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 Here we report a consanguineous Iranian family with 2 children
microcephaly caused by a novel mutation in both affected with microcephaly. The rst one was an 18-year old
MCPH1 gene 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
Keywords:
age- and sex-related mean. The second child was a 15-year old boy
Microcephaly with severe mental retardation and an OFC of 37 cm which was 12 SD
Sex-inuenced below the population mean. Both were delivered spontaneously after
MCPH1 unremarkable pregnancies. Their birth OFCs were 31 cm and 29 cm re-
New mutation
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
Autosomal Recessive Primary Microcephaly (MCPH-MIM 251200) is (MRI) of the male patient was normal, except for a small brain size.
distinguished by congenital decrease in occipito-frontal head circumfer- The heights of female and male patients were 156 cm and 144 cm
ence (OFC) of at least 2 standard deviations (SD) below the population respectively. Genomic DNA was extracted from blood samples of the pa-
average in addition to non-progressive mental retardation, without any tients after informed consent using the standard salting out method.
prominent neurological disorder. Until now, genetic studies of such pa- Whole exome sequencing was performed using Illumina's Genome
tients in different populations have revealed mutations in 12 genes Analyzer for the male patient with focus on 2752 OMIM disease genes,
(MCPH1, WDR62, CDK5RAP2, CASC5, ASPM, CENPJ, STIL, CEP135, CEP152, including 33 genes related with microcephaly (BGI-Clinical Laboratories,
ZNF335, PHC1 and CDK6) in these patients (Faheem et al., 2015). Shenzhen, China). A homozygous mutation was detected in intron 4 of
MCPH1 encodes the protein microcephalin, also called as BRIT1 for MCPH1 gene (c.322-2 ANT) which has not been reported in generalist
BRCT-Repeat Inhibitor of hTert expression. The phenotypes associated polymorphism databases (ExaC or exome variant server (EVS)). The re-
with its loss of function mutations include microcephaly with simplied sults were conrmed by Sanger sequencing in both patients and targeted
gyral pattern and premature chromosome condensation with micro- sequencing on the parents showed that they were both heterozygous for
cephaly and mental retardation (Kaindl et al., 2010). the detected mutation. In order to assess the consequence of this novel

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.
150 Letter to the Editor

splice-acceptor site mutation, the full-length MCPH1-cDNA was References

synthesized from RNAs prepared from lymphocytes and then amplied
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by PCR. A fragment of amplied cDNA in the region of exons 45 study of 112 Iranian families with primary microcephaly. J. Med. Genet. 47 (12),
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tion has been shown to result in an RNA processing defect with a 15- Kaindl, A.M., Passemard, S., Kumar, P., et al., 2010. Many roads lead to primary autosomal
nucleotide deletion in exon 5 of the mRNA transcript (r.322_336del15, recessive microcephaly. Prog. Neurobiol. 90 (3), 363383.
p.R108_Q112del5) (Fig. 1). Trimborn, M., Richter, R., Sternberg, N., et al., 2005. The rst missense alteration in
the MCPH1 gene causes autosomal recessive microcephaly with an extremely mild
Here, we detected a homozygous intronic mutation in MCPH1 gene cellular and clinical phenotype. Hum. Mutat. 26 (5), 496.
in a male patient with microcephaly and severe mental retardation in Tropeano, M., Ahn, J.W., Dobson, R.J., et al., 2013. Male-biased autosomal effect of
addition to his sister who had microcephaly but normal intelligence. 16p13.11 copy number variation in neurodevelopmental disorders. PLoS One 8 (4),
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MCPH1 has been the rst gene whose mutations were detected in
Wang, J.K., Li, Y., Su, B., 2008. A common SNP of MCPH1 is associated with cranial volume
MCPH (Kaindl et al., 2010). Few intronic mutations have been reported variation in Chinese population. Hum. Mol. Genet. 17 (9), 13291335.
in MCPH1 gene (Darvish et al., 2010). Although sex related difference in Weickert, C.S., Elashoff, M., Richards, A.B., et al., 2009. Transcriptome analysis of
clinical phenotype of MCPH1 mutations has not been previously report- malefemale differences in prefrontal cortical development. Mol. Psychiatry 14 (6),
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ed, some missense alterations in this gene have been shown to cause Xu, H., Wang, F., Liu, Y., Yu, Y., Gelernter, J., Zhang, H., 2014. Sex-biased methylome and
mild cellular and clinical phenotype (Trimborn et al., 2005). In addition, transcriptome in human prefrontal cortex. Hum. Mol. Genet. 23 (5), 12601270.
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 Soudeh Ghafouri-Fard
detected between cranial volume and a polymorphism in this gene
Department of Medical Genetics, Shahid Beheshti University of Medical
which implies that the expression of genetic variations for brain devel- Sciences, Tehran, Iran
opment is different between two sexes (Wang et al., 2008). This differ-
ence has been detected even in the early stages of brain development
Majid Fardaei
and is thought to be regulated mainly by expression of genes encoded
Department of Medical Genetics, Shiraz University of Medical Sciences,
by sex chromosomes. Furthermore, the role of autosome-encoded
Shiraz, Iran
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 Milad Gholami
16p13.11 locus has been identied. In addition, a male biased sex ratio Department of Medical Genetics, Shahid Beheshti University of Medical
has been seen in numerous neurodevelopmental disorders which may Sciences, Tehran, Iran
be attributed to several factors such as sex-specic variations in gene
regulation or sexually dimorphic epigenetic mechanisms (Tropeano Mohammad Miryounesi
et al., 2013). Recently, such differences in methylome and tran- Genomic Research Center, Shahid Beheshti University of Medical Sciences,
scriptome have been shown in human prefrontal cortex. Sex-biased Tehran, Iran
DNA methylation and gene expression could be either the cause or out- Corresponding author.
come of differential brain development between two sexes (Xu et al., E-mail address: [email protected].
2014). We hypothesize that such mechanisms may partially explain
the difference in phenotypes observed in the 2 cases, probably in 15 March 2015
addition to other mechanisms such as modier genes.