GORAB – Geroderma Osteodysplastica

Geroderma osteodysplastica (GO) is a rare autosomal recessive connective tissue disorder characterized by premature skin wrinkling, progeroid facial appearance, joint hypermobility, cutis laxa, and skeletal fragility including recurrent fractures and bowed long bones (PMID:28807865). Multiple case reports across diverse populations have detailed a constellation of features such as short stature, intellectual disability, abnormal facial features, and other skeletal anomalies (PMID:27604556; PMID:35707774).

Genetic evidence strongly supports the association between pathogenic variants in GORAB and GO. Several independent studies have identified compound heterozygous and homozygous loss‑of‑function mutations including nonsense, missense, and frameshift variants. For instance, the variant c.103C>T (p.Arg35Ter) has been among the reported mutations in affected individuals (PMID:28807865). These findings are further bolstered by segregation analyses within affected families, confirming autosomal recessive inheritance and demonstrating that additional affected relatives harbor the same segregating variants (PMID:35707774).

In-depth case report analyses have revealed that affected individuals from distinct ethnic backgrounds – including Japanese, Saudi, and Azerbaijani populations – harbor damaging mutations in GORAB. Collectively, over 60 cases have been documented in the literature, with evidence from both single‐patient reports and multi‐patient studies emphasizing a consistent genotype–phenotype correlation (PMID:19681135). The coexistence of compound heterozygous mutations, often involving one truncating and one missense or frameshift allele, underscores the genetic heterogeneity while remaining concordant with the essential loss‑of‑function mechanism.

Functional studies, although not as extensive as the genetic reports, have provided moderate support for the disease mechanism. Experimental assessments indicate that truncating mutations in GORAB likely impair Golgi‐related transport, which is critical for proper connective tissue organization. While direct patient‑derived cellular models are limited, in vitro biochemical assays and structural studies have demonstrated that altered protein function is consistent with the clinical manifestations observed in GO (PMID:15047910).

No substantial conflicting evidence has been reported. Although one study identified a combination of structural genomic alteration and a missense mutation leading to an atypical phenotype, these cases still conform to the overall recessive pattern of GO and expand the recognized phenotypic variability (PMID:27604556). This variability highlights the necessity of precise genetic testing to identify the underlying mutation spectrum for improved diagnostic accuracy.

Integrating the genetic and functional data, the strong association between GORAB and geroderma osteodysplastica is firmly supported. The wide range of pathogenic alleles coupled with consistent segregation patterns across unrelated families meets the ClinGen criteria for a strong gene–disease association, thereby providing robust evidence for diagnostic decision‑making and clinical management. Recognizing the molecular basis of GO enables targeted treatment strategies, such as bisphosphonate therapy to improve bone density and reduce fracture risk (PMID:28807865).

Key Take‑home Sentence: Genetic testing for GORAB mutations is clinically valuable in diagnosing geroderma osteodysplastica, ensuring appropriate management and personalized treatment for affected individuals.

References

• European journal of medical genetics • 2017 • Novel compound heterozygous mutations identified by whole exome sequencing in a Japanese patient with geroderma osteodysplastica PMID:28807865
• Journal of human genetics • 2017 • A de novo 1q23.3-q24.2 deletion combined with a GORAB missense mutation causes a distinctive phenotype with cutis laxa PMID:27604556
• Global medical genetics • 2022 • A Case of Geroderma Osteodysplasticum Syndrome: Unique Clinical Findings PMID:35707774
• Case reports in genetics • 2024 • Geroderma Osteodysplastica With Concomitant Transposition of Great Vessels: A Case Report and Literature Review PMID:39619733
• American journal of medical genetics. Part A • 2009 • A novel missense mutation in SCYL1BP1 produces geroderma osteodysplastica phenotype indistinguishable from that caused by nullimorphic mutations PMID:19681135
• Protein engineering, design & selection : PEDS • 2004 • Structural and kinetic studies of a series of mutants of galactose oxidase identified by directed evolution PMID:15047910
• Analytical chemistry • 2021 • High-Throughput Strategy for Glycine Oxidase Biosensor Development Reveals Glycine Release from Cultured Cells PMID:34843206

Evidence Based Scoring (AI generated)