ZTTK syndrome
[citation needed] Distinctive ocular features of the ZTTK syndrome are deep-set eyes, down-slanting palpebral fissures and horizontal eyebrows.
[4] Developmental delay is common in ZTTK syndrome patients, and appears to progressively increase the severity of intellectual disability with age.
Peripheral blood cells from the sampled patients confirmed decreased levels of the mutant RNA transcript, consistent with haploinsufficiency.
[1] De novo LoF mutations and haploinsufficiency for the SON gene are shown to cause profound developmental malformations during embryonic development as seen in the phenotypic manifestations of the ZTTK syndrome.
[9] The SON protein is mainly localised to nuclear speckles and involved in a variety of cellular processes such as transcription, cell cycle regulation and subnuclear organisation of pre-messenger RNA (mRNA) splicing.
[15] Consequently, genome stability and regulation of the cell cycle are compromised, contributing to the development of multi-organ defects in ZTTK syndrome patients.
[17][5] ZTTK syndrome individuals with SON haploinsufficiency display decreased mRNA expression and abnormal RNA splicing products of numerous genes which are necessary for neuronal cell migration, metabolic processes and neurodevelopment of the brain.
[5] RNA analyses from affected individuals with ZTTK syndrome confirmed the downregulation of genes essential for neuronal migration and cortex organisation (TUBG1, FLNA, PNKP, WDR62, PSMD3, HDAC6) and metabolism (PCK2, PFKL, IDH2, ACY1, and ADA).
[1] The mis-spliced RNA products are caused by significant intron retention (TUBG1, FLNA, PNKP, WDR62, PSMD3, PCK2, PFKL, IDH2, and ACY1) and exon skipping (HDAC6 and ADA).
[1] SON depletion downregulates and causes aberrant splicing of the pluripotency factors, OCT4, PRDM14, MED24 and E4F1, inducing spontaneous differentiation of hESCs followed by widespread cell death.
[1] Erroneous SON function causes insufficient production of downstream targets, genome instability and disrupted cell cycle progression which are fundamental to the developmental defects and organ abnormalities in individuals with ZTTK syndrome.
For example, FLNA haploinsufficiency observed in individuals with ZTTK syndrome is the main cause of a rare brain disorder, periventricular nodular heterotopia.
De novo LoF mutations in TUBG1 can result in microcephaly and cortical malformations due to compromised SON-mediated RNA splicing in affected ZTTK syndrome individuals.
[1] Embryos that survived for a longer period of time have more severe phenotypes such as spinal malformations with brain oedema, imitating features observed in affected ZTTK syndrome individuals.
[3][20] Ventriculomegaly can also be observed in MRI where the lateral ventricles become dilated in the foetus and can contribute to developmental delays in ZTTK syndrome individual.
[21] Other pathological features seen on MRI scans of ZTTK syndrome individuals include arachnoid cysts, hypoplasia of the corpus callosum and cerebellar hemispheres and loss of periventricular white matter.
[21] Whole exome sequencing (WES) can be used as a non-biased tool in the diagnostic evaluation of individuals with suspected genetic disorders such as the ZTTK syndrome.
[citation needed] ZTTK syndrome has been identified as a neurodevelopmental disorder associated with a de novo mutation in the SON gene using WES.
