Journal
GENETICS IN MEDICINE
Volume 23, Issue 10, Pages 1889-1900Publisher
SPRINGERNATURE
DOI: 10.1038/s41436-021-01216-8
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Funding
- National Institutes of Health (NIH_ Common Fund) [U01HG007942, U54NS093793, R24OD026591, U01HG007690]
- National Institutes of Health (Office of Strategic Coordination) [U01HG007942, U54NS093793, R24OD026591, U01HG007690]
- National Institutes of Health (Office of the NIH Director) [U01HG007942, U54NS093793, R24OD026591, U01HG007690]
- Genome Canada [OGI-147]
- Ontario Genomics Institute [OGI-147]
- Canadian Institutes of Health Research
- Ontario Research Fund
- Genome Alberta
- Genome British Columbia
- Genome Q8 Quebec
- Children's Hospital of Eastern Ontario Foundation
- Office of Research Infrastructure Programs (ORIP) at NIH [R24OD022005]
- genome disruption project (NIGMS) [GM132087]
- Cullen Foundation
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) at NIH [F32HD100048]
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Variants in GDF11 can lead to abnormalities in the development of multiple organ systems, with partial variants affecting human neuronal development.
Purpose Growth differentiation factor 11 (GDF11) is a key signaling protein required for proper development of many organ systems. Only one prior study has associated an inherited GDF11 variant with a dominant human disease in a family with variable craniofacial and vertebral abnormalities. Here, we expand the phenotypic spectrum associated with GDF11 variants and document the nature of the variants. Methods We present a cohort of six probands with de novo and inherited nonsense/frameshift (4/6 patients) and missense (2/6) variants in GDF11. We generated gdf11 mutant zebrafish to model loss of gdf11 phenotypes and used an overexpression screen in Drosophila to test variant functionality. Results Patients with variants in GDF11 presented with craniofacial (5/6), vertebral (5/6), neurological (6/6), visual (4/6), cardiac (3/6), auditory (3/6), and connective tissue abnormalities (3/6). gdf11 mutant zebrafish show craniofacial abnormalities and body segmentation defects that match some patient phenotypes. Expression of the patients' variants in the fly showed that one nonsense variant in GDF11 is a severe loss-of-function (LOF) allele whereas the missense variants in our cohort are partial LOF variants. Conclusion GDF11 is needed for human development, particularly neuronal development, and LOF GDF11 alleles can affect the development of numerous organs and tissues.
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