TSHZ3, which encodes a zinc-finger transcription factor, was recently positioned as a hub gene in a module of genes with the highest expression in the developing human neocortex, but its functions remained unknown. Here, we identify TSHZ3 as the critical region for a syndrome associated with heterozygous deletions at 19q12q13.11, which includes autism spectrum disorder (ASD). In Tshz3 null mice, differentially expressed genes include layer-specific markers of cerebral cortical projection neurons (CPNs) and their human orthologues are strongly associated with ASD. Furthermore, mice heterozygous for Tshz3 deletion show functional changes at synapses established by CPNs and exhibit core ASD-like behavioral abnormalities. These findings reveal essential roles for Tshz3 in CPN development and function, whose alterations can account for ASD in the newly-defined TSHZ3 deletion syndrome.
The objective of this study was to determine the aneuploidy level in spermatozoa in two men with globozoospermia. Sperm nuclei were analysed by fluorescence in-situ hybridization (FISH) in two infertile males with globozoospermia. Dual FISH for chromosomes 7 and 9, 13 and 21, and triple FISH for chromosomes X, Y, and 18 was performed. The main outcome measured was meiotic segregation differences between both globozoospermic men and controls. A statistically significant difference in disomies 13 and 21 was found between patients 1 and 2. The diploidy rate of spermatozoa of patient 1 (0.876%) was significantly increased compared with that of patient 2 (0.304%) and control men (0.293%). In conclusion there seems to be a slightly increased frequency of aneuploidy in round-headed spermatozoa. However, it is unlikely that these aneuploid spermatozoa would be used in assisted reproduction techniques.
Syndromes caused by copy number variations are described as reciprocal when they result from deletions or duplications of the same chromosomal region. When comparing the phenotypes of these syndromes, various clinical features could be described as reversed, probably due to the opposite effect of these imbalances on the expression of genes located at this locus. The NFIX gene codes for a transcription factor implicated in neurogenesis and chondrocyte differentiation. Microdeletions and loss of function variants of NFIX are responsible for Sotos syndrome-2 (also described as Malan syndrome), a syndromic form of intellectual disability associated with overgrowth and macrocephaly. Here, we report a cohort of nine patients harboring microduplications encompassing NFIX. These patients exhibit variable intellectual disability, short stature and small head circumference, which can be described as a reversed Sotos syndrome-2 phenotype. Strikingly, such a reversed phenotype has already been described in patients harboring microduplications encompassing NSD1, the gene whose deletions and loss-of-function variants are responsible for classical Sotos syndrome. Even though the type/contre-type concept has been criticized, this model seems to give a plausible explanation for the pathogenicity of 19p13 microduplications, and the common phenotype observed in our cohort.
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