Molecular analyses in Indonesian individuals with intellectual disability and microcephaly
Keywords:
intellectual disability, microcephaly, MCPH genes
Abstract
Background Intellectual disability (ID) often coincides with anabnormal head circumference (HC). Since the HC is a reflection
of brain size, abnormalities in HC may be a sign of a brain anomaly.
Although microcephaly is often secondary to ID, hereditary
(autosomal recessive) forms of primary microcephaly (MCPH)
exist that result in ID.
Objective To investigate mutations in MCPH genes in patients
with ID and microcephaly.
Methods From a population of 527 Indonesian individuals with
ID, 48 patients with microcephaly (9.1 %) were selected. These
patients were previously found to be normal upon conventional
karyotyping, fragile X mental retardation 1 (FMRl) gene analysis,
subtelomeric deletion, and duplication multiplex ligationdependent
probe amplification (MLPA). Sanger sequencing for
abnormal spindle-like microcephaly-associated (ASPM) and WD
repeat domain 62 (WDR62) was performed in all 48 subjects, while
sequencing for microcephalin (MCPHl), cyclin-dependent kinase
5 (CDK5) regulatory subunit-associated protein 2 (CD5KRAP2) ,
centromere protein} (CENPJ), and SCUfALl interrupting locus
(STIL) was conducted in only the subjects with an orbitofrontal
cortex (OFC) below -4 SD.
Results In all genes investigated, 66 single nucleotide polymorphisms
(SNPs) and 15 unclassified variants which were predicted
as unlikely to be pathogenic (lN2), were identified. Possible
pathogenic variants (lN3) were identified in ASPM. However,
since none of the patients harboured compound heterozygous
likely pathogenic mutations, no molecular MCPH diagnosis could
be established. Interestingly, one of the patients harboured the
same variants as her unaffected monozygotic twin sister, indicating
that our cohort included a discordant twin.
Conclusions This study is the first to investigate for possible genetic
causes ofMCPH in the Indonesian population. The absence
of causative pathogenic mutations in the MCPH genes tested may originate from several factors. The identification of UV2
and UV3 variants as well as the absence of causative pathogenic
mutations calls for further investigations.
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pph2/
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88 • Paediatr Irulones, Vol. 53, No. 2, March 2013
lead to Rome? Trends Genet. 2009;25 :501-10.
38. Watemberg N, Silver S, Hare! S, Lerman-Sagie T. Significance
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39. BatubaraJ, AlisjahbanaA, Gerver-JansenAJGM, Alisjahbana
B, Sadjimin T, Tasli Y, et al. Growth diagrams of Indonesian
children: the nationwide survey of 2005. Paediatr Indones.
2006;46:118-26.
inte llectual disabilities. Annu. Rev. Genet. 2011 ;45:8 1-
104.
2. Kaindl AM, Passemard S, Kumar P, Kraemer N, Issa L, Zwimer
A, et al. Many roads lead to primary autosomal recessive
microcephaly. Prog. Neurobiol. 2010;90:363-83 .
3. Mochida OH. Genetics and biology of microcephaly and
lissencephaly. Semin. Pediatr. Neurol. 2009;16: 120-6.
4. Opitz JM Holt MC. Microcephaly: gen eral considerations and
aids to nosology. J Craniofac. Genet Dev Biol. 1990; 10: 17 5-
204.
5. Leviton A, Holmes LB, Allred EN, Vargas J. Methodologic
issues in epidemiologic studies of congenital microcephaly.
Early Hum Dev. 2002;69:91-105.
6. Tarrant A, Gare! C, Germanaud D, de Villemeur TB, Mignot
C, Lenoir M, et al. Microcephaly: a radiological review. Pediatr Radio!. 2009;39:772-80.
7. Woods CG. Human microcephaly. Curr Opin Neurobiol.
2004;14:112-7.
8. Abuelo D. Microcephaly syndromes. Semin Pediatr Neurol.
2007 ;14:118-27.
9. Trimbom M, Ghani M, Walther DJ, Dopatka M, Dutrannoy
V, Busche A, et al. Establishment of a mouse model with
misregulated chromosome condensation due to defective
Mcphl function. PLoS One. 2010;5:e9242.
10. O'Dtiscoll M, Jackson AP, J eggo PA. Microcephalin: a ca us al
link between impaired damage response signalling and
microcephaly. Cell Cycle. 2006;5:2339-44.
11. Bilguvar K, Ozturk AK, Louvi A, Kwan KY, Choi M, Tatli
B, et al. Whole-exome sequencing identifies recessive
WDR62 mutations in severe brain malformations. Nature.
2010;467 :207-10.
12. Nicholas AK, Khurshid M, Desir J, Carvalho OP, Cox JJ,
Thornton G, et al. WDR62 is associated with the spindle
pole and is mutated in human microcephaly. Nat. Genet.
2010;42:1010-4.
13. Yu TW, Mochida GH, Tischfield DJ, Sgaier SK, FloresSamat
L, Sergi CM, et al. Mutations in WDR62, encoding
a centrosome -associated protein, cause microcephaly with
simplified gyri and abnormal cortical architecture. Nat.
Genet. 2010;42:1015-20.
14. Bond J, Roberts E, Springell K, Lizarraga SB, Scott S, Higgins
J, et al. A centrosomal mechanism involving CDK5RAP2 and
CENPJ controls brain size. Nat. Genet. 2005;37:353-5.
15. Fong KW, Choi YK, Rattner JB, Qi RZ. CDK5RAP2 is
a pericentriolar protein that functions in centrosomal
attachment of the gamma-tubulin ring complex. Mol Biol
Cell. 2008; 19:115-25.
16. Guernsey DL, Jiang H, Hussin J, Arnold M, Bouyakdan K,
Perry S, et al. Mutations in centrosomal protein CEP152 in
primary microcephaly families linked to M CPH 4. Am J Hum
Genet. 2010; 87 :40-5 1.
17. Kalay E, Yigit G, Asian Y, Brown KE, Pohl E, Bicknell LS, et
al. CEP152 is a genome maintenance protein disrupted in
Seckel syndrome. Nat Genet. 2011;43 :23 -6.
18. Kouprina N, Pavlicek A, Collins NK, Nakano M, N oskov VN,
OhzekiJ, etal. The microcephaly ASPM gene is expressed in
proliferating tissues and encodes for a mitotic spindle protein.
Hum. Mol. Genet. 2005;14:2155-65.
19. Zhong X, Liu L, Zhao A, Pfeifer GP, Xu X. The abnormal
spindle-like, microcephaly-associated (ASPM) gene encodes
a centrosomal protein. Cell Cycle. 2005; 4: 122 7 -9.
20. Hung LY, Ch en HL, Chang CW, Li BR, Tang TK.
Identification of a novel microtubule-destabilizing motif
in CPAP that binds to tubulin heterodimers and inhibits
microtubule assembly. Mol Biol Cell. 2004; 15 :2697-706.
21. VulprechtJ, David A, Tibelius A, CastielA, Konotop G, Liu
F, et al. STIL is required for centriole duplication in human
cells. J. Cell Sci. 2012; 125: 1353-62.
22. Kumar A, Girimaji SC, Duvvari MR, Blanton SH. Mutations
in STIL, encoding a pericentriolar and centrosomal protein,
cause primarymicrocephaly.AmJ Hum Genet. 2009;84:286-
90.
23. Hussain MS, Baig SM, Neumann S, Numberg G, Farooq M,
Ahmad I, et al. A truncating mutation of CEP135 causes
primary microcephaly and disturbed centrosomal function.
AmJ Hum Genet. 2012;90:871-8.
24. Sajid Hussain M, Marriam Bakhtiar S, Farooq M, Anjum
I, Janzen E, Reza Toliat M, et al. Genetic heterogeneity in
Pakistani microcephaly families. Clin Genet. 2012;[Epub
ahead of print].
25. Mahmood S, Ahmad W, Hassan MJ. Autosomal recessive
primary microcephaly (MCPH): clinical manifestations,
genetic heterogeneity and mutation continuum. Orphanet
J. Rare Dis. 2011;6:39.
26. Soltani Banavandi MJ, Kahrizi K, Behjati F, Mohseni M,
Darvish H, Bahman I, et al. Investigation of genetic causes
of intellectual disability in Kerman province, South East of
Iran. Iran Red. Crescent. Med J. 2012;14:79-85.
27. Wollnik B. A common mech anism for microcephaly. Nat.
Genet. 2010;42:923-4.
28. Mundhofir FE, Winarni TI, van Bon BW, Aminah S,
Nillesen WM, Merkx G, et al. A cytogenetic study in a large
population of intellectually disabled Indonesians. Genet Test
Mol Biomarkers. 2012;16:412-7.
29. N ellhaus G. Head circumference fr om birth to eighteen years.
Practical composite international and interracial graphs.
Pediatrics. 1968;41:106-14.
30. Miller SA, Dykes DD, Polesky HF. A simple salting out
procedure for extracting DNA fr om human nucleated cells.
Nucleic Acids Res. 1988; 16:1215.
31. Genome Reference Consortium. [cited October 2012]
Available from: http: //www.ncbi.nlm.nih.gov/projects/
genome/assembly/grc/human/index.shtml.
32. Align-Grantham Variation (GV) and Grantham Deviation
(GD) method. [cited October 2012] Available from: http://
agvgd. iarc.fr I .
33. Sorting Tolerant From Intolerant (SIFT). [cited October
2012] Available from: http://sift.jcvi.org/
34 Polymorphismphenotyping (PolyPhen). [cited October
2012] Available from: http://genetics.bwh.harvard. edu/
pph2/
35. Miller J, Chauhan SP, Abuhamad AZ. Discordant twins:
diagnosis, evaluation and management. Am J Obstet.
Gynecol. 2012;206:10-20.
36. Jauhari P, Boggula R, Bhave A, Bhargava R, Singh C, Kohli
N, et al. Aetiology of intellectual disability in paediatric
outpatients in Northern India. Dev Med Child Neurol.
2011 ;53: 167-72.
3 7. Thornton GK, Woods CG. Primary microcephaly: do all roads
88 • Paediatr Irulones, Vol. 53, No. 2, March 2013
lead to Rome? Trends Genet. 2009;25 :501-10.
38. Watemberg N, Silver S, Hare! S, Lerman-Sagie T. Significance
of microcephaly among children with developmental
disabilities. J. Child Neurol. 2002;17:117-22.
39. BatubaraJ, AlisjahbanaA, Gerver-JansenAJGM, Alisjahbana
B, Sadjimin T, Tasli Y, et al. Growth diagrams of Indonesian
children: the nationwide survey of 2005. Paediatr Indones.
2006;46:118-26.
Published
2013-04-30
How to Cite
1.
Mundhofir F, Tunjungputri R, Nillesen W, van Bon B, Ruiterkamp-Versteeg M, Winarni T, Hamel B, Yntema H, Faradz S. Molecular analyses in Indonesian individuals with intellectual disability and microcephaly. PI [Internet]. 30Apr.2013 [cited 22Dec.2024];53(2):83-. Available from: https://paediatricaindonesiana.org/index.php/paediatrica-indonesiana/article/view/259
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Received 2016-08-19
Accepted 2016-08-19
Published 2013-04-30
Accepted 2016-08-19
Published 2013-04-30
