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

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Tolezano, Giovanna Cantini ; Bastos, Giovanna Civitate ; da Costa, Silvia Souza ; Freire, Bruna Lucheze ; Homma, Thais Kataoka ; Honjo, Rachel Sayuri ; Yamamoto, Guilherme Lopes ; Passos-Bueno, Maria Rita ; Koiffmann, Celia Priszkulnik ; Kim, Chong Ae ; Vianna-Morgante, Angela Maria ; Jorge, Alexander Augusto de Lima ; Bertola, Debora Romeo ; Rosenberg, Carla ; Krepischi, Ana Cristina Victorino

• Document type: Journal article
• Source: JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS; v. N/A, p. 32-pg., 2022-12-11.

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. (AU)

• FAPESP's process: 20/15552-2 - Investigating the spectrum of genome copy number variations in individuals with microcephaly or macrocephaly phenotypes
• Grantee: Giovanna Civitate Bastos
• Support Opportunities: Scholarships in Brazil - Scientific Initiation