PUBLICATION

Heterozygous loss-of-function variants significantly expand the phenotypes associated with loss of GDF11

Authors
Ravenscroft, T.A., Phillips, J.B., Fieg, E., Bajikar, S.S., Peirce, J., Wegner, J., Luna, A.A., Fox, E.J., Yan, Y.L., Rosenfeld, J.A., Zirin, J., Kanca, O., Undiagnosed Diseases Network, Benke, P.J., Cameron, E.S., Strehlow, V., Platzer, K., Jamra, R.A., Klöckner, C., Osmond, M., Licata, T., Rojas, S., Dyment, D., Chong, J.S.C., Lincoln, S., Stoler, J.M., Postlethwait, J.H., Wangler, M.F., Yamamoto, S., Krier, J., Westerfield, M., Bellen, H.J.
ID
ZDB-PUB-210612-1
Date
2021
Source
Genetics in medicine : official journal of the American College of Medical Genetics   23(10): 1889-1900 (Journal)
Registered Authors
Peirce, Judy, Phillips, Jennifer, Wegner, Jeremy, Yan, Yi-Lin
Keywords
none
MeSH Terms
  • Animals
  • Bone Morphogenetic Proteins*/genetics
  • Craniofacial Abnormalities/genetics*
  • Growth Differentiation Factors*/genetics
  • Humans
  • Mutation, Missense
  • Phenotype
  • Spine
  • Zebrafish/genetics
PubMed
34113007 Full text @ Genet. Med.
Abstract
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.
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.
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.
GDF11 is needed for human development, particularly neuronal development, and LOF GDF11 alleles can affect the development of numerous organs and tissues.
Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping