Craniofacial phenotypes associated with <scp>Robinow</scp> syndrome

Conlon, Christopher J.; Abu‐Ghname, Amjed; Raghuram, Anjali C.; Davis, Matthew J.; Guillen, Diana E.; Sutton, V. Reid; Carvalho, Claudia M.B.; Maricevich, Renata S.

doi:10.1002/ajmg.a.61986

Cited by 10 publications

(16 citation statements)

References 22 publications

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“…Bifid tongue was associated with individuals with pathogenic variants in the DVL1 , ROR2 , GPC4 , or NXN genes but was not observed in individuals with WNT5A -RS. 75 The prevalence of bifid tongue is 38% (N = 3 out of 8) in our cohort of individuals with pathogenic WNT5A variation, comparable with other genotypes. Mesomelia was seen in individuals encompassing all genetic variants except one NXN individual based on previous report.…”

Section: Discussionsupporting

confidence: 71%

Novel pathogenic variants and quantitative phenotypic analyses of Robinow syndrome: WNT signaling perturbation and phenotypic variability

Zhang¹,

Jolly²,

Shayota

et al. 2022

Human Genetics and Genomics Advances

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Summary Robinow syndrome (RS) is a genetically heterogeneous disorder with six genes that converge on the WNT/planar cell polarity (PCP) signaling pathway implicated ( DVL1 , DVL3 , FZD2 , NXN , ROR2 , and WNT5A ). RS is characterized by skeletal dysplasia and distinctive facial and physical characteristics. To further explore the genetic heterogeneity, paralog contribution, and phenotypic variability of RS, we investigated a cohort of 22 individuals clinically diagnosed with RS from 18 unrelated families. Pathogenic or likely pathogenic variants in genes associated with RS or RS phenocopies were identified in all 22 individuals, including the first variant to be reported in DVL2 . We retrospectively collected medical records of 16 individuals from this cohort and extracted clinical descriptions from 52 previously published cases. We performed Human Phenotype Ontology (HPO) based quantitative phenotypic analyses to dissect allele-specific phenotypic differences. Individuals with FZD2 variants clustered into two groups with demonstrable phenotypic differences between those with missense and truncating alleles. Probands with biallelic NXN variants clustered together with the majority of probands carrying DVL1 , DVL2 , and DVL3 variants, demonstrating no phenotypic distinction between the NXN -autosomal recessive and dominant forms of RS. While phenotypically similar diseases on the RS differential matched through HPO analysis, clustering using phenotype similarity score placed RS-associated phenotypes in a unique cluster containing WNT5A , FZD2 , and ROR2 apart from non-RS-associated paralogs. Through human phenotype analyses of this RS cohort and OMIM clinical synopses of Mendelian disease, this study begins to tease apart specific biologic roles for non-canonical WNT-pathway proteins.

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Section: Discussionsupporting

confidence: 71%

Novel pathogenic variants and quantitative phenotypic analyses of Robinow syndrome: WNT signaling perturbation and phenotypic variability

Zhang¹,

Jolly²,

Shayota

et al. 2022

Human Genetics and Genomics Advances

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“…Characteristic facial features of RRS1 (Bacino, 2005; Conlon et al, 2020; Patton & Afzal, 2002) include a broad forehead, broad base of the nose, midface hypoplasia, tented upper lip, micrognathia, hypertelorism, cleft palate, and dental abnormalities. As in this case, endotracheal intubation can be difficult due to midface hypoplasia.…”

Section: Discussionmentioning

confidence: 99%

“…Families affected by missense variants in ROR2 in the literature are predominantly of Turkish (van Bokhoven et al, 2000) and Omani descent. Cranio-facial features of dominant and recessive Robinow syndrome have been recently reviewed by Conlon et al, 2020, in a set of 13 patients with a combination of dominant and recessive Robinow syndrome. However, these patients were between 5 and 51 years old and only three were female.…”

Section: Discussionmentioning

confidence: 99%

Robinow syndrome in an extremely preterm infant: Novel homozygous ROR2 variant detected by rapid exome sequencing

McDermott

Robinson

Caswell

et al. 2021

American J of Med Genetics Pt A

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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.

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“…In parallel, webtools were applied to parsed rare variant data that can predict functional effects of candidate variants into consideration, such as polymorphism phenotyping v2 (PolyPhen‐2), sorting intolerant from tolerant (SIFT), and combined annotation dependent depletion (CADD) (Adzhubei et al, 2010; Kircher et al, 2014; Sim et al, 2012). A B‐allele frequency was calculated from ES data using BafCalculator (Eldomery et al, 2017) to delineate genomic intervals showing absence of heterozygosity (AOH) as a surrogate measure for runs of homozygosity (ROH) and consistent with identity‐by‐descent (IBD).…”

Section: Subject and Methodsmentioning

confidence: 99%

“…We report the genotype and detailed HPO-term-based quantitative phenotypic analyses of 22 patients with biallelic ROR2 variants, aiming to further characterize and expand the phenotypic and genotypic spectrum of ROR2 related AR-RS. The clinical information of three patients was partially included in previous publications: A16 (Beiraghi et al, 2011);A6 and A21 (Abu-Ghname et al, 2021;Conlon et al, 2021;Gerber et al, 2021;Schwartz et al, 2021;Shayota et al, 2020;Zhang et al, 2021).…”

Section: Rs-associated Genes Not Only Encode Components In a Commonmentioning

confidence: 99%

Phenotypic and mutational spectrum of ROR2 ‐related Robinow syndrome

et al. 2022

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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.

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Craniofacial phenotypes associated with Robinow syndrome

Cited by 10 publications

References 22 publications

Novel pathogenic variants and quantitative phenotypic analyses of Robinow syndrome: WNT signaling perturbation and phenotypic variability

Novel pathogenic variants and quantitative phenotypic analyses of Robinow syndrome: WNT signaling perturbation and phenotypic variability

Robinow syndrome in an extremely preterm infant: Novel homozygous ROR2 variant detected by rapid exome sequencing

Phenotypic and mutational spectrum of ROR2 ‐related Robinow syndrome

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