Dataset Information

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.

SUBMITTER: Lima AR

PROVIDER: S-EPMC9177636 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.

Lima Ariadne R AR Ferreira Barbara M BM Zhang Chaofan C Jolly Angad A Du Haowei H White Janson J JJ Dawood Moez M Lins Tulio C TC Chiabai Marcela A MA van Beusekom Ellen E Cordoba Mara S MS Caldas Rosa Erica C C ECC Kayserili Hulya H Kimonis Virginia V Wu Erica E Mellado Cecilia C Aggarwal Vineet V Richieri-Costa Antonio A Brunoni Décio D Canó Talyta M TM Jorge Alexander A L AAL Kim Chong A CA Honjo Rachel R Bertola Débora R DR Dandalo-Girardi Raissa M RM Bayram Yavuz Y Gezdirici Alper A Yilmaz-Gulec Elif E Gumus Evren E Yilmaz Gülay C GC Okamoto Nobuhiko N Ohashi Hirofumi H Coban-Akdemir Zeynep Z Mitani Tadahiro T Jhangiani Shalini N SN Muzny Donna M DM Regattieri Neysa A P NAP Pogue Robert R Pereira Rinaldo W RW Otto Paulo A PA Gibbs Richard A RA Ali Bassam R BR van Bokhoven Hans H Brunner Han G HG Sutton V Reid VR Lupski James R JR Vianna-Morgante Angela M AM Carvalho Claudia M B CMB Mazzeu Juliana F JF

Human mutation 20220510 7

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 autosoma ...[more]

PMID: 35344616

Similar Datasets

Project description:BackgroundThe TUBA1A-associated tubulinopathy is clinically heterogeneous with brain malformations, microcephaly, developmental delay and epilepsy being the main clinical features. It is an autosomal dominant disorder mostly caused by de novo variants in TUBA1A.ResultsIn three individuals with developmental delay we identified heterozygous de novo missense variants in TUBA1A using exome sequencing. While the c.1307G > A, p.(Gly436Asp) variant was novel, the two variants c.518C > T, p.(Pro173Leu) and c.641G > A, p.(Arg214His) were previously described. We compared the variable phenotype observed in these individuals with a carefully conducted review of the current literature and identified 166 individuals, 146 born and 20 fetuses with a TUBA1A variant. In 107 cases with available clinical information we standardized the reported phenotypes according to the Human Phenotype Ontology. The most commonly reported features were developmental delay (98%), anomalies of the corpus callosum (96%), microcephaly (76%) and lissencephaly (agyria-pachygyria) (70%), although reporting was incomplete in the different studies. We identified a total of 121 specific variants, including 15 recurrent ones. Missense variants cluster in the C-terminal region around the most commonly affected amino acid position Arg402 (13.3%). In a three-dimensional protein model, 38.6% of all disease-causing variants including those in the C-terminal region are predicted to affect the binding of microtubule-associated proteins or motor proteins. Genotype-phenotype analysis for recurrent variants showed an overrepresentation of certain clinical features. However, individuals with these variants are often reported in the same publication.ConclusionsWith 166 individuals, we present the most comprehensive phenotypic and genotypic standardized synopsis for clinical interpretation of TUBA1A variants. Despite this considerable number, a detailed genotype-phenotype characterization is limited by large inter-study variability in reporting.

Dataset Information

Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.

Publications

Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets