Dataset Information

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.

SUBMITTER: Ravenscroft TA

PROVIDER: S-EPMC8487929 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Publications

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

Ravenscroft Thomas A TA Phillips Jennifer B JB Fieg Elizabeth E Bajikar Sameer S SS Peirce Judy J Wegner Jeremy J Luna Alia A AA Fox Eric J EJ Yan Yi-Lin YL Rosenfeld Jill A JA Zirin Jonathan J Kanca Oguz O Benke Paul J PJ Cameron Eric S ES Strehlow Vincent V Platzer Konrad K Jamra Rami Abou RA Klöckner Chiara C Osmond Matthew M Licata Thomas T Rojas Samantha S Dyment David D Chong Josephine S C JSC Lincoln Sharyn S Stoler Joan M JM Postlethwait John H JH Wangler Michael F MF Yamamoto Shinya S Krier Joel J Westerfield Monte M Bellen Hugo J HJ

Genetics in medicine : official journal of the American College of Medical Genetics 20210610 10

<h4>Purpose</h4>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.<h4>Methods</h4>We present a cohort of six probands with de novo and inherited nonsense/f ...[more]

PMID: 34113007

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Dataset Information

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

Purpose

Methods

Results

Conclusion

Publications

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

Similar Datasets

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