Skip to main content

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

Publication ,  Journal Article
Zhang, C; Jolly, A; Shayota, BJ; Mazzeu, JF; Du, H; Dawood, M; Soper, PC; Ramalho de Lima, A; Ferreira, BM; Coban-Akdemir, Z; White, J; Boy, R ...
Published in: HGG Adv
January 13, 2022

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.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

HGG Adv

DOI

EISSN

2666-2477

Publication Date

January 13, 2022

Volume

3

Issue

1

Start / End Page

100074

Location

United States

Related Subject Headings

  • 3105 Genetics
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Zhang, C., Jolly, A., Shayota, B. J., Mazzeu, J. F., Du, H., Dawood, M., … Carvalho, C. M. B. (2022). Novel pathogenic variants and quantitative phenotypic analyses of Robinow syndrome: WNT signaling perturbation and phenotypic variability. HGG Adv, 3(1), 100074. https://doi.org/10.1016/j.xhgg.2021.100074
Zhang, Chaofan, Angad Jolly, Brian J. Shayota, Juliana F. Mazzeu, Haowei Du, Moez Dawood, Patricia Celestino Soper, et al. “Novel pathogenic variants and quantitative phenotypic analyses of Robinow syndrome: WNT signaling perturbation and phenotypic variability.HGG Adv 3, no. 1 (January 13, 2022): 100074. https://doi.org/10.1016/j.xhgg.2021.100074.
Zhang C, Jolly A, Shayota BJ, Mazzeu JF, Du H, Dawood M, et al. Novel pathogenic variants and quantitative phenotypic analyses of Robinow syndrome: WNT signaling perturbation and phenotypic variability. HGG Adv. 2022 Jan 13;3(1):100074.
Zhang, Chaofan, et al. “Novel pathogenic variants and quantitative phenotypic analyses of Robinow syndrome: WNT signaling perturbation and phenotypic variability.HGG Adv, vol. 3, no. 1, Jan. 2022, p. 100074. Pubmed, doi:10.1016/j.xhgg.2021.100074.
Zhang C, Jolly A, Shayota BJ, Mazzeu JF, Du H, Dawood M, Soper PC, Ramalho de Lima A, Ferreira BM, Coban-Akdemir Z, White J, Shears D, Thomson FR, Douglas SL, Wainwright A, Bailey K, Wordsworth P, Oldridge M, Lester T, Calder AD, Dumic K, Banka S, Donnai D, Jhangiani SN, Potocki L, Chung WK, Mora S, Northrup H, Ashfaq M, Rosenfeld JA, Mason K, Pollack LC, McConkie-Rosell A, Kelly W, McDonald M, Hauser NS, Leahy P, Powell CM, Boy R, Honjo RS, Kok F, Martelli LR, Filho VO, Genomics England Research Consortium, Muzny DM, Gibbs RA, Posey JE, Liu P, Lupski JR, Sutton VR, Carvalho CMB. Novel pathogenic variants and quantitative phenotypic analyses of Robinow syndrome: WNT signaling perturbation and phenotypic variability. HGG Adv. 2022 Jan 13;3(1):100074.

Published In

HGG Adv

DOI

EISSN

2666-2477

Publication Date

January 13, 2022

Volume

3

Issue

1

Start / End Page

100074

Location

United States

Related Subject Headings

  • 3105 Genetics