Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.

TitlePhenotypic and mutational spectrum of ROR2-related Robinow syndrome.
Publication TypeJournal Article
Year of Publication2022
AuthorsLima, AR, Ferreira, BM, Zhang, C, Jolly, A, Du, H, White, JJ, Dawood, M, Lins, TC, Chiabai, MA, van Beusekom, E, Cordoba, MS, Rosa, ECCCaldas, Kayserili, H, Kimonis, V, Wu, E, Mellado, C, Aggarwal, V, Richieri-Costa, A, Brunoni, D, Canó, TM, Jorge, AAL, Kim, CA, Honjo, R, Bertola, DR, Dandalo-Girardi, RM, Bayram, Y, Gezdirici, A, Yilmaz-Gulec, E, Gumus, E, Yilmaz, GC, Okamoto, N, Ohashi, H, Coban-Akdemir, Z, Mitani, T, Jhangiani, SN, Muzny, DM, Regattieri, NAP, Pogue, R, Pereira, RW, Otto, PA, Gibbs, RA, Ali, BR, van Bokhoven, H, Brunner, HG, V Sutton, R, Lupski, JR, Vianna-Morgante, AM, Carvalho, CMB, Mazzeu, JF
JournalHum Mutat
Date Published2022 Jul
KeywordsCraniofacial Abnormalities, Dwarfism, Genes, Recessive, Humans, Limb Deformities, Congenital, Male, Phenotype, Receptor Tyrosine Kinase-like Orphan Receptors, Urogenital Abnormalities

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.

Alternate JournalHum Mutat
PubMed ID35344616
PubMed Central IDPMC9177636
Grant ListUM1HG006542 / HG / NHGRI NIH HHS / United States
UM1 HG006542 / HG / NHGRI NIH HHS / United States
R03 HD092569 / HD / NICHD NIH HHS / United States
R35 NS105078 / NS / NINDS NIH HHS / United States
R01 GM132589 / GM / NIGMS NIH HHS / United States

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