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Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy with an aggressive clinical course and poor prognosis. The genetic abnormalities in BPDCN are heterogeneous; therefore, its molecular pathogenesis and the prognostic importance of genomic alterations associated with the disease are not well defined. Here we report a case of BPDCN with a novel AFF4::IRF1 fusion predicted to lead to a loss-of-function of the IRF1 tumor suppressor, somatic mutations of ASXL1, TET2, and MYD88, as well as multiple intrachromosomal deletions. The patient showed resistance to Tagraxofusp and Venetoclax, and he died about 16 months after diagnosis. Considering the predicted effect of the AFF4::IRF1 fusion on IRF1's antitumor effects and immune regulation, and the possibility of its relevance to the aggressive course observed in this case, we propose further evaluation of the clinical significance of this fusion in BPDCN in future cooperative group studies and the consideration of therapeutic strategies aimed at restoring IRF1-dependent antineoplastic effects in such cases. [ABSTRACT FROM AUTHOR]

To report a case of cone dystrophy, associated with autosomal recessive homozygote POC1B gene variant, mimicking autoimmune retinopathy. A 45-year-old female presented with a complaint of decreased vision in both eyes. Her best corrected visual acuity was 20/32 in the right eye and 20/50 in the left eye. Anterior segment and dilated fundus examinations were unremarkable. Spectral domain optical coherence tomography showed a subfoveal blurred dome-shaped ellipsoid zone and an extinguished interdigitation zone affecting the entire macula. Full field electroretinography revealed reduced cone responses. The differential diagnosis included inflammatory chorioretinopathies, autoimmune retinopathies (paraneoplastic or nonparaneoplastic), and hereditary retinal dystrophies. No remarkable finding was observed on combined fluorescein and indocyanine green angiographies. Paraneoplastic autoimmune antibody panel revealed nothing; however, aldolase, enolase, pyruvate kinase M2, and glyceraldehyde-3-phosphate dehydrogenase antibodies were positive on autoimmune retinopathy panel. To exclude hereditary retinal dystrophies, whole-exome sequencing (WES) was applied. WES identified an autosomal recessive homozygote POC1B gene variant (c.680A>G, p.His227Arg). Cone dystrophy diagnosis was given. Cone dystrophy associated with POC1B gene variant may present without visible fundus abnormalities. It should be kept in mind that retinal autoantibodies may be positive in such a hereditary dystrophy case due to long-term exposure of the immune system to self-antigens. Therefore, autoimmune retinopathy is a diagnosis of exclusion and should not be diagnosed until all other causes, including hereditary dystrophies, have been ruled out. [ABSTRACT FROM AUTHOR]

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Purpose: A number of mechanisms have been proposed for the effect of chromosomal translocations on spermatogenesis and sperm maturation. However, there are still numerous ambiguous issues regarding these two processes. The aim of this study is to evaluate the effect of chromosome break areas on sperm count in the light of the literature. Material and Methods: The study was conducted on the data of 16 male patients with reciprocal or Robertsonian translocation among 152 patients who were admitted to Adana Numune Training and Research Hospital and Kanuni Sultan Süleyman Training and Research Hospital Genetic Diagnosis Centers between 2013 and 2016 due to azoospermia and oligospermia. Results: 11 of these patients had reciprocal and five patients had Robertsonian translocations. All the patients with Robertsonian translocations were detected with azoospermia. Of the patients with reciprocal translocation, five of them were azoospermic and six of them were severe oligospermic. Conclusion: A total of 21 chromosomal breakpoints were identified in the 11 patients with reciprocal translocations. These chromosomal breakpoints may contribute to the clarification of ambiguous issues related to spermatogenesis and sperm maturation. The results also showed the importance of genetic counselling in patients with translocations. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Many studies on the interrelation of cumulus cells and oocytes, and research on cumulus protein factors continue. This study aims to investigate the relationship of Pentraxin 3 level with embryo implantation in the cumulus culture fluid. STUDY DESIGN: A total of 31 women with idiopathic infertility who underwent intracytoplasmic sperm injection treatment were prospectively evaluated. Cell suspensions containing 5 million/mL cumulus cells were obtained post-hyase and incubated for 24 hours in a culture medium. A possible association between the culture media Pentraxin 3 concentrations and embryo implantation was analyzed. RESULTS: The cumulus cell culture media Pentraxin 3 concentrations were significantly higher in the pregnant group compared to the non-pregnant group (98.9 ng/mL vs 53.2 ng/mL, respectively, p=0.005). There was a significant positive correlation between the culture media Pentraxin 3 concentrations and embryo implantation (r=0.500, p=0.005). The culture media Pentraxin 3 concentration was a significant predictor for successful embryo implantation (AUC=0.845, p=0.006). A cut-off value of 64.25 ng/mL had an 86% sensitivity and 80% specificity to predict embryo implantation. There was no pregnancy under the cut-off value of 60 ng/mL, whereby seven women had good quality grade 1 oocytes according to the traditional morphological criteria. CONCLUSION: The cumulus cell culture medium Pentraxin 3 concentration was predictive for successful embryo implantation. Low Pentraxin 3 levels (<60 ng/mL were associated with failure of conception. [ABSTRACT FROM AUTHOR]

Keywords: CHM; choroideremia; genetic counseling; whole-genome sequencing EN CHM choroideremia genetic counseling whole-genome sequencing 2693 2694 2 07/15/22 20220701 NES 220701 Choroideremia (CHM, MIM 303100) is a rare X-linked recessive disease characterized by the progressive chorioretinal atrophy field.[[1]] Choroideremia is caused by pathogenic variants in the CHM gene and is estimated to affect 1 in 50,000 to 100,000 males. The CHM gene encodes Rab escort protein-1 (REP-1), which prenylated Rab GTPases to play a role in the intra-cellular trafficking.[[2]] Most of the pathogenic variants identified in the CHM gene are loss-of-function variants. [Extracted from the article]

Aim: The aim of this study was to assess the predictive value of serum substance P (SP) concentrations on oocyte maturation and clinical pregnancy. Methods: Ninety-three women with unexplained infertility underwent intracytoplasmic sperm injection (ICSI) cycles. Antagonist protocol was started for each participant and at the day of oocyte pick up, serum samples were obtained from each participant to assess SP concentrations, and these concentrations were utilized to predict mature/total oocyte ratio and clinical pregnancy. Results: SP concentration was a significant predictor for mature/total oocyte ratio > 0.75 and clinical pregnancy. In correlation analyses, maturation index was significantly correlated with FSH (r= −0.226,p = 0.03), estradiol (r = 0.239,p = 0.021), peak estradiol (r = 0.414,p < 0.001), and substance P (r = 0.796,p < 0.001). In multivariate analyses, number of immature (beta coefficient = −0.379,p < 0.001), mature oocyte (beta coefficient = 0.473,p < 0.001), SP concentration (beta coefficient = 0.723,p < 0.001) and maturation index (beta coefficient = −0.387,p = 0.003) were significantly associated with clinical pregnancy. Conclusion: SP concentrations at the day of oocyte pick up may be used to predict clinical pregnancy and may be an indirect indicator for cycle outcome in assisted reproductive technology (ART). [ABSTRACT FROM PUBLISHER]

Genetic heterogeneity, reduced penetrance, and variable expressivity, the latter including asymmetric body axis plane presentations, have all been described in families with congenital limb malformations (CLMs). Interfamilial and intrafamilial heterogeneity highlight the complexity of the underlying genetic pathogenesis of these developmental anomalies. Family-based genomics by exome sequencing (ES) and rare variant analyses combined with whole-genome array-based comparative genomic hybridization were implemented to investigate 18 families with limb birth defects. Eleven of 18 (61%) families revealed explanatory variants, including 7 single-nucleotide variant alleles and 3 copy number variants (CNVs), at previously reported "disease trait associated loci": BHLHA9 , GLI3, HOXD cluster, HOXD13 , NPR2 , and WNT10B . Breakpoint junction analyses for all three CNV alleles revealed mutational signatures consistent with microhomology-mediated break-induced replication, a mechanism facilitated by Alu/Alu -mediated rearrangement. Homozygous duplication of BHLHA9 was observed in one Turkish kindred and represents a novel contributory genetic mechanism to Gollop-Wolfgang Complex (MIM: 228250), where triplication of the locus has been reported in one family from Japan (i.e., 4n = 2n + 2n versus 4n = 3n + 1n allelic configurations). Genes acting on limb patterning are sensitive to a gene dosage effect and are often associated with an allelic series. We extend an allele-specific gene dosage model to potentially assist, in an adjuvant way, interpretations of interconnections among an allelic series, clinical severity, and reduced penetrance of the BHLHA9 -related CLM spectrum., Competing Interests: J.R.L. has stock ownership in 23andMe, is a paid consultant for the Regeneron Genetics Center, and is a co-inventor on multiple United States and European patents related to molecular diagnostics for inherited neuropathies, eye diseases, genomic disorders, and bacterial genomic fingerprinting. The Department of Molecular and Human Genetics at Baylor College of Medicine receives revenue from clinical genetic testing and genomic testing (ES, WGS, CMA, and aCGH) conducted at Baylor Genetics (BG). J.R.L. serves on the Scientific Advisory Board (SAB) of BG., (© 2022 The Author(s).)

The Mediator multiprotein complex functions as a regulator of RNA polymerase II-catalyzed gene transcription. In this study, exome sequencing detected biallelic putative disease-causing variants in MED27, encoding Mediator complex subunit 27, in 16 patients from 11 families with a novel neurodevelopmental syndrome. Patient phenotypes are highly homogeneous, including global developmental delay, intellectual disability, axial hypotonia with distal spasticity, dystonic movements, and cerebellar hypoplasia. Seizures and cataracts were noted in severely affected individuals. Identification of multiple patients with biallelic MED27 variants supports the critical role of MED27 in normal human neural development, particularly for the cerebellum. ANN NEUROL 2021;89:828-833., (© 2021 American Neurological Association.)

Previously we reported the identification of a homozygous COL27A1 (c.2089G>C; p.Gly697Arg) missense variant and proposed it as a founder allele in Puerto Rico segregating with Steel syndrome (STLS, MIM #615155); a rare osteochondrodysplasia characterized by short stature, congenital bilateral hip dysplasia, carpal coalitions, and scoliosis. We now report segregation of this variant in five probands from the initial clinical report defining the syndrome and an additional family of Puerto Rican descent with multiple affected adult individuals. We modeled the orthologous variant in murine Col27a1 and found it recapitulates some of the major Steel syndrome associated skeletal features including reduced body length, scoliosis, and a more rounded skull shape. Characterization of the in vivo murine model shows abnormal collagen deposition in the extracellular matrix and disorganization of the proliferative zone of the growth plate. We report additional COL27A1 pathogenic variant alleles identified in unrelated consanguineous Turkish kindreds suggesting Clan Genomics and identity-by-descent homozygosity contributing to disease in this population. The hypothesis that carrier states for this autosomal recessive osteochondrodysplasia may contribute to common complex traits is further explored in a large clinical population cohort. Our findings augment our understanding of COL27A1 biology and its role in skeletal development; and expand the functional allelic architecture in this gene underlying both rare and common disease phenotypes.

Celiac disease was previously reported to be frequent among individuals with Williams-Beuren syndrome; however, this suggestion was not investigated further. The present study was conducted to estimate the prevalence of celiac disease in a group of Turkish individuals with Williams-Beuren syndrome (n=33, age range: 1-24 years) by using anti-tissue transglutaminase immunoglobulin (Ig)A and IgG, anti-endomysium IgA, and intestinal biopsy in individuals with positive serology. The prevalence of celiac disease in this population was compared to its prevalence among healthy Turkish schoolchildren. Of all participants, celiac disease was diagnosed in one patient. Although statistically insignificant (p=0.145), the prevalence of celiac disease was higher among individuals with Williams-Beuren syndrome (3%) than among healthy Turkish schoolchildren (0.47%). We recommend questioning individuals with Williams-Beuren syndrome during routine visits regarding celiac disease symptoms and performing serological screening when consistent symptoms are present. Anti-tissue transglutaminase and anti-endomysial antibodies may help to identify those individuals in whom intestinal biopsy is indicated for the diagnosis of celiac disease.