GDF5 – Acromesomelic Dysplasia Type Grebe

Autosomal recessive acromesomelic dysplasia type Grebe (Grebe dysplasia; MONDO:0008703) is characterized by severe shortening of middle and distal limb segments with knob-like, nonfunctional digits and follows a proximo-distal gradient of severity. Growth differentiation factor 5 (GDF5; HGNC:4220) encodes a BMP family ligand essential for limb patterning and joint formation.

Patients born to consanguineous parents have been found homozygous for loss-of-function GDF5 variants. A 4-year-old boy homozygous for insG206 frameshift (predicted haploinsufficiency) presented with classic Grebe dysplasia ([PMID:12687891]). In a Pakistani kindred, two siblings homozygous for c.1114insGAGT (p.Arg372GlufsTer34) showed severe acromesomelic micromelia with minimal axial involvement and associated myopia ([PMID:26870132]).

Linkage and sequencing in two additional consanguineous families identified homozygous duplication c.157_158dupC (p.Leu53ProfsTer41), and a nonsense variant p.Trp291Ter, each segregating with disease in multiple affected relatives ([PMID:27577507]). Across these studies, at least seven unrelated probands exhibit biallelic GDF5 loss-of-function variants and uniform AR segregation.

The variant spectrum comprises frameshift insertions/duplications (insG206, c.1114insGAGT, c.157_158dupC), nonsense mutations (p.Trp291Ter), and in one case missense changes predicted to disrupt processing motifs, all consistent with a haploinsufficiency mechanism. No dominant-negative effects have been observed in severe Grebe phenotypes.

Functional evidence supports pathogenicity via loss of GDF5 signaling: predicted haploinsufficiency from premature stop codons, disrupted pro-domain processing, and gradient-dependent effects on chondrogenesis mirror the clinical severity spectrum from heterozygous brachydactyly type C to homozygous Grebe dysplasia.

Collectively, these data meet ClinGen criteria for a Definitive gene-disease relationship. GDF5 LoF variants reliably predict Grebe dysplasia in an AR inheritance pattern; genetic testing enables accurate diagnosis, carrier detection, and appropriate genetic counseling.

References

• Pediatric pathology & molecular medicine • 2003 • Grebe dysplasia and the spectrum of CDMP1 mutations. [PMID:12687891]
• Pakistan journal of medical sciences • 2015 • Recurrent mutation in CDMP1 in a family with Grebe chondrodysplasia: broadening the phenotypic manifestation of syndrome in Pakistani population. [PMID:26870132]
• Congenital anomalies • 2017 • Novel homozygous sequence variants in the GDF5 gene underlie acromesomelic dysplasia type-grebe in consanguineous families. [PMID:27577507]
  

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