Identification of Novel ROR2 Gene Mutations in Indian Children with Robinow Syndrome

Abstract

Ob­jec­ti­ve: Robinow syndrome (RS) is an extremely rare genetic disorder characterized by short-limbed dwarfism, defects in vertebral segmentation and abnormalities in the head, face and external genitalia. Mutations in the ROR2 gene cause autosomal recessive RS (RRS) whereas mutations in WNT5A are responsible for the autosomal dominant (AD) form of RS. In AD Robinow patients, oral manifestations are more prominent, while hemivertebrae and scoliosis rarely occur and facial abnormalities tend to be milder.Methods: Three unrelated patients from different parts of India were studied. These patients were diagnosed as RRS due to presence of characteristic fetal facies, mesomelia, short stature, micropenis, hemivertebrae and rib abnormalities. One of the patients had fetal facies and micropenis but unusually mild skeletal features. This patient’s mother had mild affection in the form of short stature and prominent eyes. Testosterone response to human chorionic gonadotropin was investigated in two patients and were normal. The exons and exon-intron boundaries of the ROR2 gene were sequenced for all probands. Bioinformatics analysis was done for putative variants using SIFT, PolyPhen2 and Mutation Taster.Results: Patients 1, 2 and 3 were homozygous for c.G545A or p.C182Y in exon 5, c.227G>A or p.G76D in exon 3 and c.668G>A or p.C223Y in exon 6 respectively. Prenatal diagnosis could be performed in an ongoing pregnancy in one family and the fetus was confirmed to be unaffected. Conclusion: ROR2 mutations were documented for the first time in the Indian population. Knowledge of the molecular basis of the disorder served to provide accurate counseling and prenatal diagnosis to the families.

Clinical and molecular characterization of seven Egyptian families with autosomal recessive robinow syndrome: Identification of four novel ROR2 gene mutations

“…Over 100 cases of RS have been reported to date, with an incidence of 1:500,000 with no sex preference [Tamhankar et al, ]. Autosomal recessive RS had been described in patients from various ethnic groups [Nazer et al, ; Balci et al, ; Aksit et al, ; Afzal et al, ; Kulkarni and Reddy, ; Mazzeu et al, ; Mehawej et al, ; Tamhankar et al, ]. Although, molecular studies were reported only in one Egyptian family with ARRS [Ali et al, ], other previous reports suggested AR inheritance in Egyptian patients with RS [El‐Ruby et al, ; Meguid and Aglan, ; Temtamy et al, ].…”

“…Three of our patients had ASD and PS while one patient had VSD. Among the abnormalities reported are bicuspid aortic valve, tetralogy of Fallot, ASD, VSD, and coarctation of aorta, but the commonest appears to be PS [Patton and Afzal, ; Tamhankar et al, ]. El‐Ruby et al [], in their report of the first Egyptian patients with RS, described dextrocardia in one patient and PS in two other patients with RS.…”

“…Homozygous or compound heterozygous loss of function mutations in ROR2 , an orphan receptor tyrosin kinase, were shown to cause ARRS [Afzal et al, ; van Bokhoven et al, ]. To date, about eighteen distinct pathogenic mutations have been identified in RS patients in various domains of the ROR2 protein [Afzal et al, ; van Bokhoven et al, ; Tufan et al, ; Ali et al, ; Brunetti‐Pierri et al, ; Mehawej et al, ; Tamhankar et al, ]. Table summarizes all ROR2 mutations identified so far in the literature causing ARRS including those identified in our study.…”

Orofacial Manifestations of Robinow’s Syndrome: 5 years Follow-up Case

“…The mutated gene responsible for RRS has been identified as ROR2 at 9q22, a member of the receptor tyrosine kinase-like gene family that encodes an orphan membrane-bound tyrosine kinase involved in cell growth and differentiation [6][7][8]. Mutations in WNT5A, locus 3p 14.3 are responsible for the DRS which is characterized by more prominent oral manifestations [4].…”

“…The important role of genetic testing by the knowledge about the molecular basis of the disorder enabled us to make a prenatal diagnosis, genetic carrier detection and proper genetic counselling for families [6]. …”