Phenotypic and mutational spectrum of ROR2 ‐related Robinow syndrome

Abstract

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.

Rare variant enrichment analysis supports GREB1L as a contributory driver gene in the etiology of Mayer-Rokitansky-Küster-Hauser syndrome

“…To visualize phenotypic overlap quantitatively, clinical phenotype descriptors for MRKH type II probands (33 MRKH type II probands and 38 MRKH type I probands) from these 71 were converted to HPO terms and used in a symmetric computational analysis, in which phenotypic similarity is calculated between the query and target HPO term sets and vice versa as described. 50 , 51 , 52 Using the Lin method for symmetric phenotypic similarity calculation, each proband’s term set was compared with each other proband’s phenotypic term set ( Figure 3 and materials and methods ). 50 , 51 , 52 Of the five GREB1L probands included in this HPO analysis, four clustered into a group ( Figure 3 , top left) representing patients with an additional phenotype of renal agenesis while one was present in a group ( Figure 3 , bottom right) of patients with an additional phenotype of renal ectopia.…”

“… 50 , 51 , 52 Using the Lin method for symmetric phenotypic similarity calculation, each proband’s term set was compared with each other proband’s phenotypic term set ( Figure 3 and materials and methods ). 50 , 51 , 52 Of the five GREB1L probands included in this HPO analysis, four clustered into a group ( Figure 3 , top left) representing patients with an additional phenotype of renal agenesis while one was present in a group ( Figure 3 , bottom right) of patients with an additional phenotype of renal ectopia.

Figure 3 GREB1L probands cluster within a phenotypic group including uterine and renal malformations Heatmap represents symmetric Lin score for proband HPO terms queried against each other.

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Prenatal diagnosis of ROR‐2 related Robinow syndrome presenting with fetal ultrasound findings of mesomelia, vertebral, digital and genital abnormalities

“…Robinow syndrome is a genetically heterogenous condition more commonly associated with autosomal dominant pathogenic variants in the DVL1, DVL3, or WNT5A genes 1 . Autosomal recessive ROR2 ‐Robinow syndrome (RRS) is caused by pathogenic variants in the ROR2 gene 2 …”

The non-canonical Wnt receptor Ror2 is required for cartilage cell polarity and morphogenesis of the craniofacial skeleton in zebrafish

“…Growing evidence suggests that Ror2 plays an essential role in non-canonical Wnt signaling, both in skeletal development and evolution. Human mutations in ROR2 can cause Robinow syndrome ( Afzal et al, 2000 ; Lima et al, 2022 ; Person et al, 2010 ; van Bokhoven et al, 2000 ; White et al, 2018 ), as well as Brachydactyly type B1 ( Oldridge et al, 2000 ; Schwabe et al, 2000 ), including autosomal recessive forms resembling our ror2 −/− mutant zebrafish. Both of these disorders are characterized by defects in elongation of endochondral bones, consistent with defects in cartilage morphogenesis during embryogenesis and later in developing growth zones.…”

“…Defects in a growing list of PCP components in the Wnt-PCP and Fat-Dchs pathways cause a variety of human syndromes that affect skeletogenesis. For non-canonical Wnt signaling these include both autosomal dominant and recessive forms of Robinow syndrome ( ROR2 , WNT5A , DVL1 , DVL3 , FZD2 , NXN ) ( Afzal et al, 2000 ; Lima et al, 2022 ; Person et al, 2010 ; van Bokhoven et al, 2000 ; White et al, 2018 ), Brachydactyly type B1 ( ROR2 ) ( Oldridge et al, 2000 ; Schwabe et al, 2000 ), Kleipert syndrome ( Amor et al, 2019 ) and Simpson-Golabi-Behmel syndrome type 1 ( GPC4 ) ( Waterson et al, 2010 ). For Fat-Dchs signaling they include Van Maldergem ( DCHS1 , FAT4 ) ( Cappello et al, 2013 ) and Hennekam ( FAT4 ) ( Alders et al, 2014 ) syndromes.…”