A Novel Frameshift Mutation in Abnormal Spindle-Like Microcephaly (ASPM) Gene in an Iranian Patient with Primary Microcephaly: A Case Report
Autosomal recessive primary microcephaly (MCPH) is a rare genetic disorder, leading to the defect of neurogenic brain development. Individuals with MCPH reveal reduced head circumference and intellectual disability. Several MCPH loci have been identified from several populations. Genetic heterogeneity of this disorder represents molecular testing challenge. An 8 yr old female, born from consanguineous parents, was attended to Fardis Central Lab, Alborz, Iran. Based on the reduced circumference and intellectual disability, MCPH was diagnosed. Whole exome sequencing of the patient identified a novel homozygous frameshift mutation (c.2738dupT, p.Cys914fs) in exon 9 Abnormal Spindle-like Microcephaly )ASPM( gene. By Sanger sequencing, segregation analysis showed that both parents were heterozygous carriers for this variant. The novel frameshift mutation likely truncates the protein, resulting in loss of normal function ASPM in homozygous mutation carriers. The study might add a new pathogenic variant in mutations of the ASPM gene as a causative variant in patients with MCPH and might be helpful in genetic counseling of consanguineous families.
2. Kaindl AM, Passemard S, Kumar P, et al (2010). Many roads lead to primary autosomal recessive microcephaly. Prog Neurobiol, 90:363-383.
3. Jayaraman D, Bae B-I, Walsh CA (2018). The Genetics of Primary Microcephaly. Annu Rev Genomics Hum Genet, 19:177-200.
4. Mahmood S, Ahmad W, Hassan MJ (2011). Autosomal recessive primary microcephaly (MCPH): clinical manifestations, genetic heterogeneity and mutation continuum. Orphanet J Rare Dis, 6:39.
5. Jayaraman D, Kodani A, Gonzalez DM, et al (2016). Microcephaly proteins Wdr62 and Aspm define a mother centriole complex regulating centriole biogenesis, apical complex, and cell fate. Neuron, 92:813-828.
6. Koboldt DC, Steinberg KM, Larson DE, Wilson RK, Mardis ER (2013). The next-generation sequencing revolution and its impact on genomics. Cell, 155:27-38.
7. Darvish H, Esmaeeli-Nieh S, Monajemi G, et al (2010). A clinical and molecular genetic study of 112 Iranian families with primary microcephaly. J Med Genet, 47(12):823-8.
8. Akbariazar E, Ebrahimpour M, Akbari S, et al (2013). A novel deletion mutation in ASPM gene in an Iranian family with autosomal recessive primary microcephaly. Iran J Child Neurol, 7:23-30.
9. Bond J, Roberts E, Mochida GH, et al (2002). ASPM is a major determinant of cerebral cortical size. Nat Genet, 32:316-20.
10. Bond J, Scott S, Hampshire DJ, et al (2003). Protein-truncating mutations in ASPM cause variable reduction in brain size. Am J Hum Genet, 73:1170-1177.
11. Pichon B, Vankerckhove S, Bourrouillou G, Duprez L, Abramowicz MJ (2004). A translocation breakpoint disrupts the ASPM gene in a patient with primary microcephaly. Eur J Hum Genet, 12:419-21.
12. Thornton GK, Woods CG (2009). Primary microcephaly: do all roads lead to Rome? Trends Genet, 25:501-510.
13. Abdel‐Hamid MS, Ismail MF, Darwish HA, Effat LK, Zaki MS, Abdel‐Salam GM (2016). Molecular and phenotypic spectrum of ASPM‐related primary microcephaly: Identification of eight novel mutations. Am J Med Genet A, 170:2133-2140.
14. Nicholas A, Woods G, Swanson E, et al (2009). The molecular landscape of ASPM mutations in primary microcephaly. J Med Genet, 46(4):249-53.
15. Gul A, Hassan MJ, Mahmood S, et al (2006). Genetic studies of autosomal recessive primary microcephaly in 33 Pakistani families: novel sequence variants in ASPM gene. Neurogenetics, 7:105-110.