ROR2 – Autosomal Recessive Robinow Syndrome

Receptor tyrosine kinase-like orphan receptor 2 (ROR2) mediates noncanonical WNT/planar cell polarity signaling essential for skeletal morphogenesis. Biallelic loss-of-function variants in ROR2 cause autosomal recessive Robinow syndrome, a rare disorder characterized by disproportionate short-limb dwarfism, craniofacial dysmorphism, and genital hypoplasia. The recessive form is clinically distinct from autosomal dominant brachydactyly type B and highlights the pivotal role of ROR2 dosage in human development.

Genetic mapping in 11 families localized recessive Robinow syndrome to 9q22-q23, implicating ROR2 in the autosomal recessive form (11 families) (PMID:10932187). Subsequent studies identified homozygous nonsense and missense mutations in at least 10 additional unrelated families, confirming a loss-of-function mechanism (10 families) (PMID:10932186). Rapid exome sequencing in a preterm infant revealed a novel homozygous missense variant c.950A>G (p.Tyr317Cys) consistent with autosomal recessive inheritance (PMID:34558814).

Affected individuals consistently present with short stature (HP:0004322), mesomelia (HP:0003027), brachydactyly (HP:0001156), hypertelorism (HP:0000316), and macrocephaly (HP:0000256). Segregation analysis across consanguineous pedigrees demonstrated co-segregation of ROR2 variants with disease in 10 families, supporting robust clinical validity.

Functional assays in cell models show that Robinow-causing ROR2 mutants are misfolded and retained in the endoplasmic reticulum, abrogating WNT5A–PCP signaling (PMID:17665217). Mouse knock-in models carrying truncating Ror2 alleles recapitulate the human phenotype, confirming dosage sensitivity and loss-of-function as the pathogenic mechanism (PMID:18353862).

Overall, extensive genetic, segregation, and functional data establish a Definitive gene–disease relationship between ROR2 and autosomal recessive Robinow syndrome. Clinical diagnostic sequencing of ROR2 enables precise molecular diagnosis, informed genetic counseling, prenatal testing, and tailored patient management. Key take-home: biallelic ROR2 loss-of-function variants are a definitive molecular cause of recessive Robinow syndrome, underpinning accurate genotype-driven clinical care.

References

• Nature Genetics | 2000 | Mutation of the gene encoding the ROR2 tyrosine kinase causes autosomal recessive Robinow syndrome. PMID:10932187
• Nature Genetics | 2000 | Recessive Robinow syndrome, allelic to dominant brachydactyly type B, is caused by mutation of ROR2. PMID:10932186
• American Journal of Medical Genetics Part A | 2022 | Robinow syndrome in an extremely preterm infant: Novel homozygous ROR2 variant detected by rapid exome sequencing. PMID:34558814
• Human Genetics | 2007 | Novel Robinow syndrome causing mutations in the proximal region of the frizzled-like domain of ROR2 are retained in the endoplasmic reticulum. PMID:17665217
• Development | 2008 | The mutation ROR2W749X, linked to human BDB, is a recessive mutation in the mouse, causing brachydactyly, mediating patterning of joints and modeling recessive Robinow syndrome. PMID:18353862

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