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Novel pathogenic genomic variants leading to autosomal dominant and recessive Robinow syndrome.
Am J Med Genet A. 2020 Oct 13 [Online ahead of print]AJ

Abstract

Robinow syndrome (RS) is a genetically heterogeneous disorder characterized by skeletal dysplasia and a distinctive facial appearance. Previous studies have revealed locus heterogeneity with rare variants in DVL1, DVL3, FZD2, NXN, ROR2, and WNT5A underlying the etiology of RS. The aforementioned "Robinow-associated genes" and their gene products all play a role in the WNT/planar cell polarity signaling pathway. We performed gene-targeted Sanger sequencing, exome sequencing, genome sequencing, and array comparative genomic hybridization on four subjects with a clinical diagnosis of RS who had not had prior DNA testing. Individuals in our cohort were found to carry pathogenic or likely pathogenic variants in three RS related genes: DVL1, ROR2, and NXN. One subject was found to have a nonsense variant (c.817C > T [p.Gln273*]) in NXN in trans with an ~1 Mb telomeric deletion on chromosome 17p containing NXN, which supports our contention that biallelic NXN variant alleles are responsible for a novel autosomal recessive RS locus. These findings provide increased understanding of the role of WNT signaling in skeletal development and maintenance. These data further support the hypothesis that dysregulation of the noncanonical WNT pathway in humans gives rise to RS.

Authors+Show Affiliations

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.University of Brasilia, Brasilia, Brazil. Robinow Syndrome Foundation, Anoka, Minnesota, USA.Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden. Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden. Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden. Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden.Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden. Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden. Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA. Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA. Texas Children's Hospital, Houston, Texas, USA. Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA. Texas Children's Hospital, Houston, Texas, USA.Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA. Pacific Northwest Research Institute (PNRI), Seattle, Washington, USA.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

33048444

Citation

Zhang, Chaofan, et al. "Novel Pathogenic Genomic Variants Leading to Autosomal Dominant and Recessive Robinow Syndrome." American Journal of Medical Genetics. Part A, 2020.
Zhang C, Mazzeu JF, Eisfeldt J, et al. Novel pathogenic genomic variants leading to autosomal dominant and recessive Robinow syndrome. Am J Med Genet A. 2020.
Zhang, C., Mazzeu, J. F., Eisfeldt, J., Grochowski, C. M., White, J., Akdemir, Z. C., Jhangiani, S. N., Muzny, D. M., Gibbs, R. A., Lindstrand, A., Lupski, J. R., Sutton, V. R., & Carvalho, C. M. B. (2020). Novel pathogenic genomic variants leading to autosomal dominant and recessive Robinow syndrome. American Journal of Medical Genetics. Part A. https://doi.org/10.1002/ajmg.a.61908
Zhang C, et al. Novel Pathogenic Genomic Variants Leading to Autosomal Dominant and Recessive Robinow Syndrome. Am J Med Genet A. 2020 Oct 13; PubMed PMID: 33048444.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Novel pathogenic genomic variants leading to autosomal dominant and recessive Robinow syndrome. AU - Zhang,Chaofan, AU - Mazzeu,Juliana F, AU - Eisfeldt,Jesper, AU - Grochowski,Christopher M, AU - White,Janson, AU - Akdemir,Zeynep C, AU - Jhangiani,Shalini N, AU - Muzny,Donna M, AU - Gibbs,Richard A, AU - Lindstrand,Anna, AU - Lupski,James R, AU - Sutton,V Reid, AU - Carvalho,Claudia M B, Y1 - 2020/10/13/ PY - 2020/04/13/received PY - 2020/09/11/revised PY - 2020/09/19/accepted PY - 2020/10/13/entrez PY - 2020/10/14/pubmed PY - 2020/10/14/medline KW - clinical diagnosis KW - deletion KW - missense KW - skeletal dysplasia KW - structural variant JF - American journal of medical genetics. Part A JO - Am J Med Genet A N2 - Robinow syndrome (RS) is a genetically heterogeneous disorder characterized by skeletal dysplasia and a distinctive facial appearance. Previous studies have revealed locus heterogeneity with rare variants in DVL1, DVL3, FZD2, NXN, ROR2, and WNT5A underlying the etiology of RS. The aforementioned "Robinow-associated genes" and their gene products all play a role in the WNT/planar cell polarity signaling pathway. We performed gene-targeted Sanger sequencing, exome sequencing, genome sequencing, and array comparative genomic hybridization on four subjects with a clinical diagnosis of RS who had not had prior DNA testing. Individuals in our cohort were found to carry pathogenic or likely pathogenic variants in three RS related genes: DVL1, ROR2, and NXN. One subject was found to have a nonsense variant (c.817C > T [p.Gln273*]) in NXN in trans with an ~1 Mb telomeric deletion on chromosome 17p containing NXN, which supports our contention that biallelic NXN variant alleles are responsible for a novel autosomal recessive RS locus. These findings provide increased understanding of the role of WNT signaling in skeletal development and maintenance. These data further support the hypothesis that dysregulation of the noncanonical WNT pathway in humans gives rise to RS. SN - 1552-4833 UR - https://www.unboundmedicine.com/medline/citation/33048444/Novel_pathogenic_genomic_variants_leading_to_autosomal_dominant_and_recessive_Robinow_syndrome_ L2 - https://doi.org/10.1002/ajmg.a.61908 DB - PRIME DP - Unbound Medicine ER -
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