A novel frameshift mutation of DVL1‐induced Robinow syndrome: A case report and literature review

Abstract

Background: Robinow syndrome is a rare genetic disorder that affects the development of multiple systems. Due to its low prevalence and diversity of phenotypic presentation it has been challenging to definitively characterize features of Robinow syndrome. Methods:We performed DNA extraction, whole-exome sequencing analysis, and mutation analysis of DVL1 to obtain genetic data on the patient. We subsequently analyzed the patient's clinical and genetic data. Results:The proband was a 3-month-old female infant who suffered from significant global developmental delay and metabolic disorder. The main clinical manifestations included facial dysmorphisms, bilateral dislocation of the hip joint, and hearing impairment. Whole-exome sequencing of the patient's DNA revealed a heterozygous mutation of c.1620delC in DVL1. Analysis with the MutationTaster application indicated that both were pathogenic (probability = 1), causing frameshift mutations affecting 107 amino acids (p.S542Vfs*107).Significant structural changes were identified in the amino acid sequence after the WNT signaling-related DEP domain site was predicted using the AlphaFold Protein structure database. The stability of the three main domains was then evaluated using SWISS-MODEL, and indicated that the mutation did not alter the DIX, PDZ, or DEP domain sequences. Because all reported pathogenic mutations were located near the DEP domain, we speculated that structural changes around the DEP domain may have impaired WNT domain function and WNT signaling, resulting in Robinow syndrome. Conclusion:The present case suggests that molecular genetic screening is useful for the diagnosis of developmental disorders, particularly in children with a positive family history. In the current patient all the related pathological variants were located within a narrow locus. This report expands the known manifestations of Robinow syndrome and contributes to refinement of its molecular basis.

TBX6 as a cause of a combined skeletal‐kidney dysplasia syndrome

“…Though not specifically attributed to TBX6 haploinsufficiency, ciliary dysfunction is believed to contribute to the 16p11.2 deletion phenotype (Migliavacca et al, 2015). We hypothesize that homozygosity for a missense variant that localizes within the T-box DNA binding domain interferes with the nodal and primary cil- (Bunn et al, 2015;Hu et al, 2022;White et al, 2015). DVL1 is a component of the Wnt signaling pathway.…”

“…The p.(Asn460Ser) missense variant is predicted to have a deleterious effect on protein function by Polyphen and SIFT and though it is reported in gnomAD in the heterozygous state in two individuals of Latino‐Admixed American descent, it is present at a low allele frequency (2/250372 alleles). Importantly, heterozygous DVL1 variants reported in Robinow syndrome are typically truncating and not missense variants (Bunn et al, 2015; Hu et al, 2022; White et al, 2015). DVL1 is a component of the Wnt signaling pathway.…”

DVL1variants and C-terminal deletions have differential effects on craniofacial development and WNT signaling

“…Depending on the position of the frameshift mutation, at least 109 novel amino acids replace at least 68 amino acids of the normal C-terminus (Fig. 1A,B)(Hu et al, 2022; Lima et al, 2022; White et al, 2015; Zhang et al, 2022). Interestingly, the novel C-terminal peptide is common to all identified ADRS- DVL1 individuals (Hu et al, 2022; White et al, 2015; Zhang et al, 2022) (Fig.…”

“…Dishevelled1 (DVL1) , an intracellular adaptor protein, is a key downstream mediator of canonical and non-canonical WNT pathways (Gao and Chen, 2010). The only genetic disease associated with mutations in DVL proteins is ADRS (23/67 patients; MIM#616331, Table S1) (Bunn et al, 2015; Gignac et al, 2023; Hu et al, 2022; White et al, 2015; Zhang et al, 2022). RS cases usually have craniofacial features that are very distinctive including jaw hypoplasia, broad nasal bridge and hypertelorism i.e.…”

“…1A,B)(Hu et al, 2022; Lima et al, 2022; White et al, 2015; Zhang et al, 2022). Interestingly, the novel C-terminal peptide is common to all identified ADRS- DVL1 individuals (Hu et al, 2022; White et al, 2015; Zhang et al, 2022) (Fig. 1A-C).…”