Clinical presentation and molecular genetic analysis of a Sudanese family with a novel mutation in the CYP2R1 gene

Gene. 2022 Nov 30:844:146809. doi: 10.1016/j.gene.2022.146809. Epub 2022 Aug 13.

Abstract

The aim of this study was to identify the genetic basis of two female siblings - born to consanguineous Sudanese parents - diagnosed clinically as having the rare condition of 25-hydroxylase deficiency (vitamin D-dependent rickets type 1B). The initial diagnosis was established based on clinical data, laboratory and radiological findings retrospectively. Primers for all exons (5) of human CYP2R1 (NM_024514) were generated followed by Sanger sequencing on exons 1-5 for both girls and their parents. Homozygosity for a point mutation (c.85C > T) was detected, leading to a nonsynonymous variant at position 29 in exon 1, resulting in a premature stop codon (p.Q29X). This is a previously unknown variant that leads to a severely truncated protein and predicted to be among the 0.1 % most deleterious genomic variants(CADD score 36). To our knowledge, this family represents the first case series from Sudan with a confirmed CYP2R1 gene mutation and the 6th world-wide. With the lack of genetic facilities, diagnosis should be suspected by the persistently low 25 hydroxyvitamin D level in spite of proper treatment and after ruling out liver disease and malabsorption. Patients in this case series showed healing of rickets when treated with high doses of 1,25-dihydroxyvitamin D3 (1,25(OH)D3; calcitriol) and oral calcium.

Keywords: 25 OH vitamin D deficiency; Hereditary rickets; Sanger sequencing; Vitamin D-dependent rickets type 1b.

MeSH terms

  • Calcitriol
  • Cholestanetriol 26-Monooxygenase / genetics
  • Cholestanetriol 26-Monooxygenase / metabolism
  • Cytochrome P-450 Enzyme System / genetics
  • Cytochrome P450 Family 2 / genetics
  • Female
  • Humans
  • Molecular Biology
  • Mutation
  • Receptors, Calcitriol / genetics
  • Retrospective Studies
  • Rickets* / drug therapy
  • Rickets* / genetics

Substances

  • Receptors, Calcitriol
  • Cytochrome P-450 Enzyme System
  • Cytochrome P450 Family 2
  • CYP2R1 protein, human
  • Cholestanetriol 26-Monooxygenase
  • Calcitriol