Two New Cases of Primary Microcephaly with Neuronal Migration Defect Caused by Truncating Mutations in the ASPM Gene

• Published in: Molecular syndromology Vol. 13; no. 1; pp. 56 - 63
• Main Authors: Türkyılmaz, Ayberk, Sager, Safiye Gunes
• Format: Journal Article
• Language: English
• Published: Basel, Switzerland S. Karger AG 01.02.2022
• Subjects: Novel Insights from Clinical Practice; Polymicrogyria; ASPM; Pachygyria; Novel variant; Whole-exome sequencing
• ISSN: 1661-8769; 1661-8777
• DOI: 10.1159/000516201

Abstract Autosomal recessive primary microcephaly (MCPH) is a uncommon disorder due to congenital deficiency in the development of the cerebral cortex, characterized by a head circumference below 2 SD. MCPH is a group of diseases with genetic heterogeneity and has been reported by the Online Mendelian Inheritance In Man® (OMIM) database and associated with 25 different genes. It is known that MCPH cases are most frequently associated with abnormal spindle-like, microcephaly-associated (ASPM) gene mutations. The ASPM protein consists of an N-terminal 81 IQ (isoleucine-glutamine) domain, a calponin-homology domain, and a C-terminal domain. It interacts with calmodulin and calmodulin-related proteins via the IQ domain and acts as a part in mitotic spindle function. The basic characteristics of cases with ASPM gene mutations are microcephaly (below −3 SD) present before 1 year of age, intellectual disability, and the absence of other congenital anomalies. Macroscopic organization of the brain is preserved in cases with ASPM mutation, and a decrease in brain volume, particularly gray matter volume loss and a simplified gyral pattern are observed. Cortical migration defects are a very rare finding in patients with ASPM mutations. In the present study, we aimed to discuss the clinical and genetic findings in 2 cases with cortical dysplasia in which truncated variants in the ASPM gene were detected, particularly in terms of genotype-phenotype correlation in comparison with the literature.