A Novel Frameshift Mutation in Abnormal Spindle-Like Microcephaly (ASPM) Gene in an Iranian Patient with Primary Microcephaly: A Case Report

Abstract

<jats:p>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.</jats:p>

An update of pathogenic variants in ASPM, WDR62, CDK5RAP2, STIL, CENPJ, and CEP135 underlying autosomal recessive primary microcephaly in 32 consanguineous families from Pakistan

“…The findings of this study are in line with previous reports because we have also observed 68.75% (22/32) families carrying a mutation in ASPM . Building on another elegant study by Letard and colleagues (Letard et al, 2018)—summarizing 189 ASPM mutations in 282 previously reported and 39 new families—we reviewed the literature published thereafter and extended the mutational spectrum to 211 in 381 families (Ahmed et al, 2019; Bazgir, Agha Gholizadeh, Sarvar, & Pakzad, 2019; Bhargav, Sreedevi, Swapna, Vivek, & Kovvali, 2017; Boonsawat et al, 2019; Khan, Wang, Han, Ahmad, & Zhang, 2018; Kvarnung et al, 2018; Li et al, 2017; Marakhonov et al, 2018; McSherry et al, 2018; Moriwaki et al, 2019; Okamoto, Kohmoto, Naruto, Masuda, & Imoto, 2018; Shaheen et al, 2019). This number also includes 10 novel mutations of 8 families identified in this study (Figure 1 and Table ).…”

Updates on Clinical and Genetic Heterogeneity of ASPM in 12 Autosomal Recessive Primary Microcephaly Families in Pakistani Population

“…Patients may exhibit mild to severe developmental delay, sloping forehead, epilepsy, and hereditary hearing loss. Predominantly, primary microcephaly shows an autosomal recessive mode of inheritance ( 4 , 5 ). So far, mutations in 25 genes have been linked with MCPH.…”

PDCD6IP, encoding a regulator of the ESCRT complex, is mutated in microcephaly

“…[1][2][3] The overall incidence of microcephaly at birth varies from 1.3 to 150/100 000 in different worldwide populations. 4 Microcephaly is predominantly autosomal recessive (AR) and is therefore more prevalent in consanguineous unions than other family structures. 3,4 However, families with either autosomal dominant or X linked inheritance have been reported.…”

“…4 Microcephaly is predominantly autosomal recessive (AR) and is therefore more prevalent in consanguineous unions than other family structures. 3,4 However, families with either autosomal dominant or X linked inheritance have been reported. 5,6 Other clinical features associated with microcephaly are delayed motor and cognitive development, intellectual disability, movement disorders, feeding and vision problems, epilepsy, and autism.…”

“…Microcephaly is a clinically and genetically heterogeneous neurodevelopmental condition that is distinguished by reduced head circumference less than two (≤2) standard deviations (SD) below the mean for sex, age, and ethnicity with mild to severe intellectual disability (ID) 1–3 . The overall incidence of microcephaly at birth varies from 1.3 to 150/100 000 in different worldwide populations 4 . Microcephaly is predominantly autosomal recessive (AR) and is therefore more prevalent in consanguineous unions than other family structures 3,4 .…”