ArticleAmerican journal of human genetics2022
De novo variants in FRMD5 are associated with developmental delay, intellectual disability, ataxia, and abnormalities of eye movement.
Article in American journal of human genetics, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 27 citations in OpenAlex.
- Data-Driven Insights into Hyperkinetic Disorders in Neurodevelopmental Syndromes and Epileptic Encephalopathies.Movement disorders clinical practice · 2026Review
- An integrative single-nucleus multiomic atlas of the human left ventricle identifies gene regulatory network dynamics across cardiac development, aging, and disease.Genome biology · 2026Article
- Loss of Frmd5 Inhibits Jak2-Stat3 Signalling Pathway and Impairs Cell Apoptosis During Vagina Luminal Formation in Puberty Mice.International journal of biological sciences · 2026Article
- Heterozygous variants ineLife · 2025Article
- De novo variants in CDKL1 and CDKL2 are associated with neurodevelopmental symptoms.American journal of human genetics · 2025Article
- Neonatal-Onset Opsoclonus-Myoclonus-Ataxia-Like Syndrome Caused by De NovoNeurology. Genetics · 2025Article
- Homozygous missense variants in YKT6 result in loss of function and are associated with developmental delay, with or without severe infantile liver disease and risk for hepatocellular carcinoma.Genetics in medicine : official journal of the American College of Medical Genetics · 2024Article
- Deficiency of FRMD5 results in neurodevelopmental dysfunction and autistic-like behavior in mice.Molecular psychiatry · 2024Article
- De novo variants in FRYL are associated with developmental delay, intellectual disability, and dysmorphic features.American journal of human genetics · 2024Article
- A Novel Type of Autosomal Dominant Episodic Nystagmus Segregating with a Variant in the FRMD5 Gene.Neuro-ophthalmology (Aeolus Press) · 2024Article
- Integrating non-mammalian model organisms in the diagnosis of rare genetic diseases in humans.Nature reviews. Genetics · 2024Review
- Allelic strengths of encephalopathy-associatedeLife · 2023Article
- A comprehensive Drosophila resource to identify key functional interactions between SARS-CoV-2 factors and host proteins.Cell reports · 2023Article
- Bi-allelic variants in INTS11 are associated with a complex neurological disorder.American journal of human genetics · 2023Article
- Sphingolipids in neurodegenerative diseases.Frontiers in neuroscience · 2023Review
- Model organisms for functional validation in genetic renal disease.Medizinische Genetik : Mitteilungsblatt des Berufsverbandes Medizinische Genetik e.V · 2022Article
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Authors and funding
20 authors at 13 institutions in 3 countries.
Funding
Abstract
Proteins containing the FERM (four-point-one, ezrin, radixin, and moesin) domain link the plasma membrane with cytoskeletal structures at specific cellular locations and have been implicated in the localization of cell-membrane-associated proteins and/or phosphoinositides. FERM domain-containing protein 5 (FRMD5) localizes at cell adherens junctions and stabilizes cell-cell contacts. To date, variants in FRMD5 have not been associated with a Mendelian disease in OMIM. Here, we describe eight probands with rare heterozygous missense variants in FRMD5 who present with developmental delay, intellectual disability, ataxia, seizures, and abnormalities of eye movement. The variants are de novo in all for whom parental testing was available (six out of eight probands), and human genetic datasets suggest that FRMD5 is intolerant to loss of function (LoF). We found that the fly ortholog of FRMD5, CG5022 (dFrmd), is expressed in the larval and adult central nervous systems where it is present in neurons but not in glia. dFrmd LoF mutant flies are viable but are extremely sensitive to heat shock, which induces severe seizures. The mutants also exhibit defective responses to light. The human FRMD5 reference (Ref) cDNA rescues the fly dFrmd LoF phenotypes. In contrast, all the FRMD5 variants tested in this study (c.340T>C, c.1051A>G, c.1053C>G, c.1054T>C, c.1045A>C, and c.1637A>G) behave as partial LoF variants. In addition, our results indicate that two variants that were tested have dominant-negative effects. In summary, the evidence supports that the observed variants in FRMD5 cause neurological symptoms in humans.
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Registered trials
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