A TSHZ3 Frame-Shift Variant Causes Neurodevelopmental and Renal Disorder Consistent with Previously Described Proximal Chromosome 19q13.11 Deletion Syndrome

Abstract

Heterozygous deletions at 19q12-q13.11 affecting TSHZ3, the teashirt zinc finger homeobox 3, have been associated with intellectual disability and behavioural issues, congenital anomalies of the kidney and urinary tract (CAKUT), and postnatal growth retardation in humans and mice. TSHZ3 encodes a transcription factor regulating the development of neurons but is ubiquitously expressed. Using exome sequencing, we identified a heterozygous frameshift variant c.119_120dup p.Pro41SerfsTer79 in TSHZ3 in a 7-year-old girl with intellectual disability, behavioural issues, pyelocaliceal dilatation, and mild urethral stenosis. The variant was present on the paternal TSHZ3 allele. The DNA from the father was not available for testing. This is the first report of a heterozygous point mutation in TSHZ3 causing the same phenotype as reported for monoallelic deletions in the same region. This confirms TSHZ3 as a novel disease gene for neurodevelopmental disorder in combination with behavioural issues and CAKUT.

Keywords: TSHZ3; neurodevelopmental disorder; novel disease loci; renal disorder.

Figure 1

Pedigree, TSHZ3 domain architecture, variant position, and habitus of the affected individual. (A) Pedigree of the family of the affected individual. (B) TSHZ3 domain architecture. DNA binding domain = grey; zinc fingers = brown. (C) Clinical photos of the hands and feet of the affected individual at the age of 6.9 years. The participant and her parents provided written and informed consent for the taking and distribution of the photographs. The forms are stored in compliance with local confidentiality laws.