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Danon disease (DD) is a rare X-linked dominant lysosomal storage disorder. Studies on DD pediatric patients are limited owing to the small number of cases and challenges in early detection.

Glanzmann thrombasthenia (GT) is an autosomal recessive platelet aggregation disorder caused by mutations in ITGA2Bor ITGB3.

To examine the overall genomic copy-number variant (CNV) landscape of Chinese pediatric patients with developmental disorders.

Analysis of chromosomal rearrangements has been highly successful in identifying genes involved in many congenital abnormalities including hearing loss. Herein, we report a subject, designated DGAP242, with congenital hearing loss (HL) and a de novo balanced translocation 46,XX,t(1;5)(q32;q15)dn. Using multiple next-generation sequencing techniques, we obtained high resolution of the breakpoints. This revealed disruption of the orphan receptor ESRRG on chromosome 1, which is differentially expressed in inner ear hair cells and has previously been implicated in HL, and disruption of KIAA0825 on chromosome 5. Given the translocation breakpoints and supporting literature, disruption of ESRRG is the most likely cause for DGAP242’s phenotype and implicates ESRRG in a monogenic form of congenital HL, although a putative contributory role for KIAA0825 in the subject’s disorder cannot be excluded.

Interstrand crosslinks (ICLs) repair by the canonical Fanconi anemia (FA) pathway generates double-strand breaks (DSBs), which are subsequently repaired by the homologous recombination (HR) pathway. Recent studies show that the NEIL3 DNA glycosylase repairs psoralen-ICLs by direct unhooking. However, whether and how NEIL3 regulates MMC and cisplatin-ICL repair remains unclear. Here we show that NEIL3 participates in DSB repair step of ICL repair by promoting HR pathway. Mechanistically, NEIL3 is recruited to the DSB sites through its GRF zinc finger motifs. NEIL3 interacts with the DSB resection machinery, including CtIP, the MRE11-RAD50-NBS1 (MRN) complex, and DNA2, which is mediated by the GRF zinc finger motifs. In addition, NEIL3 is necessary for the chromatin recruitment of the resection machinery, and depletion of NEIL3 decreases end resection and compromises HR. Taken together, our results show that NEIL3 plays an important role in MMC/cisplatin-ICL repair by promoting the HR step in FA/BRCA pathway.

Variations in the POU Class 3 Homeobox 4 (POU3F4) gene are associated with X-linked mixed deafness. Here, the identification of a novel variant of POU3F4in a male paediatric patient (the proband) with incomplete partition type III (IP-III) hearing impairment, is described. Clinical data were collected from the proband and his biological parents. Whole exome sequencing of the proband revealed a novel frameshift insertion mutation in POU3F4(c.717_718ins GTGCCTTGCAG: p.Leu240Valfs*5) in a hemizygous state. This variant likely truncates the protein within the POU-specific domain, and the proband’s biological mother was found to be a carrier of this variant. After excluding all contraindications, the proband underwent cochlear implantation in the right ear in June 2020. Cerebrospinal fluid (CSF) gushing was observed during surgery, but there were no postoperative complications, such as CSF leak, meningitis, or facial nerve stimulation. A novel pathogenic frameshift variant of POU3F4was identified, enriching the known mutation spectrum of POU3F4. Effective perioperative prevention and response measures should be taken to reduce the incidence of CSF gushing and meningitis in patients receiving IP-III cochlear implantation.