Abstract: Background：Primary microcephaly (MCPH) is a rare genetic disorder characterized by occipitofrontal circumference equal to or below -2 SDs at birth, facial deformity and intellectual disability. Objective：To summarize and analyze the clinical and genetic characteristics of patients with primary microcephaly caused by ASPM gene defects (ASPMMCPH) in both the China Neonatal Genome Project (CNGP) and HGMD database. Design：Case series report. Methods：The newborns with biallelic pathogenic/likely pathogenic (P/LP) variants in ASPM gene in the CNGP were included. The clinical and genetic features were summarized. We established the P/LP variant list of ASPM gene from CNGP, HGMD and ClinVar database, and calculated the frequency of carrying ASPM P/LP variants in the whole CNGP cohort. And finally, the genotypephenotype association of ASPMMCPH was summarized by analyzing the records from the HGMD database. Main outcome measures：The assessment of the frequency of carrying ASPM P/LP variants in the whole CNGP cohort. Results：Twelve P/LP variants in ASPM gene were identified in 6 patients, of which 6 variants were novel. Prenatal B-ultrasound showed microcephaly and primary microcephaly was diagnosed after birth for all of the 6 patients. But other typical clinical features were absent. The frequency of carrying P/LP variants in ASPM gene in the whole CNGP cohort was 0.001 206 043. In the previously reported cases, the incidence of microcephaly, facial deformity and mild to moderate developmental delay was more than 50%. Brain MRI showed abnormal gyri and ventricular dilation. Regarding the types of variants, the proportion of lossoffunction variants was 96.43%. There was no statistically significant difference between the effect of lossoffunction and missense variants on the degree of developmental delay. Conclusion：Six novel P/LP variants in ASPM gene were identified in this study. The frequency of carrying P/LP variants in ASPM gene was assessed. Genetic testing was recommended for fetuses with microcephaly.

Key words: Primary microcephaly, ASPM gene, Case reports