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Year : 2016  |  Volume : 61  |  Issue : 1  |  Page : 122
Novel ALOX12B mutation identified in parents following single nucleotide polymorphism microarray testing of banked DNA from a fatal case of congenital ichthyosis

Department of Medical Genetics, Kasturba Medical College, Manipal University, Manipal, Karnataka, India

Date of Web Publication15-Jan-2016

Correspondence Address:
Katta M Girisha
Department of Medical Genetics, Kasturba Medical College, Manipal University, Manipal, Karnataka
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0019-5154.174134

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In genetically and phenotypically heterogeneous conditions like ichthyosis, it is clinically not possible to predict mutation in a specific gene. Sequential testing of all the causative genes is time consuming and expensive. In consanguineous families with autosomal recessive genetically heterogeneous disorders, it is possible to narrow down the candidate gene/genes by recognizing the regions of homozygosity by a single nucleotide polymorphism (SNP) array. Here, we present a fatal case of autosomal recessive severe congenital ichthyosis born to a consanguineous couple. Two candidate genes were recognized by SNP array on banked DNA of the subject. Sequencing of these candidate genes in parents found them to be carriers of the same variation, a novel heterozygous deletion of single nucleotide in exon 8 (c. 1067delT) of ALOX12B gene. The present case illustrates the utility of DNA banking, SNP array and testing of parents to arrive at a definitive molecular diagnosis, essential for genetic counseling, and prenatal testing.

Keywords: Autosomal recessive congenital ichthyosis, genetics, ichthyosis, mutation

How to cite this article:
Salian S, Gupta A, Shukla A, Girisha KM. Novel ALOX12B mutation identified in parents following single nucleotide polymorphism microarray testing of banked DNA from a fatal case of congenital ichthyosis. Indian J Dermatol 2016;61:122

How to cite this URL:
Salian S, Gupta A, Shukla A, Girisha KM. Novel ALOX12B mutation identified in parents following single nucleotide polymorphism microarray testing of banked DNA from a fatal case of congenital ichthyosis. Indian J Dermatol [serial online] 2016 [cited 2020 Sep 27];61:122. Available from: http://www.e-ijd.org/text.asp?2016/61/1/122/174134

What was known?

  • Single nucleotide polymorphism array based approach for identifying candidate genes is a cost effective method in consanguineous families with genetically heterogeneous conditions like autosomal recessive congenital recessive ichthyosis.

   Introduction Top

Autosomal recessive congenital ichthyosis (ARCI) is a clinically and genetically heterogeneous group of disorders. [1] Eleven causative genes have been identified till date for ARCI. In absence of a genotype-phenotype correlation, it is very time consuming and expensive to sequence all the genes one by one. Next generation sequencing based multigene panels for testing all the causative genes at a time are expensive and beyond the reach of most physicians. Hence, the approach of narrowing down the candidate gene/genes in the regions of homozygosity by single nucleotide polymorphism (SNP) array in consanguineous families followed by Sanger sequencing of these genes is worthwhile.

   Case Report Top

A newborn male baby was referred for evaluation and management of congenital ichthyosis. He was the first child of third degree consanguineous parents, born as a collodion baby. He was delivered by cesarean section at 39 weeks of gestation in view of oligohydramnios and nonprogression of labor. Baby cried immediately after birth and weighed 2.9 kg. On examination, he had dry, thick skin with nonbullous generalized erythematous desquamation, bilateral ectropion, eclabium and digital contractures [Figure 1]. Rest of the examination was unremarkable. There was no significant antenatal and family history. Clinical diagnosis of nonsyndromic congenital ichthyosis was made and he was managed conservatively. In view of the severe disease, DNA banking of the baby was offered and accepted by the parents. Breastfeeding was established, and he was shifted back to referring hospital for primary care on day 15 of life. He developed sepsis after a week and in spite of appropriate treatment, deteriorated and succumbed on day 30 of life.
Figure 1: Collodion baby with generalized nonbullous, erythematous desquamation, ectropion, eclabium and digital contractures

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Stored DNA of the proband was investigated by an SNP array that revealed multiple large regions of homozygosity. Two candidate genes (ALOXE3 and ALOX12B) were identified in these regions of homozygosity known to cause ARCI. Since the baby's sample was not sufficient for further DNA analysis, carrier testing of parents was planned by sequencing of the two candidate genes. After analyzing ALOXE3 gene in parents, which did not show any pathogenic variation, mutation screening was extended to ALOX12B gene. Sequencing of ALOX12B gene of parents showed that both parents were carriers for a novel mutation, a heterozygous deletion, c. 1067delT in exon 8 of ALOX12B gene. This variation shifts the reading frame and terminates translation at residue 25 (p.I356Tfs*25).

   Discussion Top

ARCI are nonsyndromic forms of ichthyosis. The clinical presentation of ARCI is a continuous spectrum with the most severe harlequin ichthyosis at one end and the milder forms, lamellar ichthyosis (LI) and congenital ichthyosiform erythroderma at the other. [2] These phenotypic descriptions are mainly useful for prognostication and management. Genes known to cause ARCI include TGM1, ALOXE3, ALOX12B, NIPAL4, ABCA12, CYP4F22, PNPLA1, LIPN, ST14, ARCI7, and CERS3. Further heterogeneity is expected as few families do not carry mutations in these known genes. Mutations in four genes (TGM1, ALOXE3, ALOX12B, and ABCA12) account for more than 90% cases of ARCI. Mutations in TGM1 account for 38-55% of ARCI and about 90% of LI. Mutations in the gene ABCA12 are detected only in 5% cases of ARCI, but account for more than 93% cases of harlequin ichthyosis. Mutation in ALOXE3 and ALOX12B together cause 11-20% cases of ARCI. [3],[4],[5],[6]

Molecular diagnosis is the most important step for genetic counseling of families with genetic disorders. Genetic testing not only helps in confirming the diagnosis, but also in prognostication, management and prenatal diagnosis for the subsequent pregnancies in the family. Homozygosity mapping using SNP array is a cost-effective and useful tool for consanguineous families with genetically heterogeneous disorders. [7] The presence of candidate gene/genes in large regions of homozygosity offers an accessible approach to these heterogeneous disorders as these genes can be easily analyzed by the reasonably available and affordable conventional sequencing. [8] Thus, it helps to avoid the excessive cost and time of sequential gene testing. Here, we also highlight the importance of DNA banking in critically sick neonates. DNA banking offers a valuable approach of storage of DNA and its subsequent use for genetic testing in families.

   Conclusion Top

Option of DNA banking should be discussed with parents of any sick neonate with genetic disorder for future molecular testing as it is not possible to provide proper genetic counseling and prenatal diagnosis in future pregnancies without identification of molecular defect. SNP array-based approach for candidate gene search is a useful and cost-effective test in consanguineous families with genetically heterogeneous conditions.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.


We thank the family for consenting to participate in this study.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

   References Top

Sheth J, Shah S, Master D, Sheth F. Prenatal exclusion of lameller ichthyosis based on two novel mutations in TGM 1 gene. Indian J Dermatol 2006;51:281-2.  Back to cited text no. 1
  Medknow Journal  
Oji V, Tadini G, Akiyama M, Blanchet Bardon C, Bodemer C, Bourrat E, et al. Revised nomenclature and classification of inherited ichthyoses: Results of the First Ichthyosis Consensus Conference in Sorèze 2009. J Am Acad Dermatol 2010;63:607-41.  Back to cited text no. 2
Dahlqvist J, Klar J, Hausser I, Anton-Lamprecht I, Pigg MH, Gedde-Dahl T Jr, et al. Congenital ichthyosis: Mutations in ichthyin are associated with specific structural abnormalities in the granular layer of epidermis. J Med Genet 2007;44:615-20.  Back to cited text no. 3
Akiyama M, Sugiyama-Nakagiri Y, Sakai K, McMillan JR, Goto M, Arita K, et al. Mutations in lipid transporter ABCA12 in harlequin ichthyosis and functional recovery by corrective gene transfer. J Clin Invest 2005;115:1777-84.  Back to cited text no. 4
Cluzeau C, Hadj-Rabia S, Jambou M, Mansour S, Guigue P, Masmoudi S, et al. Only four genes (EDA1, EDAR, EDARADD, and WNT10A) account for 90% of hypohidrotic/anhidrotic ectodermal dysplasia cases. Hum Mutat 2011;32:70-2.  Back to cited text no. 5
Akiyama M, Shimizu H. An update on molecular aspects of the non-syndromic ichthyoses. Exp Dermatol 2008;17:373-82.  Back to cited text no. 6
Alkuraya FS. Homozygosity mapping: One more tool in the clinical geneticist's toolbox. Genet Med 2010;12:236-9.  Back to cited text no. 7
Wierenga KJ, Jiang Z, Yang AC, Mulvihill JJ, Tsinoremas NF. A clinical evaluation tool for SNP arrays, especially for autosomal recessive conditions in offspring of consanguineous parents. Genet Med 2013;15:354-60.  Back to cited text no. 8

What is new?

  • c. 1067delT is a novel mutation in ALOX12B gene that casues autosomal recessive congenital ichthyosis
  • DNA banking should be offered to sick neonates with severe forms of congenital ichthyosis
  • Where there is insufficient DNA from the proband, homozygosity testing can suggest candidate genes which can then be sequenced in the parents.


  [Figure 1]


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