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GeneDx, Inc.
207 Perry Parkway
Gaithersburg, MD 20877
Phone: 301-519-2100
Fax: 301-519-2892
E-mail: [email protected]
www.genedx.com
Test Information Sheet
ABCA12 Gene Analysis in Harlequin Ichthyosis, Congenital Ichthyosiform
Erythroderma and Lamellar Ichthyosis
Also known as: HI; ‘harlequin fetus’; LI, Lamellar ichthyosis type 2,
Mendelian Inheritance in Man Number: Harlequin ichthyosis: 242500; Lamellar ichthyosis type 2: 601277
Clinical features:
Harlequin ichthyosis (HI) and lamellar ichthyosis (LI) are different types of congenital recessive ichthyosis.
Harlequin ichthyosis is the most severe form of ichthyosis and life-threatening. Infants are usually born
prematurely and are encased in a thick, hard, armor-like covering that severely restricts movements. The taut
cast cracks and forms large, diamond-shaped, adherent plates, which are separated by broad, deep, and intense
red fissures. The taut skin results in deformation of facial features, such as out-turning of eyelids (ectropium)
and lips (eclabium), rudimentary development of nose and ears, and microcephaly. Hands and feet are swollen
and covered by a mitten-like casing. Malformations of inner organs are not uncommon. The postnatal period is
usually complicated by respiratory distress, dehydration, electrolyte imbalance, temperature instability, feeding
problems and bacterial infections, often with fatal consequences. In recent years, an increasing number of
patients with prolonged survival have been reported. After shedding the armor-like cast, these survivors
developed clinical features of severe non-bullous congenital ichthyosiform erythroderma (CIE) with generalized
fine, whitish scale and intense redness. Alopecia, thickening of the skin on palms and soles, and heat intolerance
are common. In lamellar ichthyosis, babies are born with a taut, translucent collodion membrane that encases
the body and may cause ectropium and eclabium. After the membrane is shed, patients develop white or brown,
plate-like scale with no or little redness over the entire body.
Inheritance pattern: Autosomal recessive
Genetics:
Harlequin ichthyosis is very rare; affected individuals in consanguineous as well as non-consanguineous families
have been reported. HI is caused by mutations of the ABCA12 gene on chromosome 2q34 (Kelsell et al. 2005,
Akiyama et al. 2005). The gene product encoded by ABCA12 belongs to a subfamily of ATP binding cassette
(ABC) transporters responsible for the energy-dependent transport of lipid substrates. Lack of this protein leads
to a profound defect in epidermal lipids and destroys the barrier function of the skin. Patients with HI surviving
the neonatal period often develop clinical features of severe congenital ichthyosiform erythroderma (CIE) and
ABCA12 mutations have been reported in these patients as well (Akiyama 2010). Lamellar ichthyosis is
genetically heterogeneous and in most cases associated with mutations in the TGM1 gene on chromosome
14q11.2. However, other gene loci were reported. Mutations in the ABCA12 gene have been identified in 9 LI
families from Northern Africa (Lefevre et al. 2003).
Reasons for referral:
1. A child born with harlequin ichthyosis or with severe congenital ichthyosiform erythroderma
2. An individual of Northern African descent with lamellar ichthyosis without identifiable mutations in TGM1
3. Carrier testing in unaffected family members
4. Genetic counseling and recurrence risk calculation
5. Prenatal diagnosis in families with an affected child and known mutation(s)
Test method:
Bi-directional sequence analysis of the ABCA12 gene in HI and LI are offered as separate tests. For testing in
HI, all 53 exons and corresponding splice junctions of the ABCA12 gene will be obtained and analyzed. For
testing in LI, analysis includes 5 selected exons (exons 28-32) of the ABCA12 gene and their splice sites, where
all reported mutations associated with LI have been found.
Information Sheet on Harlequin/Lamellar Ichthyosis-ABCA12
Page 1 of 2
GeneDx Revision Date: 03/2013
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 and mutation spectrum:
According to a literature review by Akiyama (2010), a total of 56 mutations in the ABCA12 gene have been
reported in 66 unrelated families worldwide to date. The patients from these 66 families were diagnosed with HI
(n=48), LI (n=9) and CIE (n=8). Among the 48 HI families, 100% (48/48) had mutations identified in the
ABCA12 gene (Thomas et al. 2006, 2008; Akiyama 2010). Mutations are private and scattered across the gene,
although mutation 7322delC in exon 49 is more common in the Pakistani ⁄ Indian population due to a founder
effect (Thomas 2008). About two-third of mutations are nonsense changes and small insertions/deletions
resulting in premature termination of gene translation. Less common are splice site defects. Partial gene deletions
including one or more exons (up to 35 exons) have been observed (Kelsell et al. 2005).
In patients with LI, TGM1 mutations account for the majority of cases and should be ruled out first. Of those LI
patients who do not harbor TGM1 mutations, missense mutations of the ABCA12 gene have been reported in
individuals of 9 families of Northern African decent (Morocco, Mali, Algeria) (Lefevre et al. 2005). The
mutations cluster within 5 exons (exon 28-32), which code for the first nucleotide binding fold of the ABC
transporter. Nevertheless, ABCA12 mutations do not seem to play a role in the pathogenesis of LI in patients of
other populations and ethnicities (Akiyama 2010).
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: Can be used as an alternative to blood for ABCA12 sequencing only. Gene deletion/
duplication testing requires submission of a blood sample. When sending a buccal sample, use a GeneDx
buccal kit (others not accepted). Submit by mail. Buccal brushes are not accepted on children under 6
months of age.
• Prenatal Diagnosis: For prenatal testing for a known mutation in the ABCA12 gene, please refer to the
specimen requirements table on our website at: http://www.genedx.com/test-catalog/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 ”Harlequin/Lamellar
Ichthyosis” page on our website: www.genedx.com
References cited:
(1) Lefevre et al. Hum Mol Genet 12:2369-78, 2003. (2) Kelsell et al. Am J Hum Genet 76: 794-803, 2005. (3) Akiyama et al.
J Invest Dermatol 124: A77, 2005.(4) Thomas AC et al. J Invest Dermatol. 2006 Nov;126(11):2408-13. (5) Thomas et al. Br J
Dermatol. 2008 Mar;158(3):611-3. (6) Akiyama Human Mutation 31(10): 1090-1096, 2010.
Information Sheet on Harlequin/Lamellar Ichthyosis-ABCA12
Page 2 of 2
GeneDx Revision Date: 03/2013