Content uploaded by Richard J Leventer
Author content
All content in this area was uploaded by Richard J Leventer on Aug 31, 2017
Content may be subject to copyright.
NEWS AND COMMENTARY
LIS1 and DCX MLPA
......................................
Listen carefully: LIS1 and DCX
MLPA in lissencephaly and
subcortical band heterotopia
Martin B Delatycki and Richard J Leventer
.........................................................................
European Journal of Human Genetics (2009) 17, 701 –702; doi:10.1038/
ejhg.2008.230; published online 3 December 2008
Malformations of the brain are a
common cause of morbidity
in the community. With an
estimated 100 billion neuronal cells that
migrate to their final destinations, and
subsequent formation of one quadrillion
(1 000 000 000 000 000) synapses during
pre- and postnatal development, it is not
surprising that the process of cortical de-
velopment can be disrupted by genetic
and environmental factors. Common
outcomes from such brain malformations
include severe intellectual disability,
cerebral palsy and epilepsy.
Much has been learnt over recent years
about the genetic causes of neuronal
migration disorders and other brain
malformations. In lissencephaly, there is
a thickened cortex and a paucity of
gyration ranging from absent gyri (agyria)
to less severe forms with widened gyri
(pachygyria). Subcortical band heteroto-
pia, or ‘double cortex’, is manifest by
bilateral bands of grey matter in the white
matter between the lateral ventricles and
the cerebral cortex. Both lissencephaly
and subcortical band heterotopia are dis-
orders of neuronal migration, with many
neurons failing to reach their intended
destination in the cortical mantle.
A major advance in the understanding
of these disorders occurred with the
discovery of the LIS1 gene in 1993 and
the DCX gene in 1998.
1–3
Mutations
involving the LIS1 gene, located at
17p13.3, generally cause lissencephaly,
more severe in the posterior than in the
anterior part of the brain. Lissencephaly
generally has severe manifestations
including severe intellectual disability
and intractable epilepsy. Mutations invol-
ving DCX on the X chromosome at
Xq22.3 can result in severe lissencephaly
usually in male individuals and generally
more severe anteriorly than posteriorly.
The same mutations may also result in
subcortical band heterotopia, and this is
usually in female individuals. Subcortical
band heterotopia usually results in
seizures with or without intellectual
impairment and rarely can be asympto-
matic.
4
Mutations in either LIS1 or DCX
account for approximately 80% of cases of
typical lissencephaly and subcortical band
heterotopia. Mutations in a number of
other genes including ARX,RELN and
TUBA1A account for a small percentage
of the remaining cases of lissencephaly,
leaving 10 – 20% of patients without a
genetic diagnosis.
On page XXX of this issue, Haverfield
and colleagues present data from MLPA
testing of LIS1 and DCX in 83 individuals
with lissencephaly of varying severity
or subcortical band heterotopia, in an
attempt to improve the yield of making
a genetic diagnosis in otherwise typical
forms of these conditions. These indivi-
duals earlier had sequencing of LIS1 and
DCX and FISH studies for large microdele-
tions involving LIS1, with no mutations
being found. The investigators found that
in 52 individuals with lissencephaly, sug-
gestive of LIS1 involvement (more severe
posteriorly than anteriorly), there were 12
deletions and six duplications of LIS1.In
31 individuals with brain abnormalities
suggestive of DCX involvement (more
severe anteriorly than posteriorly), three
deletions were identified in DCX. Of the
18 deletions and duplications in LIS1,
alterations varied from deletion or dupli-
cation of a single exon to deletions
involving the entire coding region of
LIS1. Notably, this whole gene deletion
was not identifiable by FISH using com-
mercially available probes. It is worth
noting that no deletions or duplications
in LIS1 were found in individuals with the
most severe lissencephaly (grade 1 or 2),
or in individuals with subcortical band
heterotopia with a gradient of severity
greater posteriorly than anteriorly. The
three DCX deletions were found in female
individuals with subcortical band hetero-
topia. No DCX deletions were found in
individuals with more severe lissence-
phaly, or in male individuals with sub-
cortical band heterotopia.
The results of the study of Haverfield
and colleagues add important knowledge
to the field. Before this study, about 75%
of individuals with lissencephaly were
known to have mutations in LIS1 or
DCX, and around 85% of individuals with
subcortical band heterotopia were known
to have mutations in DCX. The findings
of this study mean that these figures are
increased to around 85 and 90%, respec-
tively. The authors recommend that in
individuals with isolated lissencephaly
sequence, MLPA of LIS1 and DCX should
be the first step as it will identify intra-
genic deletions and duplications as well as
larger microdeletions. If normal, this
should be followed by sequencing of
LIS1 or DCX, depending on the pattern
of malformation. By contrast, the authors
recommend that where subcortical band
heterotopia is present, DCX sequencing
should be the first-line investigation as
deletions and duplications are far less
common.
These new findings mean that around
10% of additional individuals with iso-
lated lissencephaly sequence and 5% of
additional individuals with subcortical
band heterotopia will now be able to have
the cause of their brain malformation
diagnosed. This has very important im-
plications for these individuals and their
families. Female individuals identified
with DCX mutations that result in sub-
cortical band heterotopia have a 50% risk
that their sons will have lissencephaly and
European Journal of Human Genetics (2009) 17, 701 – 702
&
2009 Macmillan Publishers Limited All rights reserved 1018-4813/09
$32.00
www.nature.com/ejhg
significant morbidity. Therefore, the iden-
tification of an intragenic deletion or
duplication in DCX means that indivi-
duals can have appropriate genetic
counselling and can avail themselves of
prenatal testing or preimplantation diag-
nosis should they choose. If an individual
is found to have a deletion or duplication
involving LIS1, then families can be
reassured that the risk of similar problems
in subsequent children is very low and
that prenatal testing or preimplantation
diagnosis is available to identify the
unlikely possibility of gonadal mosaicism
resulting in a recurrence.
Using current techniques, approxi-
mately 10% of patients with typical forms
of lissencephaly and subcortical band
heterotopia remain without a genetic
diagnosis. This rate is significantly higher
for those with atypical forms such as
subcortical band heterotopia in male in-
dividuals and lissencephaly with unusual
severity gradients or abnormalities of
other brain structures such as the corpus
callosum or cerebellum. No doubt there
are other genes to be found for these
conditions, so we will continue to listen
carefully to this interesting and expand-
ing area of neurogenetics’
Professor Martin B Delatycki is at The
Bruce Lefroy Centre for Genetic Health
Research, MCRI, Royal Children’s Hosp,
10th Flr, Royal Children’s Hosptial,
Flemington Road, Parkville, Victoria 3052,
Australia.
Tel: þ61 3 8341 6284;
Fax: þ61 3 8341 6390;
E-mail: martin.delatycki@ghsv.org.au
References
1 Reiner O, Carrozzo R, Shen Y et al: Isolation
of a Miller – Dieker lissencephaly gene con-
taining G protein beta-subunit-like repeats.
Nature 1993; 364: 717 – 721.
2 Gleeson JG, Allen KM, Fox JW et al: Dou-
blecortin, a brain-specific gene mutated in
human X-linked lissencephaly and double
cortex syndrome, encodes a putative signal-
ing protein. Cell 1998; 92: 63 – 72.
3 des Portes V, Pinard JM, Billuart P et al:A
novel CNS gene required for neuronal
migration and involved in X-linked subcor-
tical laminar heterotopia and lissencephaly
syndrome. Cell 1998; 92: 51 – 61.
4 Guerrini R, Marini C: Genetic malforma-
tions of cortical development. Exp Brain Res
2006; 173: 322 – 333.
News and Commentary
702
European Journal of Human Genetics
