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BackgroundMeiotic homologous recombination (HR) plays an essential role in gametogenesis. In most eukaryotes, meiotic HR is mediated by two recombinase systems: ubiquitous RAD51 and meiosis-specific DMC1. In the RAD51-mediated HR system, RAD51 and five RAD51 paralogues are essential for normal RAD51 function, but the role of RAD51 in human meiosis is unclear. The knockout of Rad51 or any Rad51 paralogue in mice exhibits embryonic lethality. We investigated a family with meiotic arrest, azoospermia and infertility but without other abnormalities.MethodsHomozygosity mapping and whole-exome sequencing were performed in a consanguineous family. An animal model carrying a related mutation was created by using a CRISPR/Cas9 system.ResultsWe identified a 1 bp homozygous substitution (c.41T>C/p.Leu14Pro) on a RAD51 paralogue, namely, XRCC2, in the consanguineous family. We did not detect any XRCC2 recessive mutation in a cohort of 127 males with non-obstructive-azoospermia. Knockin mice with Xrcc2-c.T41C/p.Leu14Pro mutation were generated successfully by the CRISPR/Cas9 method. The homozygotes survived and exhibited meiotic arrest, azoospermia, premature ovarian failure and infertility.ConclusionA XRCC2 recessive mutation causing meiotic arrest and infertility in humans was duplicated with knockin mice. Our results revealed a new Mendelian hereditary entity and provided an experimental model of RAD51-HR gene defect in mammalian meiosis.

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Background Congenital pseudarthrosis of the tibia (CPT) is a rare disease. Some patients present neurofibromatosis type 1 (NF1), while some others do not manifest NF1 (non-NF1). The etiology of CPT, particularly non-NF1 CPT, is not well understood. Here we screened germline variants of 75 CPT cases, including 55 NF1 and 20 non-NF1. Clinical data were classified and analyzed based on NF1 gene variations to investigate the genotype-phenotype relations of the two types of patients. Results Using whole-exome sequencing and Multiplex Ligation-Dependent Probe Amplification, 44 out of 55 NF1 CPT patients (80.0%) were identified as carrying pathogenic variants of the NF1 gene. Twenty-five variants were novel; 53.5% of variants were de novo, and a higher proportion of their carriers presented bone fractures compared to inherited variant carriers. No NF1 pathogenic variants were found in all 20 non-NF1 patients. Clinical features comparing NF1 CPT to non-NF1 CPT did not show significant differences in bowing or fracture onset, lateralization, tissue pathogenical results, abnormality of the proximal tibial epiphysis, and follow-up tibial union after surgery. A considerably higher proportion of non-NF1 patients have cystic lesion (Crawford type III) and used braces after surgery. Conclusions We analyzed a large cohort of non-NF1 and NF1 CPT patients and provided a new perspective for genotype-phenotype features related to germline NF1 variants. Non-NF1 CPT in general had similar clinical features of the tibia as NF1 CPT. Germline NF1 pathogenic variants could differentiate NF1 from non-NF1 CPT but could not explain the CPT heterogeneity of NF1 patients. Our results suggested that non-NF1 CPT was probably not caused by germline NF1 pathogenic variants. In addition to NF1, other genetic variants could also contribute to CPT pathogenesis. Our findings would facilitate the interpretation of NF1 pathogenic variants in CPT genetic counseling.

BackgroundWe investigated a large family with Pierre Robin sequence (PRS).Aim of the studyThis study aims to determine the genetic cause of PRS.ResultsThe reciprocal translocation t(4;6)(q22;p21) was identified to be segregated with PRS in a three-generation family. Whole-genome sequencing and Sanger sequencing successfully detected breakpoints in the intragenic regions of BMRP1B and GRM4. We hypothesized that PRS in this family was caused by (i) haploinsufficiency for BMPR1B or (ii) a gain of function mechanism mediated by the BMPR1B-GRM4 fusion gene. In an unrelated family, we identified another BMPR1B-splicing mutation that co-segregated with PRS.ConclusionWe detected two BMPR1B mutations in two unrelated PRS families, suggesting that BMPR1B disruption is probably a cause of human PRS.MethodsGTG banding, comparative genomic hybridization, whole-genome sequencing, and Sanger sequencing were performed to identify the gene causing PRS.

This is an open access article under the terms of the Creat ive Commo ns Attri bution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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