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. 2019 Jan 15;9(1):4.
doi: 10.1038/s41398-018-0343-z.

Family-based exome sequencing and case-control analysis implicate CEP41 as an ASD gene

Ashok Patowary  1 , So Yeon Won  2 , Shin Ji Oh  2 , Ryan R Nesbitt  1 , Marilyn Archer  1 , Debbie Nickerson  3 , Wendy H Raskind  1   4 , Raphael Bernier  1 , Ji Eun Lee  5   6 , Zoran Brkanac  7
Affiliations

Family-based exome sequencing and case-control analysis implicate CEP41 as an ASD gene

Ashok Patowary et al. Transl Psychiatry. .

Abstract

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder with a strong genetic component. Although next-generation sequencing (NGS) technologies have been successfully applied to gene identification in de novo ASD, the genetic architecture of familial ASD remains largely unexplored. Our approach, which leverages the high specificity and sensitivity of NGS technology, has focused on rare variants in familial autism. We used NGS exome sequencing in 26 families with distantly related affected individuals to identify genes with private gene disrupting and missense variants of interest (VOI). We found that the genes carrying VOIs were enriched for biological processes related to cell projection organization and neuron development, which is consistent with the neurodevelopmental hypothesis of ASD. For a subset of genes carrying VOIs, we then used targeted NGS sequencing and gene-based variant burden case-control analysis to test for association with ASD. Missense variants in one gene, CEP41, associated significantly with ASD (p = 6.185e-05). Homozygous gene-disrupting variants in CEP41 were initially found to be responsible for recessive Joubert syndrome. Using a zebrafish model, we evaluated the mechanism by which the CEP41 variants might contribute to ASD. We found that CEP41 missense variants affect development of the axonal tract, cranial neural crest migration and social behavior phenotype. Our work demonstrates the involvement of CEP41 heterozygous missense variants in ASD and that biological processes involved in cell projection organization and neuron development are enriched in ASD families we have studied.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1
Fig. 1. Expression of human CEP41 variants causes axonal deficits in zebrafish brain.
a–d Axon tracts of the forebrain in zebrafish microinjected with cep41 MOs or human CEP41 mRNAs as indicated in each panel. The axons immunostained with anti-acetylated α-Tub antibodies at 35 hpf were imaged by fluorescence microscopy. AC anterior commissures, POC post optic commissure, SOT supra optic tract, TPOC tract of the post optic commissure, TPC tract of the posterior commissure. Asterisks indicate reduced and disorganized axons. Scale bar is 100 µm. e Quantified data by counting zebrafish embryos with forebrain axonal defects. The severity of defective axons is distinguished as the numbers of malformed axonal tracts. Mild: 1–2 axonal defects. Severe: 3–5 axonal defects. f–i Axon tracts of the hindbrain in MOs or mRNA-injected zebrafish. r2, r4 and r6 are rhombomere 2, 4 and 6. Asterisks indicate defective axons and scale bar is 100 µm. j Quantified data by counting zebrafish embryos with hindbrain axonal defects. The severity of defected axons is distinguished as the numbers of abnormal axons. Mild: 1–6 axonal defects. Severe: 7–10 axonal defects
Fig. 2
Fig. 2. The depletion of CEP41 affects migration of the cranial neural crest (CNC) cells in zebrafish.
Analysis of migration of CNC cells in the control MO (a–c), cep41 MO (d–f), P206A (g–i) and cep41 MO+ zebrafish cep41 mRNA (j–l)-injected zebrafish at 8, 10 and 12 somite stages. Asterisks, red arrows and white arrows indicate migrating CNC cells in the forebrain, midbrain and hindbrain, respectively. The extent of medial expansion of CNC cells (yellow arrows, zoomed in area) was compared in the hindbrain of each zebrafish (c′, f′, i′, l′). m. All data are representative of at least five independent experiments. The quantified data of zebrafish with defective CNC cell migration are graphically presented (20 embryos/counting). Abnormal: either delayed migration or medial expansion of CNC cells
Fig. 3
Fig. 3. The deficiency of CEP41 affects social behavior in zebrafish larvae.
a A diagram of experimental chamber indicating the zones for the analysis of target location. b–e Heatmap showing the cumulative location of each 5–6 dpf control MO, cep41 MO and human CEP41 P206A and A107G mRNA injected target zebrafish larvae during 1 h experiment. f Quantified data presenting the percentage of time spent in each zone during 1 h experiment. g The statistical analysis of the time target larvae spent in each zone. The cep41 MO and P206A larvae spend decreased amount of time in zone 1 adjacent to the group. The data are shown as the mean ± SD; *p < 0.05 (Student’s t-test). All data are representative of at least five independent experiments
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