Detection of Five Novel and Confirmation of Two HLA Class II Alleles.
Seven HLA class II alleles were detected and confirmed.
Humans↗
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Results for “histocompatibility testing”
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A healthy live birth after mosaic blastocyst transfer in preimplantation genetic testing for GATA1-related cytopenia combined with HLA matching.
BACKGROUND: GATA1-related cytopenia (GRC) is characterized by thrombocytopaenia and/or anaemia ranging from mild to severe. Haematopoietic stem cell transplantation (HSCT) is a healing therapeutic choice for GRC patients. We identified a novel pathogenic variant (GATA1: c.1019delG) in a boy with GATA1-related cytopenia. Then we performed preimplantation genetic testing (PGT) in this GRC family. After a mosaic embryo transfered, a healthy and HLA-compatible with the proband baby was delivered. CASE PRESENTATION: The proband is a 6-year-old boy who was diagnosed to have transfusion-dependent anaemia since 3 year old. Whole-exome sequencing (WES) showed that the proband has a hemizygous variant c.1019delG in GATA1, which is inherited from his mother. His parents decided to undergo PGT to have a health and HLA-compatible offspring. After whole genome amplification (WGA) of biopsied trophectoderm (TE) cells, next generation sequencing (NGS)-based PGT was preformed to analyse embryos on chromosomal aneuploidy, target mutation and HLA typing. There were 3 embryos HLA-matched to the proband. The genotypes of the 3 embryos were heterozygous variant, hemizygous variant, normal respectively. After a heterozygous, mosaic partial trisomy (chr)16, and HLA-matched embryo transfer, a healthy baby was delivered and whose HSCT is compatible with the proband. CONCLUSIONS: NGS-based PGT-HLA is a valuable procedure for the treatment of GATA1-related cytopenia caused by GATA1 variants, or other haematological disorders, oncological and immunological diseases. Furthermore, our study reconfirms that mosaic embryos transfer would bring healthy offspring.
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Deletion of the HLA-B Gene in One of the Inherited Haplotypes in a Northern European Family.
Targeted next generation sequencing-based HLA typing of a 17-year-old female transplant patient showed homozygosity for the HLA-B allele. The segregation analysis of HLA haplotypes of family members only allowed the conclusion that the B-allele was deleted in the haplotype inherited from the father and accordingly paternal grandfather, resulting in false homozygous genotyping. The subsequent whole-genome sequencing of the patient and her father confirmed an approximately 85 kb deletion at 6p21.33 from the 5' end of the HLA-B to the 3' end of the HLA-C gene extending telomeric to HLA-C.
Adolescent↗
Identification of the HLA-B*27:277 Allele in Individuals of European Descent and Native American Descent.
HLA-B*27:277 differs from HLA-B*27:05:02:05 by a single substitution in exon 6.
Humans↗
First Report of the HLA-DQB1*03:575 Allele in a Kidney Transplant Recipient of European Descent.
The new HLA-DQB1*03:575 differs from HLA-DQB1* 03:03:02:01 by a single base substitution at exon 2.
Humans↗
The combined impact of HLA and non-HLA mismatch between donors and recipients on kidney transplant survival: a genomic analysis in a prospective cohort.
BACKGROUND: Kidney transplantation outcomes are strongly influenced by immunological compatibility between donor and recipient. While genetic mismatches in the human leukocyte antigen (HLA) region have long been recognised as key determinants of graft survival, increasing evidence, including our own previous work, suggests that non-HLA alloimmunity also plays a critical role. METHODS: We sequenced exomes of deceased kidney donor and recipient pairs in the prospective kidney transplant cohort at the Vienna General Hospital, recruited between January 1, 2012, and June 15, 2023. Out of 1209 pairs, 1187 passed quality control for analysis. Non-HLA mismatch was computed by considering non-synonymous single nucleotide polymorphisms specifically encoding trans-cell membrane or secreted proteins in the kidney (nsSNP-tcmsk). Using adjusted Cox proportional hazards models, we replicated results from our earlier work in recipients with primary graft function after 90 days, and extended the analysis to the combination of nsSNP-tcmsk with eplet mismatch to assess their associations with graft loss in the full cohort. FINDINGS: Of 20,421 human proteins, 2371 were considered for the nsSNP-tcmsk score. In our replication analysis we estimated for nsSNP-tcmsk a hazard ratio (HR) of 1.33 (95% CI 1.02-1.74) for graft loss per increase of one interquartile range. The nsSNP-tcmsk and eplet mismatch were uncorrelated (Spearman correlation coefficient 0.02, p = 0.47). A composite score of nsSNP-tcmsk and eplet mismatch was associated with graft loss with a HR of 1.76 (95% CI 1.20-2.57) corresponding to an absolute difference in 7-year restricted mean survival time between the first and fourth quartiles of 0.52 years (95% CI 0.16-0.87 years). INTERPRETATION: The impact of non-HLA donor-recipient mismatch on transplant loss is of the same magnitude as established mismatch scores in the HLA region. Together, these scores may be further validated as guiding markers for the required strength of maintenance immunosuppression. FUNDING: Vienna Science and Technology Fund, NIH/NIAID.
Humans↗
Identification of the Novel HLA-E*01:154 Allele Using PolyseqOne and Oxford Nanopore Sequencing Technology.
HLA-E*01:154 differs from HLA-E*01:01:01:01 by a single nonsynonymous nucleotide substitution in codon 199 of exon 3.
Humans↗
Genomic Confirmation of HLA-A*02:94N By Next-Generation Sequencing.
The HLA-A*02:94N allele is characterised by a nonsense mutation in codon 89 in Exon 2.
Humans↗
Maternal-Foetal HLA-DQB1 Incompatibility Is Associated With Pregnancy-Induced Hypertensive Disorders in a Genetically Isolated Population.
In pregnancy, semi-allogenic foetal trophoblasts express a specific HLA profile mediating maternal leukocyte contact, crucial for placentation. Paradoxically, maternal immunomodulation requires foetal antigen recognition, especially involving certain HLA molecules. Pre-eclampsia, a severe hypertensive complication, has been linked to antigenic similarity. Previously, we showed no selection for HLA (in)compatibility in uncomplicated naturally conceived pregnancies. However, pre-eclamptic pregnancies were associated with increased total maternal-foetal HLA and HLA-C matching. These associations suggest a role for HLA mismatches in immune regulation leading to an uncomplicated pregnancy. To better understand HLA homozygosity in human reproduction, we aimed to determine if there is a preferential selection for HLA compatibility in a genetically isolated population, and its relation to hypertensive complications. A nested case-control study, comprising 125 uncomplicated pregnancies and 50 with hypertensive complications (29 with pregnancy-induced hypertension, 21 with pre-eclampsia) was conducted in a genetically isolated Dutch population (FROH 1.3-3.1). Maternal and foetal HLA-A, -B, -C, -DRB1, -DQA1, -DQB1 and maternal killer-cell immunoglobulin-like receptor (KIR) genotyping were performed. Maternal-foetal HLA (mis)match counts were compared to expected values from randomisation of paternal HLA haplotypes over maternal haplotypes of the foetuses. Mismatched CD4+ T cell epitopes presented by maternal HLA class II were predicted using the PIRCHE-II algorithm. In uncomplicated pregnancies, no difference was found between observed and expected maternal-foetal HLA (mis)matches. However, pregnancies with hypertensive complications showed significantly higher observed HLA-DQB1 mismatches, reflected in PIRCHE-II scores. No significant differences were found in KIR/HLA-C frequencies. Interpretation is limited by the small sample size and the grouping of distinct hypertensive disorders. Nonetheless, maternal-foetal HLA-DQB1 mismatch seems to play a role in the aetiology of hypertensive complications during pregnancy in this population.
Humans↗
Confirmation and Extension of the HLA-DPB1*1000:01 Allele by Next-Generation and Oxford Nanopore Sequencing.
The HLA-DPB1*1000:01 allele is characterised by a single nucleotide substitution in exon 3.
Humans↗
FuFiHLA: a tool for full-field HLA typing from long-read data.
MOTIVATION: Allele typing for Human Leukocyte Antigen (HLA) genes has many important clinical applications. Popular short-read typing can only accurately distinguish alleles at the coding sequence level, which potentially limit our understanding of the effect of variants in non-coding region. Long read data has been proved to be useful in typing HLA alleles in full resolution, but only a few tools are publicly available and with significant limitations in practical application. RESULTS: We developed FuFiHLA, a lightweight open-source software, to type HLA alleles. Currently it supports typing alleles of six HLA genes (HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DQA1, and HLA-DQB1) from long reads. Evaluation using 233 PacBio HiFi WGS samples from HPRC shows that FuFiHLA achieves 99.6% accuracy in the full field allele typing and QV as 51.8 for consensus allele sequence construction. Additional testing on four Nanopore R10 reads demonstrates slightly reduced accuracy in the fourth field. AVAILABILITY: FuFiHLA is available at https://github.com/jingqing-hu/FuFiHLA under MIT License.
Humans↗
Evaluating the Antigen and Eplet Accuracy of DQA1 Imputations With the HaploSFHI Two-Field HLA Typing Inference Tool.
Donor/recipient mismatched HLA antigens can lead to the production of Donor-Specific Antibodies by the recipient, which are deleterious to organ transplants. The HLA-DQ locus is the most frequent target, with both the DQ beta and alpha chains involved. For deceased donors in particular, while HLA-DQB1 has been typed in emergencies for a long time, HLA-DQA1 has only recently been included. No imputation algorithmic tool was available to impute HLA-DQA1 until the development of HaploSFHI, trained on 61,393 two-field typings by NGS methods. We evaluated the accuracy of two-field HLA-DQA1 imputation from serological and two-field level HLA-A, B, DRB1, and DQB1 typings. We report a highly accurate two-field HLA-DQA1 prediction using a French test cohort of 7696 individuals, respectively reaching 92.30% and 96.45% accuracy. The average 'False Positive eplet load' stood at 0.19 and 0.07, respectively, and the average 'False Negative eplet load' at 0.18 and 0.08, respectively. A similar performance was obtained on three independent test cohorts of European ancestry (from the USA, the UK, and Portugal). Interestingly, performance was only slightly inferior on five independent test cohorts of other ethnicities (from Hong Kong and the USA) whereas it was significantly lower for two-field DRB1 imputation from its serological level. These results suggest that DQA1 can reliably be imputed even when information is totally missing, with low error risk at both antigen and eplet levels, even if the reference population is not matched. Similar additional initiatives would be welcome to confirm these findings.
Humans↗
Association Between HLA-DRB1 Serotype and HLA-DQB1 Allele Mismatches and Acute Rejection in Kidney Transplantation.
The purpose of this single-center case-control study was to investigate the association between HLA serotype mismatch (MM), compared to other HLA MM modalities, and the occurrence of acute rejection (AR) within the first year after deceased donor kidney transplantation. The study included 198 transplants in 99 pairs of recipients of kidneys from the same donor, where one recipient experienced AR and the other survived the first year without AR. Donors and recipients were typed with NGS for 11 HLA loci at high resolution. HLA MM categories included allele groups, alleles, serotypes, amino acids, EMMA, eplet and PIRCHE-II. Additionally, we investigated Cytomegalovirus LIL peptide (CMV LIL) MM. Recipients with AR presented higher frequencies of pre-transplant HLA-ABDR DSA (20.2% vs. 6.1%, p = 0.005) and CMV LIL MM (24.2% vs. 10.1%, p = 0.01). Univariate and multivariate Cox proportional hazards regression for matched-pair analyses were used to test the association between HLA MM and AR. Univariate analyses indicated significant association with DRB1 ST, HLA-DQB1 AG, HLA-DQB1 AL, EMMA C, EMMA DQB1, Eplet ABC and Eplet DQ MM. Different models were tested in multivariate analyses, all including pre-transplant HLA-ABDR DSA and CMV LIL MM. The models were compared using the Akaike Information Criterion (AIC). The best estimate for AR prediction (AIC = 97.6) was the model that included pre-transplant HLA-ABDR DSA (HR = 11.97; p = 0.003), CMV LIL MM (HR = 367.2; p < 0.001), HLA-DRB1 serotype MM (9.65; p = 0.002) and HLA-DQB1 allele MM (HR = 3.54; p = 0.033). In conclusion, this original report demonstrates an association between the HLA-DRB1 serotype MM and AR, highlighting that serotypes are clinically relevant.
Humans↗
HLA Allele and Haplotype Frequencies Among Registered Unrelated Donors in the Western Region of Saudi Arabia.
The Saudi stem cell donor registry (SSCDR) has successfully recruited over 92,000 unrelated potential stem cell donors through nationwide campaigns. The Western region of Saudi Arabia is characterized by its unique ethnic diversity, shaped by centuries of immigration and pilgrimage. This study aimed to determine the distribution of HLA alleles and haplotypes among donors from this region. A total of 1112 donors registered with SSCDR were included, all recruited during campaigns conducted in the Western region between 2019 and 2021. Participants provided ancestry information to confirm their city of origin. High-resolution HLA typing for loci A, B, C, DRB1 and DQB1 was performed using sequence-based typing (SBT). Allele and haplotype frequencies were estimated for each subgroup using Arlequin 3.5 software. Distinct haplotype patterns were observed across cities. The most common haplotypes in the 1112 potential stem cell donors in the Western Region of Saudi Arabia were HLA-A*02:01∼C*07:02∼B*07:02∼DRB1*15:01∼DQB1*06:02 and HLA-A*02:01∼C*06:02∼B*50:01∼DRB1*07:01∼DQB1*02:01 in Jeddah; A*23:01∼C*06:02∼B*50:01∼DRB1*07:01∼DQB1*02:01 in Al-Madinah; HLA-A*26:01∼C*07:02∼B*08:01∼DRB1*03:01∼DQB1*02:01, HLA-A*30:01∼C*06:02∼B*13:02∼DRB1*07:01∼DQB1*02:01 and HLA-A*02:01∼C*06:02∼B*50:01∼DRB1*07:01∼DQB1*02:01 in Makkah; HLA-A*02:01∼C*15:02∼B*51:01∼DRB1*13:01∼DQB1*06:03 and HLA-A*02:01∼C*07:02∼B*07:02∼DRB1*15:01∼DQB1*06:02 in Al-Baha; and HLA-A*31:01∼C*15:02∼B*51:01∼DRB1*13:01∼DQB1*06:03 in Taif. HLA data are available in the Allele Frequencies Net Database (AFND: 3854, 3855, 3856, 3857 and 3858) under the population name 'Saudi Western Region'. In western Saudi Arabia, HLA allele and haplotype distributions demonstrate marked city-specific variation. Our research identifies DR7-, DR13- and DR15-based haplotypes as the most prevalent across the region. These findings are critical for optimizing unrelated donor searches for patients lacking compatible familial matches. Understanding these local frequencies allows for more targeted recruitment and better matching probabilities in stem cell registries.
Humans↗
Identification of the Novel HLA-DQA1*05:01:21 Allele by Next-Generation Sequencing.
HLA-DQA1*05:01:21 differs from HLA-DQA1*05:01:01:02 by one nucleotide substitution in codon 198 (TGC > TGT) in exon 4.
Humans↗
Identification of the Novel HLA-B*38:125 Allele by Next-Generation Sequencing.
HLA-B*38:125 differs from HLA-B*38:02:01:01 by one nucleotide substitution in codon 248 (GTG>ATG) in exon 4.
Humans↗
Detection of the HLA-A*02:924 Allele, a Variant of A*02:07:01:01, in a Taiwanese Individual.
One nucleotide mutation in exon 4 of HLA-A*02:07:01:01 results in the novel allele, HLA-A*02:924.
Humans↗
Characterisation of the Novel HLA-B*48:43:02 Allele in a Chinese Individual.
HLA-B*48:43:02 differs from HLA-B*48:43:01 by one single nucleotide substitution at position 900 G>C in exon 5.
Humans↗