Digenic inheritance of human primary microcephaly delineates centrosomal and non-centrosomal pathways
Sarah Duerinckx1,2, Valérie Jacquemin1, Séverine Drunat3,4
1Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Université Libre de Bruxelles, Brussels, Belgium.
Abstract:
Primary microcephaly (PM) is characterized by a small head since birth and is vastly heterogeneous both genetically and phenotypically. While most cases are monogenic, genetic interactions between Aspm and Wdr62 have recently been described in a mouse model of PM. Here, we used two complementary, holistic in vivo approaches: high throughput DNA sequencing of multiple PM genes in human patients with PM, and genome-edited zebrafish modeling for the digenic inheritance of PM. Exomes of patients with PM showed a significant burden of variants in 75 PM genes, that persisted after removing monogenic causes of PM (e.g., biallelic pathogenic variants in CEP152). This observation was replicated in an independent cohort of patients with PM, where a PM gene panel showed in addition that the burden was carried by six centrosomal genes. Allelic frequencies were consistent with digenic inheritance. In zebrafish, non-centrosomal gene casc5 -/- produced a severe PM phenotype, that was not modified by centrosomal genes aspm or wdr62 invalidation. A digenic, quadriallelic PM phenotype was produced by aspm and wdr62. Our observations provide strong evidence for digenic inheritance of human PM, involving centrosomal genes. Absence of genetic interaction between casc5 and aspm or wdr62 further delineates centrosomal and non-centrosomal pathways in PM.
Insights
Genetic interactions, specifically digenic inheritance involving centrosomal genes, contribute to primary microcephaly (PM). This study reveals complex genetic underpinnings beyond single-gene causes for PM.
Area of Science:
- Genetics
- Developmental Biology
- Human Disease
Background:
- Primary microcephaly (PM) is a heterogeneous condition characterized by a small head at birth.
- While often monogenic, recent studies suggest genetic interactions may play a role in PM.
- Understanding the genetic basis of PM is crucial for diagnosis and potential therapies.
Purpose of the Study:
- To investigate the role of digenic inheritance in primary microcephaly.
- To identify specific genes and pathways involved in PM pathogenesis.
- To explore genetic interactions between centrosomal and non-centrosomal genes in PM.
Main Methods:
- High-throughput DNA sequencing of 75 primary microcephaly genes in human patients.
- Genome-edited zebrafish modeling to study digenic inheritance.
- Analysis of variant burden in patient exomes and gene panels.
- Zebrafish experiments involving gene invalidation (casc5, aspm, wdr62).
Main Results:
- A significant burden of variants in 75 PM genes was observed in patients, even after excluding monogenic causes.
- Six centrosomal genes were implicated in PM in an independent cohort.
- Zebrafish models demonstrated digenic inheritance of PM involving aspm and wdr62.
- The non-centrosomal gene casc5 showed no interaction with aspm or wdr62 in zebrafish PM models.
Conclusions:
- Strong evidence supports digenic inheritance involving centrosomal genes in human primary microcephaly.
- This finding expands the understanding of PM genetics beyond monogenic forms.
- Distinct non-centrosomal and centrosomal pathways contribute to PM development.
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