Genetic spectrum of Saudi Arabian patients with antenatal cystic kidney disease and ciliopathy phenotypes using a targeted renal gene panel

Abstract

Background: Inherited cystic kidney disorders are a common cause of end-stage renal disease. Over 50 ciliopathy genes, which encode proteins that influence the structure and function of the primary cilia, are implicated in cystic kidney disease.

Methods: To define the phenotype and genotype of cystic kidney disease in fetuses and neonates, we correlated antenatal ultrasound examination and postnatal renal ultrasound examination with targeted exon sequencing, using a renal gene panel. A cohort of 44 families in whom antenatal renal ultrasound scanning findings in affected cases included bilateral cystic kidney disease, echogenic kidneys or enlarged kidneys was investigated.

Results: In this cohort, disease phenotypes were severe with 36 cases of stillbirth or perinatal death. Extra renal malformations, including encephalocele, polydactyly and heart malformations, consistent with ciliopathy phenotypes, were frequently detected. Renal gene panel testing identified causative mutations in 21 out of 34 families (62%), where patient and parental DNA was available. In the remaining 10 families, where only parental DNA was available, 7 inferred causative mutations were found. Together, mutations were found in 12 different genes with a total of 13 novel pathogenic variants, including an inferred novel variant in NEK8. Mutations in CC2D2A were the most common cause of an antenatal cystic kidney disease and a suspected ciliopathy in our cohort.

Conclusions: In families with ciliopathy phenotypes, mutational analysis using a targeted renal gene panel allows a rapid molecular diagnosis and provides important information for patients, parents and their physicians.

Figure 1

Prenatal ultrasound images of affected fetuses. (A and B) FT-8: transverse view of the fetal abdomen at 33 weeks of gestation (A), showing enlarged echogenic kidneys. Transverse view of the fetal head at 33 weeks of gestation (B), showing a cystic mass arising from the occipital area of the fetal head representing an encephalocele. (Genotype: CC2D2A homozygous mutation.) (C) FT-10: a transverse view of the fetal abdomen at 23 weeks of gestation, showing enlarged echogenic kidneys with cystic areas. (Genotype: TMEM67 homozygous mutation.) (D) FT-20: a transverse view of the fetal kidneys at 33 weeks, showing enlarged echogenic kidneys. (Genotype: TCTN2 homozygous mutation.) (E and F) FT-1: a transverse view of the fetal kidneys at 31 weeks of gestation (E), showing enlarged echogenic cystic kidneys. A transverse view of the fetal head at 31 weeks of gestation (F), showing a cystic mass arising from the fetal occiput, which represents an encephalocele. (Genotype: CC2D2A homozygous mutation.) (G) FT-9: a transverse view of the fetal abdomen at 27 weeks of gestation showing bilateral enlarged echogenic kidneys. (Genotype: INVS homozygous mutation.) (H) FT-13: a sagittal view of a fetus at 12 weeks of gestation showing a mass arising from the posterior aspect of the fetal head, which represents an encephalocele. (Genotype: MKS1 homozygous mutation). (I) FT-22: a transverse view of the fetal abdomen at 18 weeks, showing enlarged kidneys with cystic changes. (Genotype: TMEM67 homozygous mutation.) (J) FT-21: a transverse view of the fetal head at 16 weeks of gestation, showing a mass arising from the posterior aspect of the fetal head, which represents an encephalocele. (Genotype: CC2D2A homozygous allele.)

Figure 2

Novel mutations identified in cohort with antenatal cystic kidney disease and ciliopathy phenotypes. (A) Three nonsense (B), four splice site (C), three frameshift (D), two missense and (E) one deletion novel mutations (boxed) were detected homozygously in patients or heterozygously in both parents with ciliopathy phenotypes. (Just one parental chromatogram is shown but a comparison of maternal and paternal chromatograms is shown in online supplementary figure S1). Family number (FT) is shown as well as mutation and predicted translational changes. Healthy control sequence is shown alongside. Intron–exon boundaries are marked with a vertical dashed line.