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Mutational spectrum in 101 patients with hypohidrotic ectodermal dysplasia and breakpoint mapping in independent cases of rare genomic rearrangements

Journal of Human Genetics volume 61, pages 891897 (2016) | Download Citation

Abstract

Hypohidrotic ectodermal dysplasia (HED), a rare and heterogeneous hereditary disorder, is characterized by deficient development of multiple ectodermal structures including hair, sweat glands and teeth. If caused by mutations in the genes EDA, EDA1R or EDARADD, phenotypes are often very similar as the result of a common signaling pathway. Single-nucleotide polymorphisms (SNPs) affecting any gene product in this pathway may cause inter- and intrafamilial variability. In a cohort of 124 HED patients, genotyping was attempted by Sanger sequencing of EDA, EDA1R, EDARADD, TRAF6 and EDA2R and by multiplex ligation-dependent probe amplification (MLPA). Pathogenic mutations were detected in 101 subjects with HED, affecting EDA, EDA1R and EDARADD in 88%, 9% and 3% of the cases, respectively, and including 23 novel mutations. MLPA revealed exon copy-number variations in five unrelated HED families (two deletions and three duplications). In four of them, the genomic breakpoints could be localized. The EDA1R variant rs3827760 (p.Val370Ala), known to lessen HED-related symptoms, was found only in a single individual of Asian origin, but in none of the 123 European patients. Another SNP, rs1385699 (p.Arg57Lys) in EDA2R, however, appeared to have some impact on the hair phenotype of European subjects with EDA mutations.

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References

  1. 1.

    & Ectodermal dysplasias: a clinical classification and a causal review. Am. J. Med. Genet. 53, 153–162 (1994).

  2. 2.

    & Ectodermal dysplasias: a new clinical-genetic classification. J. Med. Genet. 38, 579–585 (2001).

  3. 3.

    , & Prevalence and prevention of severe complications of hypohidrotic ectodermal dysplasia in infancy. Early Hum. Dev. 86, 397–399 (2010).

  4. 4.

    , , & Clinical aspects of X-linked hypohidrotic ectodermal dysplasia. Arch. Dis. Child 62, 989–996 (1987).

  5. 5.

    , , , , , et al. Only four genes (EDA1, EDAR, EDARADD, and WNT10A) account for 90% of hypohidrotic/anhidrotic ectodermal dysplasia cases. Hum. Mutat. 32, 70–72 (2011).

  6. 6.

    Psychological aspects of hypohidrotic ectodermal dysplasia. Birth Defects Orig. Artic. Ser. 24, 263–275 (1988).

  7. 7.

    & Psychosocial stress and adaptive functioning in children and adolescents suffering from hypohidrotic ectodermal dysplasia. Pediatr. Dermatol. 14, 180–185 (1997).

  8. 8.

    , , & Salivary gland involvement in hypohidrotic ectodermal dysplasia. Oral Dis. 4, 152–154 (1998).

  9. 9.

    Ocular symptoms and signs in patients with ectodermal dysplasia syndromes. Graefes Arch. Clin. Exp. Ophthalmol. 242, 495–500 (2004).

  10. 10.

    & Persistent nasal crusting due to hypohidrotic ectodermal dysplasia. J. Laryngol. Otol. 110, 379–382 (1996).

  11. 11.

    , , , , , et al. Early respiratory and ocular involvement in X-linked hypohidrotic ectodermal dysplasia. Eur. J. Pediatr. 172, 1023–1031 (2013).

  12. 12.

    , & Ectodysplasin/NF-kappaB signaling in embryonic mammary gland development. J. Mammary Gland Biol. Neoplasia 18, 165–169 (2013).

  13. 13.

    , , , , & Bilateral amastia in a female with X-linked hypohidrotic ectodermal dysplasia. Br. J. Dermatol. 171, 671–673 (2014).

  14. 14.

    , , & A novel missense mutation in the gene EDARADD associated with an unusual phenotype of hypohidrotic ectodermal dysplasia. Am. J. Med. Genet. A 170, 249–253 (2016).

  15. 15.

    , , , , , et al. Mutation in WNT10A is associated with an autosomal recessive ectodermal dysplasia: the odonto-onycho-dermal dysplasia. Am. J. Hum. Genet. 81, 821–828 (2007).

  16. 16.

    , , , , , et al. The anhidrotic ectodermal dysplasia gene (EDA) undergoes alternative splicing and encodes ectodysplasin-A with deletion mutations in collagenous repeats. Hum. Mol. Genet. 7, 1661–1669 (1998).

  17. 17.

    , , , , , et al. Two-amino acid molecular switch in an epithelial morphogen that regulates binding to two distinct receptors. Science 290, 523–527 (2000).

  18. 18.

    , , , , & XEDAR activates the non-canonical NF-kappaB pathway. Biochem. Biophys. Res. Commun. 465, 275–280 (2015).

  19. 19.

    , , , , , et al. X-linked anhidrotic (hypohidrotic) ectodermal dysplasia is caused by mutation in a novel transmembrane protein. Nat. Genet. 13, 409–416 (1996).

  20. 20.

    & Molecular basis of hypohidrotic ectodermal dysplasia: an update. J. Appl. Genet. 57, 51–61 (2016).

  21. 21.

    , , , , & Mutations in the human homologue of mouse dl cause autosomal recessive and dominant hypohidrotic ectodermal dysplasia. Nat. Genet. 22, 366–369 (1999).

  22. 22.

    , , , , , et al. Gene defect in ectodermal dysplasia implicates a death domain adapter in development. Nature 414, 913–916 (2001).

  23. 23.

    & A new mutation resulting in the truncation of the TRAF6-interacting domain of XEDAR: a possible novel cause of hypohidrotic ectodermal dysplasia. J. Med. Genet. 49, 499–501 (2012).

  24. 24.

    & A rare heterozygous TRAF6 variant is associated with hypohidrotic ectodermal dysplasia. Br. J. Dermatol. 166, 1353–1356 (2012).

  25. 25.

    , , , , , et al. Genotype-phenotype correlation in boys with X-linked hypohidrotic ectodermal dysplasia. Am. J. Med. Genet. A 164a, 2424–2432 (2014).

  26. 26.

    , , , , , et al. Enhanced ectodysplasin-A receptor (EDAR) signaling alters multiple fiber characteristics to produce the East Asian hair form. Hum. Mutat. 29, 1405–1411 (2008).

  27. 27.

    , , , , , et al. A common variation in EDAR is a genetic determinant of shovel-shaped incisors. Am. J. Hum. Genet. 85, 528–535 (2009).

  28. 28.

    , , , , , et al. The EDAR370A allele attenuates the severity of hypohidrotic ectodermal dysplasia caused by EDA gene mutation. Br. J. Dermatol. 166, 678–681 (2012).

  29. 29.

    , , , , , et al. EDA2R is associated with androgenetic alopecia. J. Invest. Dermatol. 128, 2268–2270 (2008).

  30. 30.

    , , , , , et al. Recent positive selection of a human androgen receptor/ectodysplasin A2 receptor haplotype and its relationship to male pattern baldness. Hum. Genet. 126, 255–264 (2009).

  31. 31.

    , , , , & Characterization of X-linked SNP genotypic variation in globally distributed human populations. Genome Biol. 11, R10 (2010).

  32. 32.

    , & Identification of a new splice form of the EDA1 gene permits detection of nearly all X-linked hypohidrotic ectodermal dysplasia mutations. Am. J. Hum. Genet. 63, 380–389 (1998).

  33. 33.

    , , , , , et al. Mutations leading to X-linked hypohidrotic ectodermal dysplasia affect three major functional domains in the tumor necrosis factor family member Ectodysplasin-A. J. Biol. Chem. 276, 18819–18827 (2001).

  34. 34.

    , , & Molecular genetic analysis of patients from India with hypohidrotic ectodermal dysplasia reveals novel mutations in the EDA and EDAR genes. Br. J. Dermatol. 158, 163–167 (2008).

  35. 35.

    , , , , , et al. Mutation screening of the Ectodysplasin-A receptor gene EDAR in hypohidrotic ectodermal dysplasia. Eur. J. Hum. Genet. 16, 673–679 (2008).

  36. 36.

    , , , , , et al. Correlation between the phenotypes and genotypes of X-linked hypohidrotic ectodermal dysplasia and non-syndromic hypodontia caused by ectodysplasin-A mutations. Eur. J. Med. Genet. 54, e377–e382 (2011).

  37. 37.

    Dysplasie Ectodermique Hypohidrotique Liee a l’ x: Phenotypes Osseux et Dentaire Chez l’homme et la Souris Tabby 95 (Thèse de doctorat, Univ. Louis Pasteur, Strasbourg, 2008).

  38. 38.

    & X-chromosomal insertions at a recurrent site causing ectodermal dysplasia. Eur. J. Dermatol. 19, 178–179 (2009).

  39. 39.

    , , , , , et al. Two novel mutations in the ED1 gene in Japanese families with X-linked hypohidrotic ectodermal dysplasia. Pediatr. Res. 65, 453–457 (2009).

  40. 40.

    , , , , , et al. Mutations in EDA and EDAR genes in a large Mexican Hispanic cohort with hypohidrotic ectodermal dysplasia. Ann. Dermatol. 27, 474–477 (2015).

  41. 41.

    , , , , & Sweating ability and genotype in individuals with X-linked hypohidrotic ectodermal dysplasia. J. Med. Genet. 48, 426–432 (2011).

  42. 42.

    , , , & Candidate gene analysis of tooth agenesis identifies novel mutations in six genes and suggests significant role for WNT and EDA signaling and allele combinations. PLoS ONE 8, e73705 (2013).

  43. 43.

    , , , , , et al. Case of hypohidrotic ectodermal dysplasia caused by a large deletion mutation in the EDA gene. J. Dermatol. 40, 281–283 (2013).

  44. 44.

    & Repeated sequences in DNA. Hundreds of thousands of copies of DNA sequences have been incorporated into the genomes of higher organisms. Science 161, 529–540 (1968).

  45. 45.

    , , , , & Double-strand breaks associated with repetitive DNA can reshape the genome. Proc. Natl Acad. Sci. USA 105, 11845–11850 (2008).

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Acknowledgements

We thank all patients and their families for participation in the study and Ida Allabauer for expert technical assistance. This work was funded partially by a grant from the German-Swiss-Austrian ectodermal dysplasia patient support group (to HS).

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  1. Department of Pediatrics, German Competence Center for Children with Ectodermal Dysplasias, University Hospital Erlangen, Erlangen, Germany

    • Sigrun Wohlfart
    • , Johanna Hammersen
    •  & Holm Schneider

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The authors declare no conflict of interest.

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Correspondence to Sigrun Wohlfart.

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DOI

https://doi.org/10.1038/jhg.2016.75