BACKGROUND: TBX6, a member of the T-box gene family, encodes the transcription factor box 6 that is critical for somite segmentation in vertebrates. It is known that the compound heterozygosity of disruptive variants in trans with a common hypomorphic risk haplotype (T-C-A) in the TBX6 gene contribute to 10% of congenital scoliosis (CS) cases. The deletion of chromosome 17q12 is a rare cytogenetic abnormality, which often leads to renal cysts and diabetes mellitus. However, the affected individuals often exhibit clinical heterogeneity and incomplete penetrance.
METHODS: We here present a Chinese fetus who was shown to have CS by ultrasound examination at 17 weeks of gestation. Trio whole-exome sequencing (WES) was performed to investigate the underlying genetic defects of the fetus. In vitro functional experiments, including western-blotting and luciferase transactivation assay, were performed to determine the pathogenicity of the novel variant of TBX6.
RESULTS: WES revealed the fetus harbored a compound heterozygous variant of c.338_340del (p.Ile113del) and the common hypomorphic risk haplotype of the TBX6 gene. In vitro functional study showed the p.Ile113del variant had no impact on TBX6 expression, but almost led to complete loss of its transcriptional activity. In addition, we identified a 1.85 Mb deletion on 17q12 region in the fetus and the mother. Though there is currently no clinical phenotype associated with this copy number variation in the fetus, it can explain multiple renal cysts in the pregnant woman.
CONCLUSIONS: This study is the first to report a Chinese fetus with a single amino acid deletion variant and a T-C-A haplotype of TBX6. The clinical heterogeneity of 17q12 microdeletion poses significant challenges for prenatal genetic counseling. Our results once again suggest the complexity of prenatal genetic diagnosis.

NF1 microdeletion syndrome, accounting for 5-11% of NF1 patients, is caused by a deletion in the NF1 region and it is generally characterized by a severe phenotype. Although 70% of NF1 microdeletion patients presents the same 1.4 Mb type-I deletion, some patients may show additional clinical features. Therefore, the contribution of several pathogenic mechanisms, besides haploinsufficiency of some genes within the deletion interval, is expected and needs to be defined. We investigated an altered expression of deletion flanking genes by qPCR in patients with type-1 NF1 deletion, compared to healthy donors, possibly contributing to the clinical traits of NF1 microdeletion syndrome. In addition, the 1.4-Mb deletion leads to changes in the 3D chromatin structure in the 17q11.2 region. Specifically, this deletion alters DNA-DNA interactions in the regions flanking the breakpoints, as demonstrated by our 4C-seq analysis. This alteration likely causes position effect on the expression of deletion flanking genes.Interestingly, 4C-seq analysis revealed that in microdeletion patients, an interaction was established between the RHOT1 promoter and the SLC6A4 gene, which showed increased expression. We performed NGS on putative modifier genes, and identified two \"likely pathogenic\" rare variants in RAS pathway, possibly contributing to incidental phenotypic features.This study provides new insights into understanding the pathogenesis of NF1 microdeletion syndrome and suggests a novel pathomechanism that contributes to the expression phenotype in addition to haploinsufficiency of genes located within the deletion.This is a pivotal approach that can be applied to unravel microdeletion syndromes, improving precision medicine, prognosis and patients\' follow-up.

OBJECTIVE: Constitutional chromosomal aberrations are rare in hematologic malignancies and their pathogenetic role is mostly poorly understood. We present a comprehensive molecular characterization of a novel constitutional chromosomal translocation found in two siblings - sisters - diagnosed with myelodysplastic syndrome (MDS).
METHODS: Bone marrow and blood cells from the two patients were examined using G-banding, RNA sequencing, PCR, and Sanger sequencing.
RESULTS: We identified a balanced t(17;19)(q21;p13) translocation in both siblings\' bone marrow, blood cells, and phytohemagglutinin-stimulated lymphocytes. The translocation generated a MYO1F::WNK4 chimera on the der(19)t(17;19), encoding a chimeric serine/threonine kinase, and a VPS25::MYO1F on the der(17), potentially resulting in an aberrant VPS25 protein.
CONCLUSIONS: The t(17;19)(q21;p13) translocation found in the two sisters probably predisposed them to myelodysplasia. How the MYO1F::WNK4 and/or VPS25::MYO1F chimeras, perhaps especially MYO1F::WNK4 that encodes a chimeric serine/threonine kinase, played a role in MDS pathogenesis, remains incompletely understood.

BACKGROUND: The Koolen-de Vries syndrome (KdVS) is a relatively new rare disease caused by micro-deletion of 17q21.31 which was first reported by Koolen in 2006. Typical phenotypes for KdVS include hypotonia, developmental delay, moderate intellectual disability, and characteristic facial dysmorphism. Up to now, there was only one case report about anesthesia management of patient diagnosed KdVS. It was a 2-year-old girl who experienced an MRI exam under anesthesia.
METHODS: We described a 21-month-old boy who planned to undergo an orchidopexy under general anesthesia diagnosed with KdVS. He had an intellectual disability, characteristic facial dysmorphism, tracheo/laryngomalacia, patent foramen ovale, and cryptorchidism related to KdVS. Due to the complex condition especially the presence of tracheo/laryngomalacia, we took some special measures, including reducing the amount of long-acting opioid, keeping the spontaneous breath, performing a caudal block, and applying the laryngeal mask. But the laryngeal mask was changed to an endotracheal tube because it failed to provide adequate ventilation. The boy experienced mild laryngeal spasm and hypoxia after extubation, but lateral position and etomidate eased his breathing problem and re-intubation was avoided. It is indicated that anesthesia management for patients with orphan disease is a real challenge for all anesthesia providers.
CONCLUSIONS: The Koolen-de Vries syndrome is a relatively new orphan disease involving multiple systems. Keeping spontaneous breath, evaluating airway potency to anesthetics, applying endotracheal tube, and post-extubation lateral or prone position may be helpful for airway management for patient with hypotonia and tracheo/laryngomalacia. KdVS patient needs prolonged post-anesthesia monitoring and/or medication for airway complications.

BACKGROUND: MAPT is a causative gene in frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), a hereditary degenerative disease with various clinical manifestations, including progressive supranuclear palsy, corticobasal syndrome, Parkinson\'s disease, and frontotemporal dementia.
OBJECTIVE: To analyze genetically, biochemically, and pathologically multiple members of two families who exhibited various phenotypes of the disease.
METHODS: Genetic analysis included linkage analysis, homozygosity haplotyping, and exome sequencing. We conducted tau protein microtubule polymerization assay, heparin-induced tau aggregation, and western blotting with brain lysate from an autopsy case. We also evaluated abnormal tau aggregation by using anti-tau antibody and PM-PBB3.
RESULTS: We identified a variant, c.896_897insACA, p.K298_H299insQ, in the MAPT gene of affected patients. Similar to previous reports, most patients presented with atypical parkinsonism. Biochemical analysis revealed that the mutant tau protein had a reduced ability to polymerize microtubules and formed abnormal fibrous aggregates. Pathological study revealed frontotemporal lobe atrophy, midbrain atrophy, depigmentation of the substantia nigra, and four-repeat tau-positive inclusions in the hippocampus, brainstem, and spinal cord neurons. The inclusion bodies also stained positively with PM-PBB3.
CONCLUSIONS: This study confirmed that the insACA mutation caused FTDP-17. The affected patients showed symptoms resembling Parkinson\'s disease initially and symptoms of progressive supranuclear palsy later. Despite the initial clinical diagnosis of frontotemporal dementia in the autopsy case, the spread of lesions could explain the process of progressive supranuclear palsy. The study of more cases in the future will help clarify the common pathogenesis of MAPT mutations or specific pathogeneses of each mutation.

Pathogenic variants in KANSL1 and 17q21.31 microdeletions are causative of Koolen-de Vries syndrome (KdVS), a neurodevelopmental syndrome with characteristic facial dysmorphia. Our previous work has shown that syndromic conditions caused by pathogenic variants in epigenetic regulatory genes have identifiable patterns of DNA methylation (DNAm) change: DNAm signatures or episignatures. Given the role of KANSL1 in histone acetylation, we tested whether variants underlying KdVS are associated with a DNAm signature. We profiled whole-blood DNAm for 13 individuals with KANSL1 variants, four individuals with 17q21.31 microdeletions, and 21 typically developing individuals, using Illumina\'s Infinium EPIC array. In this study, we identified a robust DNAm signature of 456 significant CpG sites in 8 individuals with KdVS, a pattern independently validated in an additional 7 individuals with KdVS. We also demonstrate the diagnostic utility of the signature and classify two KANSL1 VUS as well as four variants in individuals with atypical clinical presentation. Lastly, we investigated tissue-specific DNAm changes in fibroblast cells from individuals with KdVS. Collectively, our findings contribute to the understanding of the epigenetic landscape related to KdVS and aid in the diagnosis and classification of variants in this structurally complex genomic region.

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Next-generation sequencing (NGS) is a valuable tool, but has limitations in sequencing through repetitive runs of single nucleotides (homopolymers). Pathogenic germline variants in WRAP53 encoding telomere Cajal body protein 1 (TCAB1) are a known cause of dyskeratosis congenita. We identified a significant NGS error in WRAP53, c.1562dup, p.Ala522Glyfs*8 (rs755116516 G>-/GG/GGG) that did not validate by Sanger sequencing. This error occurs because rs755116516 G>-/GG/GGG (Chr17:7,606,714) is polymorphic, and variants at this site challenge the ability of NGS to accurately call the correct number of nucleotides in a homopolymer run. This was further complicated by the fact that chr17:7,606,721 (rs769202794) is multiallelic G>A, C, T, and that chr17:7,606,722 is also multiallelic (rs7640C>A/G/T and rs373064567C>delC). In addition to the expert interpretation of potentially clinically actionable variants, it recommended that all variants in regions of the genome with homopolymers be validated by Sanger sequencing before clinical action.

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