Robinow syndrome is characterized by a triad of craniofacial dysmorphisms, disproportionate-limb short stature, and genital hypoplasia. A significant degree of phenotypic variability seems to correlate with different genes/loci. Disturbances of the noncanonical WNT-pathway have been identified as the main cause of the syndrome. Biallelic variants in ROR2 cause an autosomal recessive form of the syndrome with distinctive skeletal findings. Twenty-two patients with a clinical diagnosis of autosomal recessive Robinow syndrome were screened for variants in ROR2 using multiple molecular approaches. We identified 25 putatively pathogenic ROR2 variants, 16 novel, including single nucleotide variants and exonic deletions. Detailed phenotypic analyses revealed that all subjects presented with a prominent forehead, hypertelorism, short nose, abnormality of the nasal tip, brachydactyly, mesomelic limb shortening, short stature, and genital hypoplasia in male patients. A total of 19 clinical features were present in more than 75% of the subjects, thus pointing to an overall uniformity of the phenotype. Disease-causing variants in ROR2, contribute to a clinically recognizable autosomal recessive trait phenotype with multiple skeletal defects. A comprehensive quantitative clinical evaluation of this cohort delineated the phenotypic spectrum of ROR2-related Robinow syndrome. The identification of exonic deletion variant alleles further supports the contention of a loss-of-function mechanism in the etiology of the syndrome.

We present five members of a consanguineous Pakistani kinship with the most severe familial tetramelic transverse autopod deficiency reported to date and additionally having some of the common autosomal recessive Robinow syndrome-1 (RRS1) features including short stature, short neck, severe vertebral anomalies of kyphoscoliosis, hemivertebrae, fusion of thoracic vertebrae, broad forehead, and dental crowding. We mapped the locus of this atypical RRS and detected homozygous 8-nucleotide deletion c.1353_1360del (p.(Met452Alafs*4)) in ROR2, the gene responsible for RRS1. We did not find any other variant shared by all affected individuals that could possibly act as a modifier of limb defect. Autopods are affected in RRS1, but severe autopod deficiency is not a characteristic feature. Over 30 biallelic variants dispersed throughout the gene are known in ROR2-related RS, with no genotype-phenotype correlation for specific RRS1 features. Considering together with the sporadic case homozygous for variant p.(Arg442*) and the case homozygous for p.(Arg441Thrfs*16) in a family where heterozygous members have brachydactyly type B1, we propose that homozygous truncating variants that originate at residues 441-452 can cause severe autopod reduction anomalies, suggesting some genotype-phenotype correlation for this particular phenotype.

An extremely preterm infant presented with clinical and radiological features of Robinow syndrome including butterfly vertebrae, posterior rib fusion, brachydactyly, nail hypoplasia, and retromicrognathia resulting in difficult endotracheal intubation in the intensive care setting. Rapid trio exome sequencing detected a novel homozygous likely pathogenic missense variant in the ROR2 gene, NM_004560.3:c.950A>G, p.(Tyr317Cys), for which both parents were heterozygous carriers. In-silico protein modeling predicted a deleterious effect on the function of the protein. We report an extreme premature infant with novel homozygous likely pathogenic variant in the ROR2 gene consistent with autosomal recessive Robinow syndrome. This case expands the phenotypic and genotypic spectrum of this disorder and highlights the benefit of performing rapid exome sequencing early during evaluation to aid in patient management and providing accurate genetic counseling to families.

Autosomal recessive Robinow syndrome (ARRS) is a rare genetic disorder, which affects the development of multiple systems, particularly the bones. The aim of this study was to investigate the genetic cause of a ARRS fetus and to evaluate the reliability of whole-exome sequencing (WES) in prenatal diagnosis on cases with indistinguishable multiple malformation. Clinical and ultrasonic evaluations were conducted on the fetus, and multiplatform genetic techniques were used to identify the variation responsible for RS. The pathogenicity of the novel variation was evaluated by in silico methods. Western blotting (WB) and immunohistochemistry (IHC) were performed on fetal tissues after the fetus' stillbirth and postabortal autopsy. A compound heterozygous variation consisting c.613C > T and c.904C > T in ROR2 gene was identified. In silico prediction suggested that c.904C > T was a deleterious variant. IHC result demonstrated that ror2 expression level of the proband in osteochondral tissue significantly increased comparing with that of the control sample. For the first time in Chinese population, we characterized a novel variation in ROR2 gene causing ARRS. This study extended the mutation spectrum of ARRS and provided a promising strategy for prenatal diagnosis of cases with ambiguous multiple deformities.