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. 2023 Sep 1;14(9):e00619.
doi: 10.14309/ctg.0000000000000619.

Maternal Vitamin A Status as a Risk Factor of Hirschsprung Disease in the Child

Shalini G Hegde  1 , Sarita Devi  2 , Ambily Sivadas  2 , Attibele Mahadevaiah Shubha  1 , Annamma Thomas  3 , Arpita Mukhopadhyay  2 , Anura V Kurpad  4
Affiliations

Maternal Vitamin A Status as a Risk Factor of Hirschsprung Disease in the Child

Shalini G Hegde et al. Clin Transl Gastroenterol. .

Abstract

Introduction: The gene-environment interaction of the REarranged during Transfection ( RET ) gene with vitamin A in the etiopathogenesis of Hirschsprung disease (HSCR) has been suggested in rodents. The aim of this study was to evaluate vitamin A status in mothers of children with HSCR and to assess its association with pathogenic variants of the RET gene in affected children.

Methods: This was a case-control study of stable isotope-based vitamin A measurement stores of mothers of children diagnosed with HSCR (within 8 months from birth, n = 7) and age-matched mothers of normal children (n = 6). Next-generation sequencing of RET exons, along with their upstream promoter region, was performed in the 7 HSCR proband-parent triads to evaluate pathogenic variants.

Results: Maternal vitamin A stores in the HSCR group was almost 50% that of those in controls, tending toward significance (0.50 ± 0.17 vs 0.89 ± 0.51 μmol/g respectively, P = 0.079). Two novel pathogenic de novo mutations were identified in 2 cases, and a rare single-nucleotide deletion was detected in the 3.5-kb RET upstream region, in a heterozygous state, in all 7 proband-parent triads. Low-penetrance RET haplotypes associated with HSCR were detected in 5 cases.

Discussion: Mothers with children with HSCR had lower vitamin A liver stores than mothers with normal children, and the children who were affected had HSCR despite having no established pathogenic RET variants. Lower maternal vitamin A status may increase the penetrance of genetic mutations in RET , and vitamin-A mediated gene-environment interactions may underpin some of the etiology of HSCR.

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Conflict of interest statement

Guarantor of article: Anura V. Kurpad, MD, PhD.

Specific author contributions: S.G.H., S.D., A.M.S. and A.V.K.: designed the study; S.G.H. and A.M.S.: recruited subjects of HSCR group and were involved in patient care; S.G.H. and A.T.: recruited subjects of control group and were involved in patient care; S.D.: executed stable isotope dilution study for vitamin A stores, and data analysis; A.M.S. and A.S.: Next generation sequencing sample and data analysis; S.G.H. and A.V.K.: wrote the first draft of the manuscript with primary responsibility for the final content of the manuscript; all authors: critically reviewed and approved the final version of the manuscript.

Financial support: Supported by the Clinical Research Training Program (CRTP) grant from the Wellcome Trust-Department of Biotechnology (DBT) India Alliance to A.V.K. (IA/CRC/19/1/610006). S.G.H. is a Clinical Research Fellow of the CRTP grant. A.M.S. [IA/CPHI/19/1/504593] and A.S. [IA/E/19/1/504945] are independently supported by Wellcome Trust/DBT India Alliance Fellowships.

Potential competing interests: None to report.

Figures

Figure 1.
Figure 1.
Consort diagram.
See this image and copyright information in PMC

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