Harlequin ichthyosis due to novel splice site mutation in the
ABCA12 gene: postnatal to prenatal diagnosis
Jayesh J. Sheth,
, Riddhi Bhavsar,
, Dhairya Patel,
, Aishwarya Joshi,
and Frenny J. Sheth,
FRIGE’s Institute of Human Genetics,
FRIGE House, Ahmedabad, India
FRIGE’s Institute of Human Genetics
FRIGE House, Jodhpur Gam Road Satellite
Conﬂict of Interest: All authors declare that
they have no conﬂict of interest
Background Harlequin ichthyosis (HI) is a severe genetic disorder caused by the mutation
in the ABCA12 gene. Infants born with this condition have markedly thickened, hard
stratum corneum skin all over the body.
Methods A female child born with a thick white plate of skin with deep cracks all over the
body was investigated for genes associated with congenital Ichthyosis by Next Generation
sequencing. The variant relevant to the clinical indications was identiﬁed using Picard and
GATK version 3.6. Variant’s pathogenicity was predicted by “in silico” tools like Mutation
Taster 2, Mutation Assessor and LRT. Bidirectional Sanger sequencing further validated
the same variant detected in the proband and conﬁrmed in the parental blood and CVS.
Results A homozygous 5
splice site variation that affects the position at 4 nucleotides
downstream to the donor proximal splice site of intron 40 (c.5939+4A>G;
ENST00000272895) of the ABCA12 gene was detected in the proband, and the parents
were heterozygous for the same variant. This led to the conﬁrmation of diagnosis of
Harlequin ichthyosis in the proband. “In silico” prediction of the variant was found to be
damaging by MutationTaster2. The CVS sample during subsequent pregnancy was
conﬁrmed to be heterozygous for the same variant.
Conclusions The novel intronic mutation found in the proband conﬁrmed the clinical
diagnosis as a severe type of HI and has helped the family in providing precise genetic
counseling for further prevention of the disease and carrier screening of other family
Harlequin ichthyosis (HI) is a rare genodermatological disease
characterized by the defective formation of intercellular lipid lay-
ers, resulting in loss of barrier function, consequently leading to
The affected infants are typically born prema-
ture and are encased in a markedly thickened, hard stratum
corneum. This thick casing cracks soon after birth, resulting in
the formation of erythematous ﬁssures separating thick, geo-
metric plates of skin. This is accompanied by severe ectropion,
eclabium, and ﬂattened ears. On histological examination, char-
acteristic abnormalities in the structure of lamellar granules and
in the expression of epidermal keratin can be observed.
the past, an affected neonate would usually die within 2 days of
birth owing to feeding problems, bacterial infections, and/or res-
piratory distress; however, a number of patients have been
reported to have survived because of the availability of neonatal
intensive care and beneﬁts of oral retinoids.
occurring with this disorder are alopecia, digital contractures,
and growth delays. The hyperkeratotic covering is shed, leaving
the skin erythematous and scaly. This latter presentation domi-
nates for the remainder of the patient’s life,
leaving the skin
barrier severely compromised, leading to an increased transepi-
dermal water loss, hindered thermal regulation, and increased
risk of secondary infection.
HI is an autosomal recessive disorder caused by a mutation in
ABCA12 gene, with an incidence of 1 in 300,000 births. This
gene is involved in keratinocyte differentiation and epidermal lipid
It belongs to a superfamily of ATP-binding
cassettes, which perform the transport of various biomolecules
across the cell membrane.
As a consequence, lipids and pro-
teases are not secreted into the interstitial space between granu-
lar layer keratinocytes. This deﬁciency of interstitial lipid delivery
results in a profoundly abnormal epidermal permeability barrier
and subsequently increased transcutaneous water loss.
kine cascades and induction of hyperplasia is the way the body
responds to this, leading to epidermal hyperkeratosis and inﬂam-
mation, which is characteristic of HI.
Though the exact incidence of HI in India is not known, there
are anecdotal reports from the country without any molecular
International Journal of Dermatology 2018, 57, 428–433 ª 2018 The International Society of Dermatology