Bi-Allelic Variants in CEP295 Cause Seckel-Like Syndrome Presenting With Primary Microcephaly, Developmental Delay, Intellectual Disability, Short Stature, Craniofacial and Digital Abnormalities

Authors

Niu Li
Yufei Xu
Hongzhu Chen
Jingqi Lin
Lama AlAbdi
Mir Reza Bekheirnia
Guoqiang Li
Yoel Gofin
Nasim Bekheirnia
Eissa Faqeih
Lina Chen
Guoying Chang
Jie Tang
Ruen Yao
Tingting Yu
Xiumin Wang
Wei Fu
Qihua Fu
Yiping Shen
Fowzan S Alkuraya
Keren Machol
Jian Wang

Publication Date

1-1-2024

Journal

EBioMedicine

DOI

10.1016/j.ebiom.2023.104940

PMID

38154379

PMCID

PMC10784679

PubMedCentral® Posted Date

12-27-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Child, Humans, Cell Cycle, Centrioles, Intellectual Disability, Microcephaly, Proteins, Bi-allelic variants of CEP295, Centriole and centrosome development, Seckel-like syndrome, Primary microcephaly, Ciliogenesis

Abstract

BACKGROUND: Pathogenic variants in the centrosome protein (CEP) family have been implicated in primary microcephaly, Seckel syndrome, and classical ciliopathies. However, most CEP genes remain unlinked to specific Mendelian genetic diseases in humans. We sought to explore the roles of CEP295 in human pathology.

METHODS: Whole-exome sequencing was performed to screen for pathogenic variants in patients with severe microcephaly. Patient-derived fibroblasts and CEP295-depleted U2OS and RPE1 cells were used to clarify the underlying pathomechanisms, including centriole/centrosome development, cell cycle and proliferation changes, and ciliogenesis. Complementary experiments using CEP295 mRNA were performed to determine the pathogenicity of the identified missense variant.

FINDINGS: Here, we report bi-allelic variants of CEP295 in four children from two unrelated families, characterized by severe primary microcephaly, short stature, developmental delay, intellectual disability, facial deformities, and abnormalities of fingers and toes, suggesting a Seckel-like syndrome. Mechanistically, depletion of CEP295 resulted in a decrease in the numbers of centrioles and centrosomes and triggered p53-dependent G

INTERPRETATION: This study reports CEP295 as a causative gene of the syndromic microcephaly phenotype in humans. Our study also demonstrates that defects in CEP295 result in primary ciliary defects.

FUNDING: A full list of funding bodies that contributed to this study can be found under "Acknowledgments."