ANKS6 Variants Underlie Polycystic Kidneys in Prenatal and Neonatal Cases

Abstract

Background: Nephronophthisis (NPHP) is an autosomal recessive genetic disorder that can cause early-onset kidney failure. ANKS6 plays an important role in early kidney development and encodes a protein that interacts with other proteins within the primary cilium. ANKS6 mutations are known to cause nephronophthisis 16 (NPHP-16). Little is known regarding fetal ultrasound imaging and the antenatal diagnosis of fetuses with ANKS6-associated kidney disease. Here, we report the detection of ANKS6 variants in consanguineous families with polycystic kidney antenatally and in the early stages of life.

Methods: Three unrelated Saudi Arabian patients (two prenatal patients and one neonate) were investigated. These cases were referred to the hospital due to the presence of echogenic kidneys on antenatal scanning. After clinical and phenotypic evaluation, whole-exome sequencing (WES) was performed on the cord and peripheral blood to identify the molecular genetic causes associated with the echogenic kidney phenotypes.

Results: Two homozygous sequence variants were detected in ANKS6. The homozygous missense novel variant ANKS6: c.1159A>C was detected in Families 1 and 2. In the third family, the known homozygous loss-of-function variant ANKS6: c.907+2T>A was detected.

Conclusions: We identified homozygous ANKS6 variants in three families presenting with antenatal polycystic kidney disease. The findings provide an expanded clinical presentation of ANKS6 and emphasize the utility of WES in the diagnosis of echogenic kidneys in prenatal settings.

Keywords: ANKS6; consanguineous; echogenic kidney; nephronophthisis; whole-exome sequencing.

Figure 1

Pedigrees of participating families and fetal ultrasound of Family 1. (A) Pedigree diagram of Family 1. (B) Pedigree diagram of Family 2. (C) Pedigree diagram of Family 3. (D) Fetal ultrasound for Family 1 showing atrial septal defect. (E) Fetal ultrasound for Family 1 showing bilateral echogenic kidneys. (F) Fetal ultrasound for Family 1 showing situs inversus (stomach on right side).

Figure 2

A sequence chromatogram of ANKS6 variant c.1159A>C and the modeling of ANKS6 p.Thr387Pro. (A) The predicted 3-dimensional structural model of human ankyrin repeat and sterile a motif (SAM) domain-containing six protein encoded by ANKS6 on chromosome 9, generated using the Alfafold Protein Structure Database (https://alphafold.ebi.ac.uk accessed on 21 May 2024) and UniProtKB (https://www.uniprot.org/uniprot/ accessed on 21 May 2024) with associated codes AF-Q68DC2-F1 and Q68DC2, respectively. The protein contains 11 ankyrin repeats (turquoise) starting near the protein’s N-terminus and a sterile a motif (SAM) (yellow) ending near the C-terminus. (B) The missense SNV c.1159A>C (p.Thr387Pro) position is highlighted in red at the border between ankyrin repeats 10 and 11. (C) Missense SNV c.1159A>C; p.(Thr387Pro) is modeled at the border between ankyrin repeats 10 and 11. The most probable rotamer (86% likelihood) is demonstrated. Considering mutational alteration SNV c.1159A>C; p.(Thr387Pro), the red discs represent the significant pairwise overlap of atomic van der Waals radii causing a likely structural ‘clash’. (D) A sequence chromatogram of ANKS6 homozygous missense variant NM_173551.5: c.1159A>C; p.(Thr387Pro).