Paternal De Novo Variant of TAOK1 in a Fetus With Structural Brain Abnormalities

Abstract

A dilated lateral ventricle is a relatively common finding on prenatal ultrasound, and the causes are complex. We aimed to explore the etiology of a fetus with a dilated lateral ventricle. Trio whole-exome sequencing was performed to detect causative variants. A de novo variant of TAOK1 (NM_020791.2: c.227A>G) was detected in the proband and evaluated for potential functional impacts using a variety of prediction tools. Droplet digital polymerase chain reaction was used to exclude the parental mosaicism and to verify the phasing of the de novo variant. Based on peripheral blood analysis, the parents did not exhibit mosaicism at this site, and the de novo variant was paternally derived. Here, we describe a fetus with a de novo likely pathogenic variant of TAOK1 who had a dilated lateral ventricle and a series of particular phenotypes. This case expands the clinical spectrum of TAOK1-associated disorders. We propose a method for solving genetic disorders in which the responsible genes have not yet gone through ClinGen curation, particularly for prenatal cases.

Keywords: TAOK1; dilated lateral ventricle; neurodevelopment disorder; rare disease; trio-whole exome sequencing.

FIGURE 1

(A,B) Enlarged left lateral ventricle (10.1 and 11 mm) at 25 and 31 gestational weeks. (C) Axial T2-weighted imaging at 32 weeks of gestation shows poor bilateral and frontal operculum formation and shallow bilateral lateral fissures (arrows). The left ventricle is slightly wider.

FIGURE 2

Structure of the kinase domain of the TAOK1 protein from amino acids 28 to 281, showing the localization of the identified variant p.Glu76Gly.

FIGURE 3

Validation of the de novo variant c.227A>G of TAOK1 (chr17: 27802710) identified by trio WES and the reference variant c.306+468G>T (chr17: 27803257) identified by WGS by Sanger sequencing. (A) c.227A>G was found in the proband, but not in either parent. (B) c.306+468G>T was detected in the proband and mother, but not in the father.

FIGURE 4

Droplet digital PCR (ddPCR) for mosaic variation detection. The four ddPCRs are divided by vertical dotted yellow lines for the proband, mother, father, and negative control. The pink line is the threshold, above which are positive droplets (blue and green), and below which are negative droplets (gray) without any target DNA. There is no target DNA for the mutant locus c.227A>G in the mother and father (top panel).

FIGURE 5

2D cluster plot of droplet fluorescence for the de novo locus and reference locus. (A) The result of c.306+468G>T mutant and c.227A>G mutant probes. (B) The result of c.306+468G>T wild-type and c.227A>G mutant probes. FAM™ positive (Channel 1, mt−) droplets form the top-left blue cluster, HEX™ positive (Channel 2, mt+) droplets form the bottom-right green cluster, negative droplets for both targets form the bottom-left gray cluster, and positive droplets for both targets form the top-right orange cluster.