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Burden of Rare Copy Number Variants in Microcephaly: A Brazilian Cohort of 185 Microcephalic Patients and Review of the Literature

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Abstract

Microcephaly presents heterogeneous genetic etiology linked to several neurodevelopmental disorders (NDD). Copy number variants (CNVs) are a causal mechanism of microcephaly whose investigation is a crucial step for unraveling its molecular basis. Our purpose was to investigate the burden of rare CNVs in microcephalic individuals and to review genes and CNV syndromes associated with microcephaly. We performed chromosomal microarray analysis (CMA) in 185 Brazilian patients with microcephaly and evaluated microcephalic patients carrying < 200 kb CNVs documented in the DECIPHER database. Additionally, we reviewed known genes and CNV syndromes causally linked to microcephaly through the PubMed, OMIM, DECIPHER, and ClinGen databases. Rare clinically relevant CNVs were detected in 39 out of the 185 Brazilian patients investigated by CMA (21%). In 31 among the 60 DECIPHER patients carrying < 200 kb CNVs, at least one known microcephaly gene was observed. Overall, four gene sets implicated in microcephaly were disclosed: known microcephaly genes; genes with supporting evidence of association with microcephaly; known macrocephaly genes; and novel candidates, including OTUD7A, BBC3, CNTN6, and NAA15. In the review, we compiled 957 known microcephaly genes and 58 genomic CNV loci, comprising 13 duplications and 50 deletions, which have already been associated with clinical findings including microcephaly. We reviewed genes and CNV syndromes previously associated with microcephaly, reinforced the high CMA diagnostic yield for this condition, pinpointed novel candidate loci linked to microcephaly deserving further evaluation, and provided a useful resource for future research on the field of neurodevelopment.

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Data Availability

All the patient’s data reported in this work can be accessed in the DECIPHER website (https://www.deciphergenomics.org/) through the IDs presented in Tables 2 and 4.

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Acknowledgments

The authors would like to thank the patients and their families and the funding agencies São Paulo Research Foundation ([FAPESP] Grant Numbers 2013/080828-1, 2020/15552- 2) and National Council for Scientific and Technological Development ([CNPq] Grant Numbers 157816/2018-4, 305806/2019-0, 140271/2020-1, 303294/2020-5, 303375/2019-1) for supporting this work. This study makes use of data generated by the DECIPHER community. A full list of centres who contributed to the generation of the data is available from https://www.deciphergenomics.org/about/stats and via email from contact@deciphergenomics.org. Funding for the DECIPHER project was provided by Wellcome. Those who carried out the original analysis and collection of the Data bear no responsibility for the further analysis or interpretation of them.

Funding

São Paulo Research Foundation ([FAPESP] Grant Numbers 2013/080828-1, 2020/15552-2) and National Council for Scientific and Technological Development ([CNPq] Grant Numbers 157816/2018-4, 305806/2019-0, 140271/2020-1, 303294/2020-5, 303375/2019-1).

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  1. Giovanna Cantini Tolezano, Giovanna Civitate Bastos and Ana Cristina Victorino Krepischi have contributed equally to this work.

Authors and Affiliations

  1. Department of Genetics and Evolutionary Biology, Human Genome and Stem-Cell Research Center, Institute of Biosciences, University of São Paulo, 106 Rua do Matão, São Paulo, SP, 05508-090, Brazil

    Giovanna Cantini Tolezano, Giovanna Civitate Bastos, Silvia Souza da Costa, Guilherme Lopes Yamamoto, Maria Rita Passos-Bueno, Celia Priszkulnik Koiffmann, Angela Maria Vianna-Morgante, Débora Romeo Bertola, Carla Rosenberg & Ana Cristina Victorino Krepischi

  2. Unidade de Endocrinologia Genética (LIM25), Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, 455 Avenida Doutor Arnaldo, São Paulo, SP, 01246-903, Brazil

    Bruna Lucheze Freire, Thais Kataoka Homma & Alexander Augusto de Lima Jorge

  3. Unidade de Genética do Instituto da Criança, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, 647 Avenida Doutor Enéas Carvalho de Aguiar, São Paulo, SP, 05403-900, Brazil

    Rachel Sayuri Honjo, Guilherme Lopes Yamamoto, Chong Ae Kim & Débora Romeo Bertola

  4. Institute of Biosciences, University of São Paulo, 277 Rua do Matão, São Paulo, SP, 05508-090, Brazil

    Ana Cristina Victorino Krepischi

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  1. Giovanna Cantini Tolezano
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Contributions

ACVK designed this study and obtained funding; BLF, TKH, RSH, GLY, MRPB, CPK, CAK, AALJ, and DRB referred the patients for CMA; SSC, CR, and ACVK performed the CMA experiments and analysis; GCT and GCB conducted the bibliographic research; AALJ and DRB reviewed the patient's clinical data; GCT wrote the manuscript; GCT, GCB, AMVM, CR, and ACVK reviewed the text. All the authors have read and approved the final manuscript.

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Correspondence to Ana Cristina Victorino Krepischi.

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Supplementary Information

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10803_2022_5853_MOESM1_ESM.xlsx

Supplementary Table 1. List of genes reported to be associated with phenotypes including microcephaly according to OMIM and PubMed. (XLSX 44 kb)

10803_2022_5853_MOESM2_ESM.xlsx

Supplementary Table 2. Full description of the clinical presentation of the 39 Brazilian microcephalic patients carrying pathogenic, likely pathogenic, VUS, and susceptibility CNVs for neurodevelopmental disorders. (XLSX 20 kb)

10803_2022_5853_MOESM3_ESM.jpg

Supplementary Figure 1. Overlapping copy number changes affecting known microcephaly genes that were detected in Brazilian patients and prioritized microcephalic DECIPHER patients carrying <200 kb CNVs. Genomic features of each overlapping segment are displayed with the encompassed protein-coding genes (GENCODE v36 track). Blue line tracks indicate duplications, red lines indicate deletions, and lilac areas highlight known genes for the microcephaly phenotype; darker tracks denote known CNV syndromes already associated with a reduction in brain size. Patients’ DECIPHER IDs are shown; T2 corresponds to “Table 2”, and T4 corresponds to “Table 4” (images derived from the UCSC Genome Browser, up to July 2021). (a) CNVs at 15q26.3 encompassing IGF1R and overlapping with the known chromosome 15q26-qter deletion syndrome region. (b) Overlapping segment at Xq13.1-q13.2, encompassing HDAC8. Note that patient 322306 carries two adjacent CNVs, a 484 kb deletion and a 184 kb duplication. (JPG 418 kb)

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Tolezano, G.C., Bastos, G.C., da Costa, S.S. et al. Burden of Rare Copy Number Variants in Microcephaly: A Brazilian Cohort of 185 Microcephalic Patients and Review of the Literature. J Autism Dev Disord 54, 1181–1212 (2024). https://doi.org/10.1007/s10803-022-05853-z

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