Background: Geroderma osteodysplasticum (GO; MIM #231070) is a rare autosomal recessive connective tissue disorder characterized by lax, wrinkled skin of the acral extremities, joint hypermobility, short stature, and skeletal fragility with osteopenia. Biallelic loss-of-function variants in GORAB are an established cause of the disorder.
Case Presentation: A 12-year-old girl presented with recurrent low-trauma fractures, blue sclerae, generalized joint hypermobility, and wrinkled, lax skin of the dorsa of the hands and feet; bilateral congenital hip dislocation had been treated in infancy. Serum calcium, phosphorus, alkaline phosphatase (ALP), intact parathyroid hormone (PTH), 25-OH vitamin D, and renal function (creatinine, BUN) were all within reference limits, arguing against metabolic or renal bone disease. Whole-exome sequencing (WES) identified a novel homozygous nonsense variant in GORAB exon 4, NM_152281.3:c.535C>T (p.Gln179Ter), absent from gnomAD v2.1.1/v3.1.2, ExAC, 1000 Genomes, ClinVar, and the Human Gene Mutation Database (HGMD).
Variant Interpretation and Diagnostic Considerations: Applying American College of Medical Genetics and Genomics / Association for Molecular Pathology (ACMG/AMP) criteria, the variant met PVS1 (applied on the basis of predicted nonsense-mediated mRNA decay (NMD) combined with the known loss-of-function disease mechanism of GORAB), PM2_Supporting, and PP4, yielding a classification of likely pathogenic. Parental segregation testing was not performed owing to financial constraints, and no functional validation was undertaken.
Conclusion: The combination of documented clinical findings and the identified variant extends the observed GORAB variant spectrum. However, because segregation in both parents could not be tested, the molecular findings remain provisional and do not constitute a definitive molecular diagnosis; parental segregation testing remains indispensable for confirmation.