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Test Information Sheet
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Phone: 301-519-2100
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ITGB4, ITGA6 and PLEC1 Gene Analysis in Epidermolysis Bullosa with Pyloric Atresia
Mendelian Inheritance in Man Number: ITGB4 (147557) (beta-4 integrin), ITGA6 (147556) (alpha-6 integrin),
PLEC1 (601282) (plectin), 226730 (Epidermolysis Bullosa with pyloric atresia, EB-PA (Carmi Syndrome)
Clinical features:
In this clinical sub-type of JEB, blistering begins in the neonatal period and continues throughout life. Blisters
are usually generalized and include oral and esophageal lesions. In addition, pyloric atresia or pyloric stenosis
is present. In some patients urogenital malformations may also be evident. JEB-PA is often lethal in the
newborn period; however surviving patients may show less severe blistering as they age 1-8, although in the
patients described with ITGA6 mutations no surviving patients are described. The tissue separation (blister)
occurs within or just above the lamina lucida at the level of the hemidesmosome. Alpha-6/Beta-4 integrin
staining may be reduced or absent consistent with either ITGB4 or ITGA6 mutations. Plectin staining of a skin
biopsy may be reduced or absent, consistent with PLEC1 mutations. In rare cases EB-PA has been identified on
ultrasound in fetuses of families with no family history and mutation detection has identified ITGB4 or ITGA6
mutations,10-13 although this has not been described in EB cases with plectin defects. In one rare case, EB-PA
with desquamative enteropathy but without skin disease has been reported.14
Inheritance pattern:
The junctional EBs are a genetically heterogeneous group of disorders, which generally show autosomal
recessive inheritance and high penetrance, although one instance of autosomal dominant JEB due to COL17A1
mutations has been reported 9. The recurrence risk for couples with an affected child is 25%. The recurrence
risk to extended family members is rare in the absence of consanguinity. No de novo mutations have been
reported in the literature.
Reasons for referral:
1. Confirmation of a clinical diagnosis
2. Genetic counseling and recurrence risk calculation
3. Prenatal diagnosis in families with an affected child and defined mutation
Test method:
Sequencing of the ITGB4, ITGA6, and PLEC1 genes are offered as separate tests, usually performed in
sequential order, starting with ITGB4. Using genomic DNA obtained from the submitted biological material, bidirectional sequence of the coding region and splice junctions of the ITGB4 gene (41 coding exons) and ITGA6
gene (26 coding exons) are analyzed. Sequencing of the coding region and splice sites of the PLEC1 gene is
offered in two tiers. Tier 1 comprises the two main exons 31 and 32, while Tier 2 includes bi-directional
sequence analysis of the remaining 30 exons. Mutations found in the first person of a family to be tested are
confirmed by repeat analysis using sequencing, restriction fragment analysis, or another appropriate method.
Test sensitivity:
About 75% of patients who have EB-PA have mutations in the ITGB4 gene, the remainder has mutations in
ITGA6 (5%) or PLEC1 (15%) 1. The remaining 5% of patients will have no detectable mutations in any of these
three genes.
Mutation spectrum:
Over 50 cases of EB-PA with ITGB4 mutations and only 5 cases with deleterious ITGA6 mutations have been
reported in the literature.1-8, 10-13, 16 A total of 9 cases have been reported in the literature of EB-PA due to PLEC1
mutations.17-19 The mutation spectrum includes missense, nonsense, splicing, insertion and deletion mutations.
Information Sheet on Junctional Epidermolysis Bullosa with Pyloric Atresia Page 1 of 2
© GeneDx, Rev. Date: 02/2013
Specimen Requirements and Shipping/Handling:
• Blood: A single tube with 1-5 mL whole blood in EDTA. Ship overnight at ambient temperature, using a
cool pack in hot weather. Specimens may be refrigerated for 7 days prior to shipping.
• Buccal Brushes: As an alternative to blood, use a GeneDx buccal kit (others not accepted).
Submit by mail. Buccal brushes are not accepted on children under 6 months of age.
Buccal brushes not accepted for PLEC1 sequencing.
• Prenatal Diagnosis: For prenatal testing for a known mutation in the ITGB4, ITGA6 and PLEC1 genes,
please refer to the specimen requirements table on our website at: http://www.genedx.com/testcatalog/prenatal/. Ship specimen overnight at ambient temperature, using a cool pack in hot weather.
Required Forms:
• Sample Submission (Requisition) Form – complete all pages
• Payment Options Form or Institutional Billing Instructions
For test codes, prices, CPT codes, and turn-around-times, please refer to the “Junctional Epidermolysis
Bullosa with Pyloric Atresia” page on our website: www.genedx.com
References Cited:
1. Varki et al. 2006 J Med Genet 43:641-52. 2. Ashton et al. 2001 Br J Dermatol. 144:408-14. 3. Mellerio et al. 1998 Br J Dermatol. 139:862-71. 4. Pulkkinen
et al. 1998 Am J Patho l152:157-166. 5. Pulkkinen et al. 1998 Am J Hum Genet 63:1376-1387. 6. Iacovacci et al. 2003 Exp Dermatol 12:716-20. 7. Chavanas
et al. 1999 Hum Mol Genet. 8:2097-105. 8. Jonkman et al. 2002 J Invest Dermatol 119:1275-81. 9. Almaani et al. 2009 Br J Dermatol 160:1094-1097. 10.
Azarian et al. 2006 Prenat Diagn 26:57-9. 11. Dolan et al. 1993 Am J Med Genet 47:395-400. 12. Lepinard et al. 2000 Prenat Diagn 20:70-5. 13. Gache et al.
1998 J Invest Dermatol 111:914-6. 14. Salvestrini et al. 2008 J Ped Gastroenterol and Nutrition 47:585-591 15. Inoue et al. 2000 J Invest Dermatol 114:1061-4.
16. Ruzzi et al. 1997 J Clin Invest 99:2826-31. 17. Sawamura et al 2007 J Invest Dermatol 127:1537-40. 18. Nakamura et. al. 2005 J Mol Diagn 7:28-35. 19.
Pfendner 2005 J Invest Dermatol 124:111-5.
Information Sheet on Junctional Epidermolysis Bullosa with Pyloric Atresia Page 2 of 2
© GeneDx, Rev. Date: 02/2013