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Recessive variants of the SLC26A4 gene are an important cause of hereditary hearing impairment. Several transgenic mice with different Slc26a4 variants have been generated. However, none have recapitulated the auditory phenotypes in humans. Of the SLC26A4 variants identified thus far, the p.T721M variant is of interest, as it appears to confer a more severe pathogenicity than most of the other missense variants, but milder pathogenicity than non-sense and frameshift variants. Using a genotype-driven approach, we established a knock-in mouse model homozygous for p.T721M. To verify the pathogenicity of p.T721M, we generated mice with compound heterozygous variants by intercrossing Slc26a4+/T721M mice with Slc26a4919-2A>G/919-2A>G mice, which segregated the c.919-2A > G variant with abolished Slc26a4 function. We then performed serial audiological assessments, vestibular evaluations, and inner ear morphological studies. Surprisingly, both Slc26a4T721M/T721M and Slc26a4919-2A>G/T721M showed normal audiovestibular functions and inner ear morphology, indicating that p.T721M is non-pathogenic in mice and a single p.T721M allele is sufficient to maintain normal inner ear physiology. The evidence together with previous reports on mouse models with Slc26a4 p.C565Y and p.H723R variants, support our speculation that the absence of audiovestibular phenotypes in these mouse models could be attributed to different protein structures at the C-terminus of human and mouse pendrin. [ABSTRACT FROM AUTHOR]

Hearing loss is the most prevalent hereditary sensory disorder in children. Approximately 2 in 1000 infants are affected by genetic hearing loss. The PJVK gene, which encodes the pejvakin protein, has been linked to autosomal recessive non-syndromic hearing loss DFNB59. Previous clinical studies have revealed that PJVK mutations might be associated with a wide spectrum of auditory manifestations, ranging from hearing loss of pure cochlear origin to that involving the retrocochlear central auditory pathway. The phenotypic variety makes the pathogenesis of this disease difficult to determine. Similarly, mouse models carrying different Pjvk defects show phenotypic variability and inconsistency. In this study, we generated a knockin mouse model carrying the c.874G > A (p.G292R) variant to model and investigate the auditory and vestibular phenotypes of DFNB59. • A mouse model of DFNB59 with the Pjvk c.874G > A mutation was established by CRISPR/Cas9 approach. • Pjvk c.874G > A mutant mice exhibited progressive hearing loss, with cochlear hair cell and spiral ganglion degeneration. • Vestibular dysfunction with progressive loss of vestibular ganglion neurons was observed in Pjvk c.874G > A mutant mice. [ABSTRACT FROM AUTHOR]

Composite lymphoma (CL) occurs when two lymphomas with distinct WHO subtypes arise in one patient. Here, we present two cases of CL. Case 1 presented with diffuse large B-cell lymphoma (DLBCL), Hodgkin lymphoma (HL), and follicular lymphoma (FL). Case 2 presented with FL and HL in two distinct areas of one lymph node. We performed exome sequencing on matched tumor/normal samples (mean depth per sample >70x) from each lymphoma, excluding the FL in case 1. SNVs and indels were filtered and manually reviewed. A subset of variants were validated using Ampliseq. In case 1, following Ampliseq, 44 DLBCL variants were confirmed and 64 HL variants were confirmed. We observed a KMT2D frameshift in DLBCL and a B2M stop gain in HL, both of which are recurrently mutated in DLBCL and HL, respectively. We report 17 shared variants including a stop gain variant in TNFRSF14. In case 2, the validated data showed 94 sites shared between the HL and FL. These shared variants include missense variants in PCLO , and a stop gain variant in TNFRSF14. We sequenced the B-cell receptor locus (BCR) in all samples. In case 1, a dominant BCR clone representing 98.7%, 74.2%, and 33.2% of rearrangements from the DLBCL, FL, and HL was detected. For case 2, a shared rearrangement was detected comprising 1.4% and 1.3% of the rearrangements in the FL and HL. In summary, the cases presented here provide evidence of a common clonal origin for two cases of Hodgkin and non-Hodgkin lymphoma CL. [ABSTRACT FROM AUTHOR]