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

Abstract

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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Fig. 1: Overview of patients with GDF11 variants.
Fig. 2: GDF11 is conserved across species.
Fig. 3: Zebrafish models of gdf11 loss of function exhibit craniofacial and body axis patterning defects.
Fig. 4: Patient variants behave as strong or mild loss-of-function alleles in flies.

Data and code availability

The paper includes all data sets/code generated or analyzed during this study.

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Acknowledgements

We thank the patients and their families who participated in this study. The research reported in this paper was supported by the National Institutes of Health (NIH_ Common Fund, the Office of Strategic Coordination and Office of the NIH Director under award numbers U01HG007942 (BCM sequencing core), U54NS093793 (Model Organism Screening Center of the Undiagnosed Diseases Network), R24OD026591 (J.H.P and M.W), and U01HG007690 (BWH clinical site). The Care4Rare Research Consortium performed the reanalysis of the exome data for patient 5 and is funded by Genome Canada and the Ontario Genomics Institute (OGI-147), the Canadian Institutes of Health Research, Ontario Research Fund, Genome Alberta, Genome British Columbia, Genome Q8 Quebec, and Children’s Hospital of Eastern Ontario Foundation. H.J.B. and S.Y. are supported by R24OD022005 from the Office of Research Infrastructure Programs (ORIP) at NIH. myo-T2A-GAL4 generation was funded as part of the genome disruption project (NIGMS GM132087). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. T.A.R. has been supported by The Cullen Foundation. S.S.B. is supported by F32HD100048 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) at NIH. H.J.B. is an investigator of the Howard Hughes Medical Institute.

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Contributions

Conceptualization: T.A.R, J.B.P., E.F., S.S.B., U.D.N., J.H.P., M.F.W., S.Y., J.K., M.W., H.J.B. Data curation: T.A.R., J.B.P., J.A.R., J.Z., O.K., P.J.B, E.S.C., V.S., K.P., R.A.J., C.K., M.O., T.L., S.R., D.D., J.S.C.C., S.L., J.M.S., J.K. Formal analysis: T.A.R., J.B.P., S.S.B; Funding acquisition: T.A.R., S.S.B., U.D.N., J.H.P., M.F.W., S.Y., J.K., M.W., H.J.B., D.D. Investigation: T.A.R, J.B.P., S.S.B., J.P., A.A.L., E.J.F., Y.L.Y., J.Z. Resources: T.A.R., J.B.P, E.F., S.S.B, J.Z, O.K. Supervision: T.A.R, J.B.P; Visualization: T.A.R, J.B.P. Writing—original draft: T.A.R. Writing—review & editing: T.A.R, J.B.P., E.F., S.S.B., A.A.L, J.A.R, J.Z., O.K., P.J.B., V.S., D.D., J.S.C.C., J.H.P., S.Y., J.K., M.W., H.J.B.

Corresponding author

Correspondence to Hugo J. Bellen.

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Ethics declaration

Written informed consent for genetic testing and publication of relevant findings and photographs was obtained from all patients or their parents. Research using patient cells is approved by the Institutional Review Board for Human Subject Research for Baylor College of Medicine and Affiliated Hospitals (BCM IRB) for translational models of neurological disease at the neurological research institute (Human Subjects Assurance Number: 00000286). The BCM IRB is organized, operates, and is registered with the United States Office for Human Research Protections according to the regulations codified in the United States Code of Federal Regulations at 45 CFR 46 and 21 CFR 56. The BCM IRB operates under the BCM Federal Wide Assurance Number 00000286, as well as those of hospitals and institutions affiliated with the College. Zebrafish were raised and all experiments were conducted according to standard protocols approved by the University of Oregon Institutional Animal Care and Use Committee (IACUC).

Competing interests

The Department of Molecular and Human Genetics at Baylor College of Medicine receives revenue from clinical genetic testing conducted at Baylor Genetics Laboratories. The other authors declare no competing interests.

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Ravenscroft, T.A., Phillips, J.B., Fieg, E. et al. Heterozygous loss-of-function variants significantly expand the phenotypes associated with loss of GDF11. Genet Med (2021). https://doi.org/10.1038/s41436-021-01216-8

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