Robinow Syndrome and Autosomal Recessive Brachydactyly, Type B1 via the ROR2 Gene

Robinow syndrome is characterized by dysmorphic facial features, short stature, genital hypoplasia, shortening of the forearms, and other skeletal abnormalities. All patients exhibit hypertelorism and a small upturned nose. The majority of patients also have frontal bossing, prominent eyes, downslanting palpebral fissures, long philtrum, downturned triangular mouth, micrognathia, and crowded teeth. Mesomelic shortness is another universal finding, and most patients have small hands with clinodactyly. Thumbs and great toes are sometimes broad. Vertebral anomalies distinguish recessive Robinow syndrome (OMIM 268310) resulting from ROR2 variants from the dominant form (see below). Patients with recessive Robinow syndrome often have thoracic hemivertebrae, rib anomalies, and scoliosis, while patients with the dominant form do not (von Bokhoven et al. Nature Genet 25:423-426, 2000). Brachydactyly occurs as part of many syndromes or as an isolated finding. ROR2-associated type B brachydactyly (OMIM 113000) can be distinguished from other nonsyndromic forms by shortening and hypoplasia of the distal phalanges, dysplasia or aplasia of the nails, and hypoplasia of the middle phalanges (Schwabe et al. Am J Hum Genet 67:822-831, 2000). Other distinguishing features are biphalangeal digits, syndactyly, and bilateral symmetry of the abnormalities (Oldridge et al. Nature Genet 24:275-278, 2000).

Both autosomal recessive and dominant forms of Robinow syndrome are known. Recessive Robinow syndrome is associated with loss of function variants in ROR2 (Ali et al. Nat Genet 25:419-422, 2000), many of which result in defective intracellular trafficking (Ali et al. Hum Genet 122:389-395, 2007). The ROR2 gene (OMIM 602337) encodes a cell surface receptor tyrosine kinase involved in development of the skeletal, cardiovascular, and genital systems. The etiology of dominant Robinow syndrome, which is clinically milder and probably the rarer form, is unknown. Type B1 brachydactyly is inherited as an autosomal dominant condition. Variants that lead to truncation of the intracellular part of the protein after the tyrosine kinase domain cause dominant brachydactyly via a gain of function mechanism (Oldridge et al. 2000; Schwabe et al. 2000).

Clinical sensitivity should be high for Robinow syndrome when patients meet strict phenotypic criteria and evidence exists for recessive inheritance. Analytic sensitivity may be limited due to the presence of intragenic deletions (Brunetti-Pierri et al. Am J Med Genet 146A:2804-2809, 2008). Clinical and analytical sensitivity for type B1 brachydactyly should be high in cases with characteristic findings of the phalanges.

This test provides full coverage of all coding exons of the ROR2 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).