Whole‐exome sequencing identified novel variants in CPLANE1 that causes oral‐facial‐digital syndrome Ⅵ by inducing primary cilia abnormality

Abstract

Oral‐facial‐digital syndrome (OFDS) is a multisystemic ciliopathic disorder with an autosomal recessive mode of inheritance. OFDS usually manifests with typical craniofacial anomalies and variable occurrence of polydactyly. Germline variants in CPLANE1 cause OFDS VI. In this study, we investigated a 26‐year‐old Chinese female patient who was 23 +1 weeks pregnant. She had a history of adverse pregnancy outcomes with multiple foetal malformations. We performed ultrasonography and identified the foetus as having a posterior fossa Blake cyst and postaxial polydactyly. The patient decided to terminate her pregnancy, and further genetic molecular analysis was performed. We identified the aborted foetus as having postaxial polydactyly. Whole‐exome sequencing identified a missense variant (c.3599C>T, p.A1200V) in exon 20 and a c.834+1G>T variant in exon 7 of CPLANE1 (NM_023073.3) in the foetus. Sanger sequencing confirmed that these variants came from the parents of the foetus. In this study, we investigated a family with OFDS VI through genetic testing and bioinformatics analysis, which provided powerful help for prenatal diagnosis. Then, we demonstrated that the cell migration rate and the number of cilia were decreased after interference with CPLANE1 expression in NIH/3T3 cells. After CPLANE1 knockdown, the Hh signalling pathway was inhibited, and the Hh pathway activator SAG reversed the inhibitory effect. This is the first report of a family with OFDS VI in the Chinese population.

When NIPT meets WES, prenatal diagnosticians face the dilemma: genetic etiological analysis of 2,328 cases of NT thickening and follow-up of pregnancy outcomes

“…Whole-exon sequencing and Sanger sequencing (NextSeq 2000, Illumina, United States) were performed on DNA samples. Variants were identified by sequence alignment with the NCBI Reference Sequence; the pathogenicity of the identified variant was assessed based on the adapted American College of Medical Genetics and Genomics (ACMG) guidelines ( Chen et al, 2022 ; Qian et al, 2022 ).…”

High Incidence of CPLANE1-Related Joubert Syndrome in the Products of Conceptions from Early Pregnancy Losses

“… 19 , 20 According to the Human Protein Atlas Database, the CPLANE1 gene is expressed in placental tissue during pregnancy, indicating that the function of the CPLANE1 gene product may be crucial in pregnancy maintenance. 21 , 22 Defects in this gene cause JS type 17, which is caused by pathogenic homozygous or compound heterozygous loss of function variants, as well as orofaciodigital syndrome VI, which is caused by a combination of pathogenic loss of function and missense variants. 18 JS type 17 is an autosomal recessive condition found primarily in patients of French-Canadian origin.…”