Non-classic splicing mutation in the CPLANE1 (C5orf42) gene cause Joubert syndrome in a fetus with severe craniocerebral dysplasia

Haiyan Zhu; Wangyang Chen; He Ren; Yunshan Zhang; Yanyan Niu; Di Wu; Lin Jiang

doi:10.1016/j.ejmg.2021.104212

Non-classic splicing mutation in the CPLANE1 (C5orf42) gene cause Joubert syndrome in a fetus with severe craniocerebral dysplasia

Eur J Med Genet. 2021 Jun;64(6):104212. doi: 10.1016/j.ejmg.2021.104212. Epub 2021 Mar 30.

Authors

Haiyan Zhu¹, Wangyang Chen², He Ren³, Yunshan Zhang³, Yanyan Niu⁴, Di Wu⁴, Lin Jiang⁴

Affiliations

¹ Departments of Gynecology and Obstetrics, The Sixth Medical Center of PLA General Hospital, Beijing, 100048, China. Electronic address: fbird2004@sina.com.
² Kaiumph Medical Diagnostics Co, Ltd, Cuihuyun Center 17-3-3, Beijing, 100102, China.
³ Departments of Ultrasound Medicine, The Sixth Medical Center of PLA General Hospital, Beijing, 100048, China.
⁴ Departments of Gynecology and Obstetrics, The Sixth Medical Center of PLA General Hospital, Beijing, 100048, China.

PMID: 33794348
DOI: 10.1016/j.ejmg.2021.104212

Abstract

Backgroud: Joubert syndrome is a rare neurodevelopmental disorder characterized by clinical and genetic heterogeneity. The characteristic molar tooth sign, which resulted from cerebellar vermis hypoplasia and midbrain anomalies, is expected to be the key diagnostic feature for this disease. However, it is not easy to make a definite diagnosis in prenatal only based on the imageology due to its clinical heterogeneity.

Case report: We report on a fetus who was detected cerebellum dysplasia and encephalocele by ultrasound at 19 and 23 gestational weeks and confirmed by MRI examination. The pregnancy was terminated at 23 weeks of gestation. Postaxial polydactyly and deficiency in occipital bone and skin were identified in the induced fetus.

Results: The whole exome sequencing identified a novel compound heterozygous variation in the CPLANE1 gene related with Joubert syndrome, including a 2-bp insertion, NM_023073.3:c.1383_1384dup; p.(Gly462Glufs*3) and a non-classic splicing variation, NC_000005.10(NM_023073.3):c.7691-5_7691-4del. The pathogenicity of the non-classic splicing variation was further confirmed by cDNA level sequencing, which showed a exon 39 skipping that would introduce a premature termination. The novel compound heterozygous variation caused a complete function loss of the CPLANE1 gene.

Conclusion: The cerebellum dysplasia fetus without obvious molar tooth sign was finally diagnosed as Joubert syndrome, combined with genetic detecting and the postnatal clinical symptoms. We also highlight the clinical heterogeneity of encephalodysplasia in Joubert syndrome, which increases the clinical diagnosis difficulty, especially for prenatal diagnosis. Our findings provided a new perspective for the prenatal diagnosis of Joubert syndrome with severe craniocerebral dysplasia and expanded the variation spectrum of the CPLANE1 gene.

Keywords: CPLANE1 gene; Ciliopathy; Encephalocele; Joubert syndrome; Splicing; Whole exome sequencing.

Publication types

Case Reports

MeSH terms

Abnormalities, Multiple / genetics*
Abnormalities, Multiple / pathology
Aborted Fetus / abnormalities*
Adult
Cerebellum / abnormalities*
Cerebellum / diagnostic imaging
Cerebellum / pathology
Eye Abnormalities / genetics*
Eye Abnormalities / pathology
Female
Humans
Kidney Diseases, Cystic / genetics*
Kidney Diseases, Cystic / pathology
Membrane Proteins / genetics*
Mutation*
RNA Splicing
Retina / abnormalities*
Retina / pathology
Ultrasonography, Prenatal

Substances

CPLANE1 protein, human
Membrane Proteins

Supplementary concepts

Agenesis of Cerebellar Vermis