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The novel HLA‐C*07:1132 allele differs from HLA‐C*07:01:01 by one nucleotide substitution in Exon 5. [ABSTRACT FROM AUTHOR]

The novel HLA‐DPA1*01:130 allele differs from HLA‐DPA1*01:03:01:03 by one nucleotide substitution in Exon 3. [ABSTRACT FROM AUTHOR]

High-resolution HLA typing identifies a new "super responder" subgroup of HLA-C*06:02-positive psoriatic patients: HLA-C*06:02/HLA-C*04, in response to ustekinumab Cumulative probability of drug survival in HLA-C*06:02-POS and HLA-C*06:02-NEG patients (d) as well as patients in subgroups of HLA-C*06:02-POS patients: HLA-C*06:02/HLA-C*04, HLA-C*06:02/HLA-C*07 and HLA-C*06:02/HLA-C*12 (e). The 2-year retention rate was 81% in HLA-C*06:02-POS patients and 54% in HLA-C*06:02-NEG patients, with significant difference observed between groups (HR: 0.30, 95% CI: 0.14-0.63; I P i = 0.002; Fig. d). [Extracted from the article]

The novel allele HLA-C*16:07:02 differs from HLA-C* 16:07:01 by a silent nucleotide substitution at codon 220 (TAC → TAT). [ABSTRACT FROM AUTHOR]

HLA-DQA1*01:02:24 differs from HLA-DQA1*01:02:01:03 by one nucleotide substitution in codon 167 in exon 3., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Fanconi anemia (FA) is a clinically variable and genetically heterogeneous cancer-predisposing disorder representing the most common bone marrow failure syndrome. It is caused by inactivating predominantly biallelic mutations involving >20 genes encoding proteins with roles in the FA/BRCA DNA repair pathway. Molecular diagnosis of FA is challenging due to the wide spectrum of the contributing gene mutations and structural rearrangements. The assessment of chromosomal fragility after exposure to DNA cross-linking agents is generally required to definitively confirm diagnosis. We assessed peripheral blood genome-wide DNA methylation (DNAm) profiles in 25 subjects with molecularly confirmed clinical diagnosis of FA (FANCA complementation group) using Illumina's Infinium EPIC array. We identified 82 differentially methylated CpG sites that allow to distinguish subjects with FA from healthy individuals and subjects with other genetic disorders, defining an FA-specific DNAm signature. The episignature was validated using a second cohort of subjects with FA involving different complementation groups, documenting broader genetic sensitivity and demonstrating its specificity using the EpiSign Knowledge Database. The episignature properly classified DNA samples obtained from bone marrow aspirates, demonstrating robustness. Using the selected probes, we trained a machine-learning model able to classify EPIC DNAm profiles in molecularly unsolved cases. Finally, we show that the generated episignature includes CpG sites that do not undergo functional selective pressure, allowing diagnosis of FA in individuals with reverted phenotype due to gene conversion. These findings provide a tool to accelerate diagnostic testing in FA and broaden the clinical utility of DNAm profiling in the diagnostic setting., Competing Interests: Declaration of interests Dr. Sadikovic is a shareholder in EpiSign Inc, a software company involved in commercialization of EpiSign Technology., (Copyright © 2023 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

HLA-DPA1*01:159 differs from HLA-DPA1*01:03:01:03 by one nucleotide substitution in codon 120 in exon 3., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

HLA-DRB3*02:179N differs from DRB3*02:02:01:02 by one nucleotide substitution in codon 98 in exon 3., (© 2022 The Authors. HLA: Immune Response Genetics published by John Wiley & Sons Ltd.)

Background: Inactivating NSD1 mutations causing Sotos syndrome have been previously associated with a specific genome-wide DNA methylation (DNAm) pattern. Sotos syndrome is characterized by phenotypic overlap with other overgrowth syndromes, and a definite diagnosis might not be easily reached due to the high prevalence of variants of unknown significance (VoUS) that are identified in patients with a suggestive phenotype., Objective: we performed microarray DNAm profiling in a set of 11 individuals with a clinical suspicion of Sotos syndrome and carrying an NSD1 VoUS or previously unreported variants to solve uncertainty in defining pathogenicity of the observed variants. The impact of the training cohort size on sensitivity and prediction confidence of the classifier was assessed., Results: The Sotos syndrome-specific DNAm signature was validated in six individuals with a clinical diagnosis of Sotos syndrome and carrying bona fide pathogenic NSD1 variants. Applying this approach to the remaining 11 individuals with NSD1 variants, we succeeded in confirming pathogenicity in eight subjects and excluding the diagnosis of Sotos syndrome in three. The sensitivity and prediction confidence of the classifier based on the different sizes of the training sets did not show substantial differences, though the overall performance was improved by using a data balancing strategy., Conclusions: The present approach solved uncertainty in cases with NDS1 VoUS, further demonstrating the clinical utility of DNAm profiling.

The novel HLA-B*44:532 allele differs from HLA-B*44:02:01:01 by one nucleotide substitution in Exon 3., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The novel HLA-DPA1*02:53 allele differs from HLA-DPA1*02:01:01:02 by one nucleotide substitution in exon 3., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The novel HLA-DRB1*03:01:32 allele differs from HLA-DRB1*03:01:01:01 by one nucleotide substitution in exon 4., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective : Our pharmacogenomic study evaluated the influence of the presence/absence of genetic variants of psoriasis-risk loci on the clinical response to secukinumab. Differences in the single-nucleotide polymorphism (SNP) pattern characterizing HLA-Cw6 + or HLA-Cw6 - patient subpopulations, showing high or low responses to secukinumab, were also analyzed. Methods : 417 SNPs were analyzed by Next-Generation Sequencing technology, in a cohort of 62 psoriatic patients and undergone secukinumab treatment. Univariate regression analysis was employed to examine the association between SNP and clinical response to secukinumab. Multivariate analysis was also performed to assess multivariate differences in SNP pattern of HLA-Cw6 + or HLA-Cw6 - patients showing high or low responses to secukinumab. Results : Eight SNPs in HLA-C and upstream region (rs13207315, rs6900444, rs12189871, rs12191877, rs4406273, and rs10484554), including HLA-Cw6 classical allele (rs1131118), and three in MICB-DT (rs9267325), DDX58 (rs34085293) and TYK2 (rs2304255) genes, associating with excellent response to secukinumab were identified. Importantly, rs34085293 or r s2304255 SNP status defined a subgroup of super-responder patients. We also found that HLA-Cw6 + and HLA-Cw6 - patients carried out specific patterns of SNPs associating with different responses to secukinumab. Conclusion : Assessment of HLA-Cw6 , together with other allelic variants of genes, could be helpful to define patients which better benefit from anti-IL-17 therapy. Abbreviations: PASI: Psoriasis Area and Severity Index; SNP: Single-Nucleotide Polymorphism Rs: Reference SNP; PASI75: 75% reduction in Psoriasis Area and Severity Index; PASI90: 90% reduction in Psoriasis Area and Severity Index; PASI100: 100% reduction in Psoriasis Area and Severity Index; NGS: Next-Generation Sequencing; OR: Odds Ratio; CAP: Canonical Analysis of Principal coordinates; BMI: Body Mass Index; LD: Linkage Disequilibrium.

HLA-DPA1*01:42 differs from DPA1*01:03:01:02 by one nucleotide substitution in Codon 76 in Exon 2., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

HLA-DRB3*01:86 differs from HLA-DRB3*01:01:02:01 by one nucleotide substitution in codon 225 in exon 4., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

HLA-DQA1*01:25 differs from HLA-DQA1*01:02:01:01 by one nucleotide substitution in codon 8 in exon 2., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The new allele HLA-A*01:289 differs from HLA-A*01:95 by one nucleotide substitution in exon 2., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

HLA-DRB3*03:01:07 differs from HLA-DRB3*03:01:01 by one nucleotide substitution at codon 203 in exon 4., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

HLA-DRB3*02:02:11 differs from HLA-DRB3*02:02:01:01 by a single synonymous substitution in exon 3'., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

We examined outcomes of haploidentical hematopoietic cell transplantation (haplo-HCT) using T-cell receptor αβ + (TCRαβ + )/CD19 + -depleted grafts (TCR group, 14 patients) in children with hemoglobinopathies. Patients received a preparative regimen consisting of busulfan, thiotepa, cyclophosphamide, and antithymocyte globulin preceded by fludarabine, hydroxyurea, and azathioprine. The median follow-up among surviving patients was 3.9 years. The 5-year probabilities of overall survival (OS) and disease-free survival (DFS) were 84% and 69%, respectively. The incidence of graft failure was 14%. We compared outcomes to a historical group of 40 patients with hemoglobinopathies who received CD34 + -selected grafts (CD34 group). The median follow-up of surviving patients for the CD34 group was 7.5 years. The 5-year probabilities of OS and DFS were 78% and 39%, respectively. The CD34 group had a significantly higher incidence of graft failure (45%) than the TCR group (14%) ( P = .048). The incidences of grades 2 to 4 acute graft-versus-host disease (GVHD) in the TCR and CD34 groups were 28% and 29%, respectively, and 21% and 10% ( P = .1), respectively, for extensive chronic GVHD. Viral reactivation was common in both groups. The overall incidence of posttransplant lymphoproliferative disorders for the entire group was 16%. Among all patients, 5 developed autoimmune hemolytic anemia or thrombocytopenia, with the overall cumulative incidence of 11%. The 2 groups showed suboptimal CD4 + recovery within the first 6 months of transplantation with no significant difference between groups. These data demonstrate that TCRαβ + /CD19 + -depleted grafts are associated with a reduced incidence of graft failure, but delayed immune reconstitution and associated morbidity and mortality remain a significant challenge., (© 2018 by The American Society of Hematology.)

Background: Bone marrow transplantation (BMT) for class 3 patients with thalassemia is challenging due to high rates of graft rejection and transplant-related mortality. Since the first studies of BMT in the late 1980s, a number of conditioning regimens have been designed to improve outcomes, but with suboptimal results. Here we report the outcome of transplantation in class 3 patients using a modified protocol., Methods: Sixty-three patients between 5 and 16.7 years of age with class 3 thalassemia received HLA-matched sibling BMT following either the original protocol (26 patients) or the modified protocol (37 patients). Both regimens comprised preconditioning cytoreduction with hydroxyurea and azathioprine starting at -45 days pretransplant, and fludarabine from days -16 to -12. Conditioning was performed with busulfan and cyclophosphamide (original protocol) or with busulfan, thiotepa, and cyclophosphamide (modified protocol)., Results: The 2 groups showed similar patient demographics. At day 0, the degree of cytoreduction (lymphopenia, neuthropenia, and thrombocytopenia) achieved by the modified protocol was greater than the original protocol. The incidence of graft failure/rejection was significantly higher in the original group (15%; 95% confidence interval [95% CI], 5-32%) compared with the modified group (0%) (P = 0.014). The respective 5-year thalassemia-free survival rates were 73% (95% CI, 51-86%) and 92% (95% CI, 77-97%) (P = 0.047). Both groups showed similar incidences of grades II to IV acute graft-versus host disease. Modified protocol did not increase nonhematological toxicity or infectious complications., Conclusions: The modified treatment protocol effectively and safely prevented graft failure/rejection and significantly increased thalassemia-free survival of class 3 patients with thalassemia.

Human leukocyte antigen (HLA) typing was done in 426 Lebanese subjects of 88 families, in which 347 haplotypes were identified. The A, B, C, DRB1, DRB3/4/5, DQB1 and DPB1 loci were typed at high resolution. This study shows that information theory, as originally developed by Claude Shannon in 1948, provides a promising theoretical foundation to study the population genetics of a genetic system like HLA. Although Lebanese carry HLA alleles found in other populations, the association of these alleles into haplotypes is quite unique. Comparisons are made with the main ethnic groups. Two haplotypes well represented in the Lebanese population are not identified in any global population: L1 = {A*26:01:01 - B*35:01:01:01- C*04:01:01:01- DRB1*16:01:01 - DRB5*02:02 - DQB1*05:02:01} and L2 = {A*02:02 - B*41:01- C*17:01:01:01 -DRB1*11:04:01 - DRB3*02:02:01:01- DQB1*03:01:01:01}. By studying linkage disequilibrium in two blocks at a time, with the division of the blocks at different levels in consecutive cycles, conserved haplotypes in full linkage disequilibrium come to light, such as {A*26:01:01- B*35:01:01:01 - C*04:01:01:01 - DRB1*16:01:01 - DRB5*02:02 - DQB1*05:02:01- DPB1*03:01:01} and {A*33:01:01 - B*14:02:01 - C*08:02:01 - DRB1*01:02:01- DQB1*05:01:01:01 - DPB1*04:01:01:01}., (© 2012 John Wiley & Sons A/S.)

Cerebello-oculo-renal syndromes (CORSs) and Joubert syndrome (JS) are clinically and genetically heterogeneous autosomal recessive syndromes that share a complex neuroradiological malformation resembling a molar tooth on brain axial images, a condition referred to as "molar tooth on imaging" (MTI) or the "molar tooth sign." The current literature on these syndromes is complex, with overlapping and incomplete phenotypes that complicate the selection of clinically homogeneous cases for genetic purposes. So far, only one locus (JBTS1 on 9q34) has been mapped, in two families with JS. Here, we describe a large consanguineous family with JS and nephronophthisis, representing a novel cerebello-renal phenotype. We have mapped this condition to the pericentromeric region of chromosome 11 and have named the locus "CORS2." The acronym "CORS" is proposed for all loci associated with JS, CORSs, and related phenotypes sharing the MTI, because this neuroradiological sign seems to be the unifying feature of these clinically heterogeneous syndromes.