Neonatal polycystic kidney disease: a novel variant

First pregnancy

The proband was a female fetus noted on ultrasound at gestational age (GA) of 18 weeks to have enlarged kidneys in an otherwise unremarkable pregnancy. Renal echotexture appeared normal and amniotic fluid volume was normal. Renal dimensions were above the 95th centile for GA. The mother has no known renal disease or history of hypertension. The father’s family history was significant for ADPKD, with his father and aunt affected by adult-onset renal cysts. The proband’s father was known to have a renal cysts, but had not yet undergone any genetic testing and does not have hypertension.

Non-invasive prenatal testing was reported as low risk for or trisomies 13, 18, 21, monosomy X and triploidy.

At GA of 23 weeks, ultrasound findings indicated significant progression. The fetal abdominal circumference was markedly distended by enlarged polycystic kidneys. Loss of corticomedullary differentiation was noted and a hyperechoic cortical rim. Infantile PKD was suspected, with near-anhydramnios (single pocket of amniotic fluid just 2 cm deep), precluding genetic amniocentesis.

The sonographic findings progressed to complete anhydramnios by 25 weeks’ gestation. The thoracoabdominal contour indicated a high likelihood of pulmonary hypoplasia, and multidisciplinary discussions involving maternal-fetal medicine, neonatology and paediatric nephrology determined that the prenatal findings indicated a lethal diagnosis. The couple opted to terminate the pregnancy at the GA of 27 weeks, and a stillborn female infant was delivered, weighing 1770 g.

Post-mortem examination findings were consistent with Potter sequence in the setting of diffuse cystic renal dysplasia and severe pulmonary hypoplasia. Cytogenetic analysis identified no mutation in the PKHD1 gene as would be seen in ARPKD, such that the prospect of recurrence was perceived to be low. Testing was not performed for any other renal genes associated with PKD, such as HNF1B. Karyotype results showed a female profile with no autosomal or sex chromosome aneuploidies.

Second pregnancy

A second pregnancy ensued 2 years later. Ultrasound examination at GA of 15 weeks demonstrated a normally growing fetus and normal amniotic fluid volume, but by GA of 17 weeks, the kidneys were measuring >90th percentile for GA. By GA of 19 weeks, dominant, enlarged echogenic kidneys were seen, measuring above the 98th centile for GA and with normal surrounding amniotic fluid volume (figure 1), so an amniocentesis was performed. Microarray analysis identified a female profile with no significant copy number variations, with karyotype 46XX and whole exome sequencing was requested.

Figure 1

Kidneys of second fetus at 25 weeks, with normal amniotic fluid.

Although the sonographic appearance of the kidneys was similar to the first pregnancy, the key differentiating feature in this second pregnancy was the preservation of normal amniotic fluid volumes, serially measured at alternate week intervals throughout the remainder of the pregnancy. Although diaphragmatic elevation was noted, the thoracoabdominal contour was normal, and in the setting of ongoing amniotic fluid production, the risk of pulmonary hypoplasia was, therefore, anticipated to be low.

Renal panel screening

The renal panel testing for ARPKD and ADPKD returned a result positive in PKD1. The fetus was heterozygous in AD PKD1 for a variant designated c.8792-2A>T, which is known to result in ADPKD.2 In addition, the fetus was noted to be heterozygous for sequence variant c.9829C>T. This variant has been reported to be a likely hypomorphic allele for ADPKD3 4 On its own, this variant may cause no or mild disease, but in combination with other pathogenic variants can contribute to disease severity. Therefore, on its own, this variant was deemed to be of uncertain significance, but in combination with the aforementioned AD PKD1 variant, resulted in this fetal phenotypic manifestation of ADPKD.

The fetus was also heterozygous in the AR PKHD1 gene for a variant designated c.10171G>A which, to our knowledge, has not been reported in the literature to date.

Genomic DNA was isolated from the submitted specimen. The DNA was barcoded and enriched for the coding exons of targeted genes using hybrid capture technology. Following alignment to the human genome reference sequence (assembly GRCh37/hg19), variants were detected in regions of at least 10× coverage. For this specimen, 100% of coding regions and splicing junctions of genes listed had been sequenced with coverage of at least 10× and 20×, respectively. The remaining regions did not have 10× coverage and were not evaluated. Variants were interpreted manually using locus-specific databases, literature searches and other molecular biological principles. All genes listed were evaluated for large deletions and/or duplications.

Testing for other genes related with PKD, such as AB, DNAJB11 and HNF1β was not performed.

At GA of 34 weeks, the fetal abdomen was massively distended, measuring 435 mm (above the 99th percentile for GA) and normal amniotic fluid. A decision was made for caesarean delivery at GA of 36 weeks to optimise fetal maturity while ensuring a safe delivery was achievable without undue uterine trauma.

A female infant weighing 4.18 kg (>99th centile) was delivered by elective caesarean section at 36 weeks. The Apgar scores were 6 at 1 min and 6 at 5 min. The infant breathed spontaneously at birth, but required intubation for hypoxia and was admitted to the neonatal intensive care unit.

Parental genetic testing results were received following her delivery. The paternal results revealed he is heterozygous in the PKD1 gene, which is reported to be causative of ADPKD. He is also heterozygous in the PKHD1 gene for a variant designated c.10171G>A which, as seen in the second fetus, has not been reported in the literature.

Maternal results revealed she is heterozygous for the PKD1 gene c.9829C>T, which is likely a hypomorphic allele for ADPKD. As discussed above, this variant on its own may not cause significant disease, but in combination with other pathogenic variants, as seen in the father, can exacerbate disease severity in the offspring.