Chromosome 19q13.11 Deletion Syndrome, Proximal

A number sign (#) is used with this entry because it represents a contiguous gene deletion syndrome on chromosome 19q13.11. One patient carried a deletion (chr19:31,765,881-31,812,396, GRCh37) which spanned only the TSHZ3 gene (614119).

See also distal chromosome 19q13.11 deletion syndrome (613026), which shows some phenotypic overlap.

Description

Proximal chromosome 19q13.11 deletion syndrome is an autosomal dominant neurodevelopmental disorder characterized by delayed development, intellectual disability with poor speech, feeding difficulties, and autistic features. Some patients may have additional features, including renal tract anomalies (summary by Caubit et al., 2016).

Clinical Features

Chowdhury et al. (2014) reported 3 unrelated patients (patients 3, 4, and 5) with a neurodevelopmental disorder associated with de novo heterozygous deletions involving chromosome 19q12-q31.1. The patients had feeding difficulties, postnatal growth retardation, delayed development, and other distinct features: congenital hydroureter, clubfoot, and hip dysplasia in patient 3, anemia in patient 4, hypotonia in patients 4 and 5, and pyloric stenosis and autism in patient 5. Two patients had dysmorphic facial features.

Caubit et al. (2016) reported 7 patients from 6 unrelated families with a neurodevelopmental disorder associated with heterozygous deletion of 19q12-q13.11. Six of the patients had autism or autism-like behaviors. Three patients had renal abnormalities, including pyelocalyceal dilatation, nephrolithiasis, and vesicoureteral reflux. Other common features included feeding difficulties, growth retardation, speech delay, and cognitive impairment. The phenotype could be distinguished from that observed in distal chromosome 19q13.11 deletion syndrome.

Cytogenetics

Chowdhury et al. (2014) reported 3 unrelated patients with de novo heterozygous deletions involving chromosome 19q12-q31.1 that were proximal to the smallest region of overlap described for chromosome 19q13.11 deletion syndrome. The deletions, which were found by array CGH testing, were 6.25, 3.91, and 4.61 Mb, respectively.

Caubit et al. (2016) reported 7 patients from 6 unrelated families with a neurodevelopmental disorder associated with heterozygous deletion of 19q12-q13.11. The mutations in 6 patients ranged from 0.46 to 4.02 Mb. The deletions occurred de novo in 3 patients and were inherited from an unaffected parent in 3 cases, suggesting incomplete penetrance in some patients. The seventh patient had a 50-kb intragenic microdeletion that deleted the second exon and part of the intron of the TSHZ3 gene. This deletion was not detected in the unaffected mother, but DNA from the father was unavailable. The smallest region of overlap of all deletions included only the TSHZ3 gene, suggesting to the authors that this gene is responsible for the phenotype.

Animal Model

Caubit et al. (2008) found that Tshz3-null mutant mice developed congenital hydronephrosis without anatomic obstruction. Tshz3 was demonstrated to be required for differentiation of smooth muscle cells in the proximal ureter. The authors concluded that this mouse model of functional urinary obstruction resembles congenital pelviureteric junction obstruction in humans.

Caubit et al. (2016) noted that homozygous Tshz3-null mice die at birth from respiratory failure due to poor survival of neurons in the hindbrain that control breathing, and that heterozygous Tshz3 +/- mutant mice have decreased neonatal viability, even up to 100% lethality, depending on the genetic background. In the mouse cortex, Caubit et al. (2016) found that homozygous and heterozygous deletion of the Tshz3 gene altered the expression of genes involved in pathways related to neurotransmitter/neuropeptide signaling and neuronal and axon development, projection, and differentiation. The changes in gene expression showed spatial caudal-rostral variation and layer specificity. For example, there was increased expression of Fezf2 (607414) and decreased expression of Ngfr (162010). These findings suggested that the TSHZ3 gene is a nexus in a brain developmental gene network. The brains of these mice did not show defects in cortical layering, neuronal density, or axonal pathfinding compared to controls. However, detailed study of heterozygous Tshz3 mutant mice showed alterations in synaptic transmission with increased probability of action potential-dependent glutamate release from cortical projection neurons compared to wildtype. Corticostriatal long-term potentiation was also enhanced in heterozygous mice, indicating altered plasticity. Heterozygous mice showed behavioral abnormalities consistent with autistic behaviors, including impaired social interaction, increased repetitive behaviors, and increased anxiety.