Supplementary Material for: Molecular Genetic Analysis of Newborns with Congenital Microcephaly

<b><i>Introduction:</i></b> Data on the genetic landscape of congenital microcephaly (CM) in China are scarce, and the incidence of CM caused by the most commonly mutated gene <i>ASPM</i> in China remains unknown. <b><i>Methods:</i></b> Sixty-one neonates with CM who were hospitalized in the Children’s Hospital of Fudan University between August 1, 2016, and August 31, 2020, were enrolled, and the clinical data and clinical exome-sequencing data were analyzed. An additional 18,103 parental data entries from the Chinese Children’s Genetic Testing Clinical Collaboration System database were collected to estimate the incidence of <i>ASPM</i>-related congenital microcephaly (<i>ASPM</i>-CM) in East China by analyzing the carrier frequency of <i>ASPM</i> mutations. <b><i>Results:</i></b> Among the 61 neonates with CM, 35 (57.4%) patients were identified with genetic findings, including 24 patients with single nucleotide variants (SNVs) and 11 patients with copy number variations (CNVs). <i>ASPM</i> was the most common gene with detrimental SNVs detected in 3 patients. Patients with genetic findings showed a significantly higher incidence of developmental delay (91.3%, 21/23) than those without genetic findings (60%, 9/15) (<i>p</i> = 0.04). All the 3 decreased patients had genetic findings. The estimated <i>ASPM</i>-CM incidence in East China was 1/1,295,044. <b><i>Conclusion:</i></b> Comprehensive genetic testing, detecting both SNVs and CNVs, is recommended for newborns with CM. Patients with genetic findings should be aware of the potential for developmental delay. <i>ASPM</i> gene defect was the most common genetic cause of CM in this study. The estimation of the incidence of <i>ASPM</i>-CM in East China might provide a reference for analyzing overall incidence.

引言：目前中国关于先天性小头畸形（congenital microcephaly, CM）的遗传特征相关数据较为匮乏，且由最常见突变基因ASPM所致的先天性小头畸形的发病率在国内仍未明确。方法：本研究纳入2016年8月1日至2020年8月31日期间于复旦大学附属儿童医院住院的61例先天性小头畸形新生儿，对其临床资料及临床外显子组测序数据进行分析。此外，从中国儿童基因检测临床协作系统数据库中额外收集了18103条亲本数据条目，通过分析ASPM突变的携带者频率，估算华东地区ASPM相关先天性小头畸形（ASPM-CM）的发病率。结果：在61例先天性小头畸形新生儿中，35例（57.4%）检出遗传学异常，其中24例存在单核苷酸变异（single nucleotide variants, SNVs），11例存在拷贝数变异（copy number variations, CNVs）。ASPM是本研究中最常见的致病基因，共在3例患者中检出有害单核苷酸变异。检出遗传学异常的患儿，其发育迟缓发生率（91.3%，21/23）显著高于未检出遗传学异常者（60%，9/15）（p=0.04）。所有3例功能减退患者均检出遗传学异常。本次研究估算得出华东地区ASPM相关先天性小头畸形的发病率为1/1295044。结论：建议对先天性小头畸形新生儿开展同时覆盖单核苷酸变异与拷贝数变异的综合遗传学检测。检出遗传学异常的患儿需警惕发生发育迟缓的风险。本研究中，ASPM基因缺陷是先天性小头畸形最常见的遗传学病因。本次对华东地区ASPM相关先天性小头畸形发病率的估算，可为整体发病率的分析提供参考依据。