Contribution of rare coding variants to microcephaly in individuals with neurodevelopmental disorders

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dc.catalogadorjca
dc.contributor.authorYoon, Jihoon G.
dc.contributor.authorJang, Hyunsoo
dc.contributor.authorLee, Seungbok
dc.contributor.authorJang, Se S.
dc.contributor.authorPark, Soojin
dc.contributor.authorCho, Jaeso
dc.contributor.authorKim, Minji
dc.contributor.authorHan, Jiye
dc.contributor.authorYun, Hyounji
dc.contributor.authorKim, Man J.
dc.contributor.authorKim, Soo Y.
dc.contributor.authorKim, Woo J.
dc.contributor.authorCho, Anna
dc.contributor.authorLee, Jin S.
dc.contributor.authorChoi, Murim
dc.contributor.authorFernandez-Jaen, Alberto
dc.contributor.authorSilva, Sebastian
dc.contributor.authorUribe San Martin, Reinaldo Moises
dc.contributor.authorCantillano, Christian
dc.contributor.authorMiyake, Noriko
dc.contributor.authorLim, Byung C.
dc.contributor.authorKo, Jung M.
dc.contributor.authorKim, Ki J.
dc.contributor.authorYoon, Ki-Jun
dc.contributor.authorChae, Jong-Hee
dc.date.accessioned2025-08-18T17:25:20Z
dc.date.available2025-08-18T17:25:20Z
dc.date.issued2025
dc.date.updated2025-08-10T00:03:01Z
dc.description.abstractBackground Microcephaly, characterized by an abnormally small head size, frequently co-occurs with neurodevelopmental disorders (NDDs). While the genetic basis of NDDs has been widely investigated, the contribution of rare coding variants to microcephaly remains poorly understood. Methods We investigated the relationships between head circumference and rare coding variants in 418 individuals with microcephaly, analyzing data from 1050 exomes (312 trios and 106 proband-only samples). Participants were classified into primary microcephaly (PM) and secondary microcephaly (SM) groups, and their clinical and genetic characteristics were systematically assessed. The functional impact of high-priority candidate genes, RTF1 and ASAP2, was further validated using neural progenitor cells (NPCs) and human forebrain organoid models. Results Exome sequencing revealed 142 causative and 12 candidate genes associated with microcephaly. Pathway analyses indicated that PM genes are linked to early phases of brain development, whereas SM genes are more associated with later stages of neuronal maturation. In addition, the PM group had a significantly higher proportion of autosomal recessive disorders and exhibited more severe microcephaly than the SM group. Notably, females displayed greater microcephaly severity than males, primarily attributable to differences in the origin of the allele and inheritance patterns on the X chromosome. Functional experiments using CRISPR-Cas9 knockout in NPCs and brain organoids demonstrated reduced NPC proliferation, supporting the essential role of RTF1 and ASAP2 in brain development. Conclusions This study sheds light on the complex genetic architecture of microcephaly, emphasizing the impact of rare coding variants on brain development and delineating distinct clinical and molecular profiles underlying PM and SM.
dc.fechaingreso.objetodigital2025-08-09
dc.format.extent20 páginas
dc.fuente.origenBiomed Central
dc.identifier.issn1756-994X
dc.identifier.urihttps://doi.org/10.1186/s13073-025-01513-w
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/105213
dc.information.autorucEscuela de Medicina; Uribe San Martin, Reinaldo Moises; 0000-0002-3422-7962; 127201
dc.issue.numero86
dc.language.isoen
dc.nota.accesocontenido completo
dc.revistaGenome Medicine
dc.rightsacceso abierto
dc.subjectMicrocephaly
dc.subjectHead circumference
dc.subjectNeurodevelopmental disorder
dc.subjectExome sequencing
dc.subjectBrain organoids
dc.subject.ddc610
dc.subject.deweyMedicina y saludes_ES
dc.subject.ods03 Good health and well-being
dc.subject.odspa03 Salud y bienestar
dc.titleContribution of rare coding variants to microcephaly in individuals with neurodevelopmental disorders
dc.typeartículo
dc.volumen17
sipa.codpersvinculados127201
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