developmental milestone. Axial hypotonia and appendicular hypertonia were observed in all individuals. Seizures were present in all patients and have been described as myoclonic seizures or stimulus-related seizures.

The Solve-RD RDMM-Europe Seeding grant supports a study to characterize the gene variant in the Drosophila orthologue. Vladimir Katanaev and his team at the University of Geneva, Switzerland will perform gene editing using the CRISPR/Cas9 technology to introduce the mutation. Established lines will first be characterized with basic parameters such as viability/ lethality in the homo- and heterozygous state, longevity and any clear visible phenotype (e.g. morphological deviations). Further experiments will focus on the analysis of the movement behaviour and eventual seizures. The successful establishment of a Drosophila model with the truncating variant can then be followed by two types of translational investigations: a suppressor-enhancer screening and a drug candidate screening.

Start date: June 2022

The group of Henry Houlden at the UCL Queen Square Institute of Neurology has identified a novel candidate gene with suspected implication in non-syndromic sensorineural hearing loss with prelingual onset.

Nicola Strenzke (Department of Otolaryngology and Institute for Auditory Neuroscience, University Medical Center Göttingen, Göttingen, Germany) receive Seeding Grant funding by Solve-RD to support the investigation of the gene in a mouse model with a targeted deletion of the respective gene. Most valuable to this study is the analysis of homozygous mice, which should mirror the human null mutation. Phenotypic analysis of the mice will focus on the assessment of hearing functions complemented by comprehensive morphological studies of inner and outer hair cells, their stereocilia, and ribbon synapses. The highly complex inner ear of the mouse is strikingly similar to human in terms of anatomy, physiology and genetics. Despite the availability and successful use of other animal models in hearing research, the mouse still continues to be the predominant and preferred model organism in the auditory field, especially with regards to genetic deafness.

Start date: June 2022

Stephanie Efthymiou and colleagues at the UCL Queen Square Institute of Neurology have identified a cohort of paediatric patients that share variable developmental delay, epileptic abnormalities, and occasionally craniofacial features. WES filtering identified homozygous or compound heterozygous missense variants in a gene with implicated relevance for neuropediatric pathology.

Paul C Marcogliese, trained in the Bellen lab at the Baylor College of Medicine, who has now started his own group at the University of Manitoba in Canada will receive RDMM-Europe Seeding Grant funding by Solve-RD to support a validation study in Drosophila. Paul provides an excellent match to model the respective gene, that has a highly conserved one-to-one orthologue in the fly. The group has already produced a knockout fly line, which has reduced viability, reduced lifespan, and behavioral phenotypes. They will now test whether wild-type or patient variants can rescue the null phenotype. In addition, they plan to apply drugs to test if the null phenotype can be ameliorated.

Start date: June 2022

Solve RD partners Iris te Paske & Richarda de Voer at the Radboudumc, Nijmegen, the Netherlands have identified a homozygous missense variant in a new gene in a female patient with early-onset thyroid and breast cancer. Regions-of-Homozygosity (ROH) analysis performed by the ROH and Relatedness working group within Solve-RD predicted that the proband has consanguineous parents. The affected gene product is a protein known to be involved in pathways to maintain genetic stability.

The Solve-RD RDMM-Europe Seeding Grant will support a validation project performed by Máté Varga, at the Department of Genetics, Eötvös Loránd University in Budapest, Hungary. The applicant will generate knockout zebrafish and strains that express the patient´s variant. Phenotyping will be done based on morphology, changes in double-strand break frequency, and sensitivity to genotoxic agents. Máté has an excellent track record and extensive experience with the generation and phenotyping of genetically modified zebrafish models to study morphological or behavioural abnormalities and DNA damage.

Start date: June 2022

The group of Henry Houlden at the UCL Queen Square Institute of Neurology identified three unrelated families with four affected individuals presenting with novel ultrarare variants in a gene that encodes an RNA binding protein. All affected individuals have overlapping phenotypes such as facial and skeletal abnormalities, some individuals also suffer from hypogammaglobulinemia with recurrent chest infections.

Kris Vleminckx and Sarah Vergult (Ghent University, Belgium) will receive seeding grant funding by Solve-RD to support the investigation of the gene in Xenopus tropicalis and zebrafish models. Both scientists are part of the Rare-Med consortium that has recently been initiated at Ghent University and both have excellent expertise in their respective animal models. Phenotypic assessment will include histological determination of the craniofacial and skeletal development as well as RNAseq of the brains of frogs and fish.

Start date: June 2022

By WGS analysis of two affected siblings suffering from Hereditary Spastic Paraplegia (HSP) the group of Henry Houlden at the UCL Queen Square Institute of Neurology identified a homozygous frameshift mutation within a shared RoH region. Biallelic loss of function mutations of the same gene were found in 14 additional affected individuals from 6 consanguineous families.

The RDMM-Europe Seeding Grant awarded to Stefan Barakat and Tjakko van Ham at Erasmus University Medical Center in Rotterdam will allow to assess the pathogenicity of the new HSP candidate gene using zebrafish models. The group has been able to show in pilot experiments that the respective zebrafish Crispants show reduced locomotor activity compared to wild-type, indicating that the larvae phenocopy symptoms seen in patients. The group will perform detailed investigations of cellular abnormalities and neuronal functions in these zebrafish and will explore options to modulate the phenotype by exposing zebrafish larvae to a selected library of chemical compounds, incl. FDA approved drugs, to study whether specific compounds suppress locomotor and cellular abnormalities identified in mutants.

Start date: May 2022

Publication:
Ruizhi Deng, Eva Medico‑Salsench, […], Tahsin Stefan Barakat: AMFR dysfunction causes autosomal recessive spastic paraplegia in human that is amenable to statin treatment in a preclinical model. Acta Neuropathol (2023). https://doi.org/10.1007/s00401-023-02579-9

The group of Antonio Vitobello from CHU Dijon identified the same de novo missense variant in several unrelated patients with polymalformative syndromes. The patients are seen in different medical centres and present concordant phenotypes with developmental delay, major birth defects and considerable medical need. The gene has not been associated with developmental disorders so far.

Bart Dermaut and Elke Bogaert (Ghent University, Belgium) will receive Seeding Grant funding by Solve-RD to support the investigation of the gene variant in respect to its pathological phenotype in fly models. Wing and eye phenotype studies will be conducted to investigate whether the overexpression of the human ortholog will phenocopy the fly protein. Additional loss-of-function and transgenic approaches in Drosophila melanogaster will help to evaluate the impact of the gene variant on morphological, pathological and developmental processes.

Start date: May 2022

The group of Henry Houlden at the UCL Queen Square Institute of Neurology identified novel missense gene variants in several unrelated patients with complex dystonia parkinsonism ataxia phenotype. The patients presented moderate-to-severe delay in psychomotor development predominantly affecting the acquisition of walking skills, speech, intellectual functioning (global developmental delay, moderate to severe intellectual disability, severe speech disorder, diverse behavioural abnormalities), variable dysmorphisms and seizures.

The Solve-RD RDMM-Europe Seeding Grant supports a study to elucidate the functional role of the gene in disease pathogenesis using a zebrafish model by Gaurav K. Varshney and his group at the Oklahoma Medical Research Foundation. The group will study morphological and behavioral effects of the gene knockout in zebrafish and will try to rescue the phenotype(s) by using wildtype and variant mRNA overexpression.

Start date: May 2022

Publication:

Rauan Kaiyrzhanov, Aboulfazl Rad, Sheng-Jia Lin, […], Gaurav K Varshney, Henry Houlden, Reza Maroofian: Bi-allelic ACBD6 variants lead to a neurodevelopmental syndrome with progressive and complex movement disorders. Brain (2023) https://doi.org/10.1093/brain/awad380

The group of Manuela Morleo at the Telethon Institute of Genetics and Medicine, Naples, Italy have performed Trio-based WES analysis in a patient with perinatal complications, developmental delay and dysmorphisms and identified a heterozygous de novo gene variant that is not present in the non-consanguineous healthy parents. By querying the Match Maker Exchange databases, they identified 3 additional families with the recurrent variant and the patients sharing a phenotype of global developmental delay, intellectual disability, microcephaly and craniofacial abnormalities.

A Solve-RD RDMM-Europe Seeding Grant was awarded to Filippo Del Bene at Institut de la Vision, Sorbonne Université, Paris, France to support a project that is extremely well aligned with the validation need of the clinical group. Filippo will generate two complementary zebrafish models and study the effect of the human variant and of the homologous mutation in the respective zebrafish gene on brain size and structure, locomotor activity and behavior. Gene expression analysis and immunohistochemistry will be done as well.

Solve RD partner Arne Jahn from the Institute of Clinical Genetics at the University Hospital Dresden in Germany has identified de novo loss-of-function (LOF) mutations of a gene in a cohort of patients with neurodevelopmental disorder. Phenotypic data and NGS samples of affected families were collected through different networks (Decipher, ClinVar, GeneMatcher and Solve-RD).

The Solve-RD RDMM-Europe Seeding Grant will support a validation study in CRISPR/Cas9 knock-out zebrafish performed by Caroline Hill, at the Francis Crick Institute London, UK. Caroline has an excellent track record and extensive experience with genetically modified zebrafish models and the analysis of neuronal morphology, migration and behavioural anomalies.

Laurence Faivre and colleagues at the CHU Dijon identified three different de novo start-loss codon variants of a gene encoding a RNA-binding-protein. Similar variants of the gene were found through international collaborations in nine patients from unrelated families with a clinical spectrum including variable associations of altered growth parameters, skeletal anomalies, impaired neurodevelopmental and more. The Solve-RD RDMM-Europe Seeding grant will support a validation studies in mutant mouse lines proposed by Martin Hrabĕ de Angelis at the Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, Germany. The German Mouse Clinic provides an advanced phenotyping platform for mouse models that covers all disease relevant organs.

Solve RD partner Manuela Morleo from Telethon Institute of Genetics and Medicine, Naples, Italy identified two new gene variants in cohorts of patients suffering from severe developmental delay, facial dysmorphisms and seizures or cardiac anomalies, respectively.

Two Solve-RD RDMM-Europe Seeding grants will facilitate validation of pathogenicity for both gene variants by supporting combined functional studies in zebrafish and mouse models of the respective genes. Radislav Sedlacek and his group at the Czech Centre for Phenogenomics (CCP), Institute of Molecular Genetics of the Czech Academy of Sciences in Prague will do comprehensive phenotyping of the models using high resolution microCT scanning. The CCP is an outstanding facility in combining genetic engineering capabilities and advanced phenotyping. Therefore, Radislav Sedlacek and team will be ideal to uncover the molecular mechanisms and the underlying pathological conditions of the given gene variants.

By using WES bioinformatics filtering, the group of Henry Houlden at the UCL Queen Square Institute of Neurology identified five homozygous or compound heterozygous frameshift or missense variants in an autophagy regulator gene in a cohort of patients from unrelated families with severely delayed psychomotor development.

Tamotsu Yoshimori and his group at the Department of Genetics, Graduate School of Medicine, Osaka University, Japan received Solve-RD RDMM-Europe Seeding Grant funding to support a validation study in a conditional knockout mouse model. Tamotsu Yoshimori is an expert in studying autophagy in vivo and has already generated and analysed tissue-specific knockout mice.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.