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  3. CYP26B1-related disorder: expanding the ends of the spectrum through clinical and molecular evidence

CYP26B1-related disorder: expanding the ends of the spectrum through clinical and molecular evidence

  • Hum Genet. 2023 Nov;142(11):1571-1586. doi: 10.1007/s00439-023-02598-2.
Karina C Silveira # 1,  Inara Chacon Fonseca # 2,  Connor Oborn 1,  Parker Wengryn 1,  Saima Ghafoor 1,  Alexander Beke 1,  Ema S Dreseris 3,  Cassandra Wong 4,  Aline Iacovone 5,  Carrie-Lynn Soltys 1,  Riyana Babul-Hirji 6,  Osvaldo Artigalas 7,  Arthur Antolini-Tavares 8,  Anne-Claude Gingras 4 9,  Eric Campos # 3 9,  Denise P Cavalcanti # 10,  Peter Kannu # 11
Affiliations

Affiliations

  • 1 Department of Medical Genetics, University of Alberta, Edmonton, AB, T6G 2H7, Canada.
  • 2 Clinical Genetics, Durham Region Cancer Centre, Lakeridge Health Oshawa, Oshawa, ON, L1G 2B9, Canada.
  • 3 Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON, M5G 0A4, Canada.
  • 4 Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Sinai Health System, Toronto, ON, Canada.
  • 5 Skeletal Dysplasia Group, Medical Genetics Area, Translational Medicine Department, FCM, University of Campinas (UNICAMP), R. Tessália V de Camargo, 126, Campinas, SP, 13083-887, Brazil.
  • 6 Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
  • 7 Clinical Genetics Unit, Children's Hospital, Grupo Hospitalar Conceicao, Porto Alegre, Brazil.
  • 8 Department of Pathological Anatomy, University of Campinas, Campinas, 13083-888, Brazil.
  • 9 Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada.
  • 10 Skeletal Dysplasia Group, Medical Genetics Area, Translational Medicine Department, FCM, University of Campinas (UNICAMP), R. Tessália V de Camargo, 126, Campinas, SP, 13083-887, Brazil. denisepcavalcanti@gmail.com.
  • 11 Department of Medical Genetics, University of Alberta, Edmonton, AB, T6G 2H7, Canada. kannu@ualberta.ca.
  • # Contributed equally.
PMID: 37755482 DOI: 10.1007/s00439-023-02598-2
Abstract

CYP26B1 metabolizes retinoic acid in the developing embryo to regulate its levels. A limited number of individuals with pathogenic variants in CYP26B1 have been documented with a varied phenotypic spectrum, spanning from a severe manifestation involving skull anomalies, craniosynostosis, encephalocele, radio-humeral fusion, oligodactyly, and a narrow thorax, to a milder presentation characterized by craniosynostosis, restricted radio-humeral joint mobility, hearing loss, and intellectual disability. Here, we report two families with CYP26B1-related phenotypes and describe the data obtained from functional studies of the variants. Exome and Sanger Sequencing were used for variant identification in family 1 and family 2, respectively. Family 1 reflects a mild phenotype, which includes craniofacial dysmorphism with brachycephaly (without craniosynostosis), arachnodactyly, reduced radioulnar joint movement, conductive hearing loss, learning disability-and compound heterozygous CYP26B1 variants: (p.[(Pro118Leu)];[(Arg234Gln)]) were found. In family 2, a stillborn fetus presented a lethal phenotype with spina bifida occulta, hydrocephalus, poor skeletal mineralization, synostosis, limb defects, and a synonymous homozygous variant in CYP26B1: c.1083C > A. A minigene assay revealed that the synonymous variant created a new splice site, removing part of exon 5 (p.Val361_Asp382del). Enzymatic activity was assessed using a luciferase assay, demonstrating a notable reduction in exogenous retinoic acid metabolism for the variant p.Val361_Asp382del. (~ 3.5 × decrease compared to wild-type); comparatively, the variants p.(Pro118Leu) and p.(Arg234Gln) demonstrated a partial loss of metabolism (1.7× and 2.3× reduction, respectively). A proximity-dependent biotin identification assay reaffirmed previously reported ER-resident protein interactions. Additional work into these interactions is critical to determine if CYP26B1 is involved with Other biological events on the ER. Immunofluorescence assay suggests that mutant CYP26B1 is still localized in the endoplasmic reticulum. These results indicate that novel pathogenic variants in CYP26B1 result in varying levels of enzymatic activity that impact retinoic acid metabolism and relate to the distinct phenotypes observed.

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