Gene 571 (2015) 149150
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Gene
journal homepage: www.elsevier.com/locate/gene
Letter to the Editor
A case report: Autosomal recessive
microcephaly caused by a novel mutation in
MCPH1 gene
Keywords:
Microcephaly
Sex-inuenced
MCPH1
New mutation
Autosomal Recessive Primary Microcephaly (MCPH-MIM 251200) is
distinguished by congenital decrease in occipito-frontal head circumfer-
ence (OFC) of at least 2 standard deviations (SD) below the population
average in addition to non-progressive mental retardation, without any
prominent neurological disorder. Until now, genetic studies of such pa-
tients in different populations have revealed mutations in 12 genes
(MCPH1, WDR62, CDK5RAP2, CASC5, ASPM, CENPJ, STIL, CEP135, CEP152,
ZNF335, PHC1 and CDK6) in these patients (Faheem et al., 2015).
MCPH1 encodes the protein microcephalin, also called as BRIT1 for
BRCT-Repeat Inhibitor of hTert expression. The phenotypes associated
with its loss of function mutations include microcephaly with simplied
gyral pattern and premature chromosome condensation with micro-
cephaly and mental retardation (Kaindl et al., 2010).
Fig. 1. The homozygous mutation detected in the MCPH1 gene in the patients results in a 15-nucleotide deletion in exon 5 (the cDNA sequencing result by Sanger method is shown).
No conicts of interests exist.No nancial support was utilized in this research.
http://dx.doi.org/10.1016/j.gene.2015.07.058
0378-1119/ 2015 Elsevier B.V. All rights reserved.
Here we report a consanguineous Iranian family with 2 children
both affected with microcephaly. The rst one was an 18-year old
female with normal intelligence and no delay in motor milestones or
speech, but an OFC of 47 cm which was 5 SD below the population
age- and sex-related mean. The second child was a 15-year old boy
with severe mental retardation and an OFC of 37 cm which was 12 SD
below the population mean. Both were delivered spontaneously after
unremarkable pregnancies. Their birth OFCs were 31 cm and 29 cm re-
spectively. Cytogenetic analysis of the male patient showed numerically
normal male karyotype without signicant increase in the fraction of
prophase stage chromosomes. The brain magnetic resonance imaging
(MRI) of the male patient was normal, except for a small brain size.
The heights of female and male patients were 156 cm and 144 cm
respectively. Genomic DNA was extracted from blood samples of the pa-
tients after informed consent using the standard salting out method.
Whole exome sequencing was performed using Illumina's Genome
Analyzer for the male patient with focus on 2752 OMIM disease genes,
including 33 genes related with microcephaly (BGI-Clinical Laboratories,
Shenzhen, China). A homozygous mutation was detected in intron 4 of
MCPH1 gene (c.322-2 ANT) which has not been reported in generalist
polymorphism databases (ExaC or exome variant server (EVS)). The re-
sults were conrmed by Sanger sequencing in both patients and targeted
sequencing on the parents showed that they were both heterozygous for
the detected mutation. In order to assess the consequence of this novel
150 Letter to the Editor
splice-acceptor site mutation, the full-length MCPH1-cDNA was
synthesized from RNAs prepared from lymphocytes and then amplied
by PCR. A fragment of amplied cDNA in the region of exons 45
were sequenced using the ABI Prism3130 Genetic Analyzer (Applied
Biosystems, Foster City, CA, USA). This novel splice-acceptor site muta-
tion has been shown to result in an RNA processing defect with a 15-
nucleotide deletion in exon 5 of the mRNA transcript (r.322_336del15,
p.R108_Q112del5) (Fig. 1).
Here, we detected a homozygous intronic mutation in MCPH1 gene
in a male patient with microcephaly and severe mental retardation in
addition to his sister who had microcephaly but normal intelligence.
MCPH1 has been the rst gene whose mutations were detected in
MCPH (Kaindl et al., 2010). Few intronic mutations have been reported
in MCPH1 gene (Darvish et al., 2010). Although sex related difference in
clinical phenotype of MCPH1 mutations has not been previously report-
ed, some missense alterations in this gene have been shown to cause
mild cellular and clinical phenotype (Trimborn et al., 2005). In addition,
polymorphisms in this gene have been suggested as possible mecha-
nisms which elucidate the brain volume variation detected in existing
human populations. Notably, a gender dependent association has been
detected between cranial volume and a polymorphism in this gene
which implies that the expression of genetic variations for brain devel-
opment is different between two sexes (Wang et al., 2008). This differ-
ence has been detected even in the early stages of brain development
and is thought to be regulated mainly by expression of genes encoded
by sex chromosomes. Furthermore, the role of autosome-encoded
genes in sexually dimorphic brain development is being elucidated
(Weickert et al., 2009). For instance, a sex-limited effect on the pene-
trance of the pathological neurodevelopmental phenotypes at the
16p13.11 locus has been identied. In addition, a male biased sex ratio
has been seen in numerous neurodevelopmental disorders which may
be attributed to several factors such as sex-specic variations in gene
regulation or sexually dimorphic epigenetic mechanisms (Tropeano
et al., 2013). Recently, such differences in methylome and tran-
scriptome have been shown in human prefrontal cortex. Sex-biased
DNA methylation and gene expression could be either the cause or out-
come of differential brain development between two sexes (Xu et al.,
2014). We hypothesize that such mechanisms may partially explain
the difference in phenotypes observed in the 2 cases, probably in
addition to other mechanisms such as modier genes.
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Soudeh Ghafouri-Fard
Department of Medical Genetics, Shahid Beheshti University of Medical
Sciences, Tehran, Iran
Majid Fardaei
Department of Medical Genetics, Shiraz University of Medical Sciences,
Shiraz, Iran
Milad Gholami
Department of Medical Genetics, Shahid Beheshti University of Medical
Sciences, Tehran, Iran
Mohammad Miryounesi
Genomic Research Center, Shahid Beheshti University of Medical Sciences,
Tehran, Iran
Corresponding author.
E-mail address: miryounesi@gmail.com.
15 March 2015