AMP case report: Celiac genetic health risk screening by NGS in the family of a child with clinical findings of dermatitis herpetiformis and gluten sensitivity

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In a recent large-scale pediatric screening study of 9,973 children ages one to 17 years, a high prevalence of undiagnosed celiac disease was confirmed in both asymptomatic and symptomatic participants.¹¹ A limitation of the study was the use of IgA tTG antibody testing as the screening method, which can produce false-negative results in high-risk children who have not consumed adequate gluten before the test. Using a one-time, DNA-based, celiac genetic health risk test may become a preferred screening method in pediatric populations for identifying those who are genetically at risk and would benefit from repeated antibody screening as well as those without risk alleles who can forgo such testing. As a screening method, NGS has advantages over other celiac-disease–associated HLA typing methods, such as allele-specific PCR and Sanger sequencing. These include the cost-effectiveness of multiplexing samples for family screening and scalability for large-population applications, such as mass screening in high-risk groups.¹²

In this case, the patient was suspected to have subclinical celiac disease based on his dermatologic findings and had complete reversal of symptoms on a gluten-free diet. Retrospective molecular testing identified the DQ2/DQ2 homozygous genotype correlated with strongly increased risk for celiac disease development due to a phenotype of enhanced gluten antigen presentation to the immune system.^13,14 The child’s genotype likely contributed to the rare presentation of DH at such a young age. As the patient was in remission after removal of dietary gluten, the family elected to forgo gluten challenge and invasive confirmatory testing. However, launching a toddler on a lifetime gluten-free diet is best approached with objective evaluation of the clinical evidence in consultation with the family’s health care providers. If the child’s symptoms recur due to dietary noncompliance or other reasons, there would be an opportunity to repeat the antibody testing and proceed with tissue biopsies. The hope for this child and his family, however, is that knowledge of their celiac genetic risk will result in a lifetime of informed dietary choices based on a shared commitment to wellness.

1. Reunala T, Salmi TT, Hervonen K. Dermatitis herpetiformis: pathognomonic transglutaminase IgA deposits in the skin and excellent prognosis on a gluten-free diet. Acta Derm Venereol. 2015;95(8):917–922.
2. Dermatitis herpetiformis. National Organization for Rare Disorders. https://rarediseases.org/rare-diseases/dermatitis-herpetiformis.
3. Nellikkal SS, Hafed Y, Larson JJ, Murray JA, Absah I. High prevalence of celiac disease among screened first-degree relatives. Mayo Clin Proc. 2019;94(9):1807–1813.
4. Megiorni F, Pizzuti A. HLA-DQA1 and HLA-DQB1 in celiac disease predisposition: practical implications of the HLA molecular typing. J Biomed Sci. 2012;19(1):88.
5. Lau MS, Sanders DS. Optimizing the diagnosis of celiac disease. Curr Opin Gastroenterol. 2017;33(1):173–180.
6. Leonard J, Haffenden G, Tucker W, et al. Gluten challenge in dermatitis herpetiformis. N Engl J Med. 1983;308(14):816–819.
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8. Pietzak MM, Schofield TC, McGinnis MJ, Nakamura RM. Stratifying risk for celiac disease in a large at-risk United States population by using HLA alleles. Clin Gastroenterol Hepatol. 2009;7(9):966–971.
9. Megiorni F, Mora B, Bonamico M, et al. HLA-DQ and risk gradient for celiac disease. Hum Immunol. 2009;70(1):55–59.
10. Taylor AK, Lebwohl B, Snyder CL, Green P. Celiac disease. GeneReviews; 2008. Updated Jan. 31, 2019. https://www.ncbi.nlm.nih.gov/books/NBK1727.
11. Stahl MG, Rasmussen CG, Dong F, et al. Mass screening for celiac disease: the autoimmunity screening for kids study. Am J Gastroenterol. 2021;116(1):180–187.
12. Ludvigsson JF, Card TR, Kaukinen K, et al. Screening for celiac disease in the general population and in high-risk groups. United European Gastroenterol J. 2015;3(2):106–120.
13. Vader W, Stepniak D, Kooy Y, et al. The HLA-DQ2 gene dose effect in celiac disease is directly related to the magnitude and breadth of gluten-specific T cell responses. Proc Natl Acad Sci USA. 2003;100(21):12390–12395.
14. De Silvestri A, Capittini C, Poddighe D, et al. HLA-DQ genetics in children with celiac disease: a meta-analysis suggesting a two-step genetic screening procedure starting with HLA-DQ β chains. Pediatr Res. 2018;83(3):564–572.

Test yourself

Here are three questions taken from the case report.

1. Which of these haplotype/genotypes is associated with the highest celiac genetic health risk?

a. DQ7
b. DQ2
c. DQ2/DQ7
d. DQ2/DQ2

2. Which is the most preferred test in the evaluation of celiac disease in individuals on a gluten-free diet?

a. Punch biopsy of the skin for DIF testing
b. Endoscopic small bowel biopsy
c. DNA-based celiac genetic health risk testing
d. tTG antibody testing

3. In which population are celiac disease and dermatitis herpetiformis most prevalent?

a. Northern European
b. Asian
c. African American
d. Ashkenazi Jewish

Answers are online now at www.amp.org/casereports and will be published next month in CAP TODAY.

Dr. Gunn is chief medical officer of ResearchDx and medical director of PacificDx clinical laboratory, a subsidiary of ResearchDx, and Dr. Moore and Dr. Cotter are principals and co-founders of ResearchDx—all in Irvine, Calif.