Clinical and Molecular Features of Ciliopathies Diagnosed by Prenatal Exome Sequencing in Fetuses With Ultrasound...

To characterize prenatal phenotypes and genetic basis of ciliopathies identified by prenatal exome sequencing (pES) in fetuses with ultrasound abnormalities.

Singleton pregnancies who underwent pES due to fetal ultrasound abnormalities were retrospectively reviewed between 2020 and 2023. Cases affected by ciliopathies were included if diagnostic variants were identified in 959 ciliopathy-associated gene entries in the manually curated SCGSv2 and integrated database CilioGenics (top 500). Phenotype-genotype correlations were analyzed.

A total of 41 cases were diagnosed as ciliopathies by pES with a detection rate of 7.4% (41/555). DYNC2H1 and FGFR3 were the most common genes associated with first-order and second-order skeletal ciliopathies, while PKD1 was the major causative gene of renal ciliopathies. Consistent with genetic diagnoses, skeletal (53.7%, 22/41) and kidney (34.1%, 14/41) abnormalities were frequent features by ultrasound. Kidney abnormalities (59.1%, 13/22) were more prominent in first-order ciliopathies, especially hyperechogenic kidneys. By contrast, skeletal findings (78.9%, 15/19) were the leading ultrasound sign in second-order ciliopathies, usually manifesting as short limbs.

Ciliopathies prenatally present with variable ultrasound features, with kidney and skeletal systems frequently affected in first-order and second-order ciliopathies. Characterization of the genetic etiology and phenotypes of prenatal ciliopathies will increase our understanding of fetal genetic disorders.