Bi-allelic variants in CEP295 cause Seckel-like syndrome presenting with primary microcephaly, developmental delay, intellectual disability, short stature, craniofacial and digital abnormalitiesResearch in context
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
Affiliations
Niu Li
Department of Reproductive Genetics, International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China; Shanghai Key Laboratory of Embryo Original Diseases, International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China; Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China; Faculty of Medical Laboratory Science, College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
Yufei Xu
Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
Hongzhu Chen
Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
Jingqi Lin
Shanghai Key Laboratory of Embryo Original Diseases, International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
Lama AlAbdi
Department of Zoology, College of Science, King Saud University, Riyadh, 11533, Saudi Arabia
Mir Reza Bekheirnia
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA; Texas Children's Hospital, Houston, TX, 77030, USA; Renal Section, Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030, USA
Guoqiang Li
Department of Reproductive Genetics, International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China; Shanghai Key Laboratory of Embryo Original Diseases, International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
Yoel Gofin
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA; Texas Children's Hospital, Houston, TX, 77030, USA
Nasim Bekheirnia
Texas Children's Hospital, Houston, TX, 77030, USA; Renal Section, Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030, USA
Eissa Faqeih
Department of Pediatric Subspecialties, Children's Hospital, King Fahad Medical City, Riyadh, 11533, Saudi Arabia
Lina Chen
Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
Guoying Chang
Department of Endocrinology and Metabolism, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
Jie Tang
Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
Ruen Yao
Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China; Faculty of Medical Laboratory Science, College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
Tingting Yu
Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China; Faculty of Medical Laboratory Science, College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
Xiumin Wang
Department of Endocrinology and Metabolism, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
Wei Fu
Institute of Pediatric Translational Medicine, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
Qihua Fu
Institute of Pediatric Translational Medicine, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China; Shanghai Key Laboratory of Clinical Molecular Diagnostics for Pediatrics, Shanghai, 200127, China
Yiping Shen
Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
Fowzan S. Alkuraya
Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, 11211, Saudi Arabia
Keren Machol
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA; Texas Children's Hospital, Houston, TX, 77030, USA; Corresponding author. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
Jian Wang
Shanghai Key Laboratory of Embryo Original Diseases, International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China; Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China; Faculty of Medical Laboratory Science, College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China; Shanghai Key Laboratory of Clinical Molecular Diagnostics for Pediatrics, Shanghai, 200127, China; Corresponding author. Central Laboratory, International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China.
Summary: 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 G1 cell cycle arrest. Moreover, loss of CEP295 causes extensive primary ciliary defects in both patient-derived fibroblasts and RPE1 cells. The results from complementary experiments revealed that the wild-type CEP295, but not the mutant protein, can correct the developmental defects of the centrosome/centriole and cilia in the patient-derived skin fibroblasts. 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.”
