title: Molecular and phenotypic spectrum of ASPM-related primary microcephaly: Identification of eight novel mutations.
abstract: Autosomal recessive primary microcephaly (MCPH) is an abnormal proliferation of neurons during brain development that leads to a small brain size but architecturally normal in most instances. Mutations in the ASPM gene have been identified to be the most prevalent. Thirty-seven patients from 30 unrelated families with a clinical diagnosis of MCPH were enrolled in this study. Screening of ASPM gene mutations was performed by targeted linkage analysis followed by direct sequencing. Thirteen protein truncating mutations of the ASPM were identified in 15 families (50%), eight of which were novel mutations. The mutations detected were eight nonsense, four frameshift, and one splice site. Two of these mutations (p.R1327* and p.R3181*) were recurrent and shared similar haplotypes suggesting founder effect. Patients with ASPM mutations had mild to severe intellectual disability and variable degrees of simplified gyral pattern and small frontal lobe. In addition, hypoplasia of corpus callosum (18 patients), mildly small cerebellar vermis (10 patients), and relatively small pons (13 patients) were found in 85.7%, 47.6%, and 61.9%, respectively. Furthermore, one patient had porencephaly and another had a small midline cyst. Epilepsy was documented in two patients (9.5%). Non-neurologic abnormalities consisted of growth retardation (four patients), and co-incidental association of oculo-cutaneous albinism (one patient). Our study expands the mutation spectrum of ASPM. Moreover, the simplified gyral pattern and small frontal lobe together with hypoplastic corpus callosum, small cerebellum and pons enable ASPM mutated patients to be distinguished. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Medical Molecular Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt.
authors.forename: Mohamed S
authors.initials: MS
authors.lastname: Abdel-Hamid
authors.affiliation: Biochemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
authors.forename: Manal F
authors.initials: MF
authors.lastname: Ismail
authors.affiliation: Biochemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
authors.forename: Hebatallh A
authors.initials: HA
authors.lastname: Darwish
authors.affiliation: Medical Molecular Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt.
authors.forename: Laila K
authors.initials: LK
authors.lastname: Effat
authors.affiliation: Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt.
authors.forename: Maha S
authors.initials: MS
authors.lastname: Zaki
authors.affiliation: Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt.
authors.forename: Ghada M H
authors.initials: GM
authors.lastname: Abdel-Salam
mesh_terms: D000293:Adolescent; D000483:Alleles; D019943:Amino Acid Substitution; D001921:Brain / Q000002:abnormalities; D002648:Child; D002675:Child, Preschool; D003241:Consanguinity; D005091:Exons; D019066:Facies; D005260:Female; D056726:Genetic Association Studies; D008040:Genetic Linkage; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging; D008297:Male; D008831:Microcephaly / Q000175:diagnosis* / Q000235:genetics*; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010641:Phenotype
chemical_list: C467202:ASPM protein, human; D009419:Nerve Tissue Proteins
keywords: ASPM gene; Egyptian; autosomal recessive; founder effect; novel mutations; primary microcephaly