PUBLICATION

Digenic inheritance of human primary microcephaly delineates centrosomal and non centrosomal pathways

Authors
Duerinckx, S., Jacquemin, V., Drunat, S., Vial, Y., Passemard, S., Perazzolo, C., Massart, A., Soblet, J., Racapé, J., Desmyter, L., Badoer, C., Papadimitriou, S., Borgne, Y.L., Lefort, A., Libert, F., Maertelaer, V., Rooman, M., Costagliola, S., Verloes, A., Lenaerts, T., Pirson, I., Abramowicz, M.
ID
ZDB-PUB-191108-31
Date
2019
Source
Human Mutation   41(2): 512-524 (Journal)
Registered Authors
Costagliola, Sabine, Pirson, Isabelle
Keywords
Primary microcephaly, complex inheritance, digenic inheritance, exome sequencing, zebrafish
MeSH Terms
  • Animals
  • Centrosome/metabolism*
  • Databases, Genetic
  • Exome Sequencing
  • Genetic Association Studies*/methods
  • Genetic Predisposition to Disease*
  • Humans
  • Inheritance Patterns*
  • Microcephaly/diagnosis*
  • Microcephaly/genetics*
  • Mutation
  • Open Reading Frames
  • Phenotype
  • Signal Transduction
  • Zebrafish
(all 15)
PubMed
31696992 Full text @ Hum. Mutat.
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 PM patients, and genome-edited zebrafish modeling for digenic inheritance of PM. Exomes of PM patients 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 PM patients, 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. This article is protected by copyright. All rights reserved.
Genes / Markers
Marker Marker Type Name
aspmGENEassembly factor for spindle microtubules
knl1GENEkinetochore scaffold 1
wdr62GENEWD repeat domain 62
1 - 3 of 3
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Figures
No images available
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Expression
Phenotype
Fish Conditions Stage Phenotype Figure
aspmulb7/+; knl1ulb9/+standard conditionsDay 4 to Day 5
aspmulb7/+; knl1ulb9/+standard conditionsDay 4 to Day 5
aspmulb7/+; knl1ulb9/ulb9standard conditionsDay 4 to Day 5
aspmulb7/+; knl1ulb9/ulb9standard conditionsDay 4 to Day 5
aspmulb7/+; knl1ulb9/ulb9standard conditionsDay 4 to Day 5
aspmulb7/+; knl1ulb9/ulb9standard conditionsDay 4 to Day 5
aspmulb7/+; knl1ulb9/ulb9standard conditionsDay 4 to Day 5
aspmulb7/+; knl1ulb9/ulb9standard conditionsDay 4 to Day 5
aspmulb7/ulb7standard conditionsDay 4 to Day 5
aspmulb7/ulb7standard conditionsDay 4 to Day 5
1 - 10 of 104
Show
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
ulb7
    		Small Deletion
    ulb8
      		Indel
      ulb9
        		Indel
        ulb10
          		Indel
          ulb11
            		Small Deletion
            ulb12
              		Small Deletion
              1 - 6 of 6
              Show
              Human Disease / Model
              Human Disease Fish Conditions Evidence
              primary microcephalyknl1ulb10/ulb10standard conditionsTAS
              primary microcephalyknl1ulb9/ulb9standard conditionsTAS
              primary microcephalyaspmulb7/ulb7; wdr62ulb11/ulb11standard conditionsTAS
              1 - 3 of 3
              Show
              Sequence Targeting Reagents
              Target Reagent Reagent Type
              aspmTALEN1-aspmTALEN
              knl1TALEN1-knl1TALEN
              wdr62TALEN1-wdr62TALEN
              1 - 3 of 3
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              Fish
              Antibodies
              No data available
              Orthology
              Engineered Foreign Genes
              No data available
              Mapping
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              Citation
              Duerinckx, S., Jacquemin, V., Drunat, S., Vial, Y., Passemard, S., Perazzolo, C., Massart, A., Soblet, J., Racapé, J., Desmyter, L., Badoer, C., Papadimitriou, S., Borgne, Y.L., Lefort, A., Libert, F., Maertelaer, V., Rooman, M., Costagliola, S., Verloes, A., Lenaerts, T., Pirson, I., Abramowicz, M. (2019) Digenic inheritance of human primary microcephaly delineates centrosomal and non centrosomal pathways. Human Mutation. 41(2):512-524.