Inherited and de novo variants extend the etiology of TAOK1-associated neurodevelopmental disorder

Abstract

Alterations in the TAOK1 gene have recently emerged as the cause of developmental delay with or without intellectual impairment or behavioral abnormalities (MIM # 619575). The 32 cases currently described in the literature have predominantly de novo alterations in TAOK1 and a wide spectrum of neurodevelopmental abnormalities. Here, we report four patients with novel pathogenic TAOK1 variants identified by research genome sequencing, clinical exome sequencing, and international matchmaking. The overlapping clinical features of our patients are consistent with the emerging core phenotype of TAOK1-associated syndrome: facial dysmorphism, feeding difficulties, global developmental delay, joint laxity, and hypotonia. However, behavioral abnormalities and gastrointestinal issues are more common in our cohort than previously reported. Two patients have de novo TAOK1 variants (one missense, one splice site) consistent with most known alterations in this gene. However, we also report the first sibling pair who both inherited a TAOK1 frameshift variant from a mildly affected mother. Our findings suggest that incomplete penetrance and variable expressivity are relatively common in TAOK1-associated syndrome, which holds important implications for clinical genetic testing.

Keywords: autism; failure to thrive in infancy; generalized joint laxity; generalized neonatal hypotonia; moderate global developmental delay; relative macrocephaly.

Figure 1.

Pedigrees for families 1–3. Arrows indicate the index proband in each family; colored shading indicates variant carrier status and reported clinical features. (A) Pedigree for Family 1. (B) Pedigree for Family 2. (C) Pedigree for Family 3.

Figure 2.

Genomic analysis uncovers rare deletions in TAOK1 in two families. Both panels show sequencing data aligned to the GRCh38 reference sequence as visualized in the Integrative Genomics Viewer (IGV) v2.8.0. (A) Quad whole-genome sequencing data for Family 1, in which Patients 1 and 2 are heterozygous for a single-base deletion inherited from their mother. (B) Trio exome sequencing data for Family 2, in which the proband is heterozygous for a de novo four-base splice site deletion.

Figure 3.

Protein structure of TAOK1 and location of reported variants (amino acid position) by source. The first plot shows the variants in this study; the second and third show variants reported in two previous studies. The bottom plot shows ClinVar pathogenic/likely pathogenic variants retrieved 27 September 2021. Variant diagrams were generated using Lollipops v1.5.3 using information from UniProt (ID #Q7L7X3).