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Both DNA damage response and methylation play a crucial role in antigen receptor recombination by creating a diverse repertoire in developing lymphocytes, but how their defects relate to T cell repertoire and phenotypic heterogeneity of immunodeficiency remains obscure. We studied the TCR repertoire in patients with the mutation in different genes (ATM, DNMT3B,ZBTB24,RAG1,DCLRE1C, andJAK3) and uncovered distinct characteristics of repertoire diversity. We propose that early aberrancies in thymus T cell development predispose to the heterogeneous phenotypes of the immunodeficiency spectrum. Shorter CDR3 lengths in ATM-deficient patients, resulting from a decreased number of nucleotide insertions during VDJ recombination in the pre-selected TCR repertoire, as well as the increment of CDR3 tyrosine residues, lead to the enrichment of pathology-associated TCRs, which may contribute to the phenotypes of ATM deficiency. Furthermore, patients withDNMT3BandZBTB24mutations who exhibit discrepant phenotypes present longer CDR3 lengths and reduced number of known pathology-associated TCRs.

NAD(P)HX dehydratase (NAXD) catalyzes the recovery of toxic derivatives of nicotinamide adenine dinucleotides which play an essential role in mitochondrial metabolism. Mutations in NAXD were recently shown to cause early-onset neurodegeneration exacerbated by febrile illness. Here, we report a novel homozygous stop-gain variant in NAXD in an infant who presented with a fulminant course of autoinflammation, dermatitis, colitis, and cystic encephalomalacia beginning at 3 weeks of age. Our findings support the central role of NAXD-mediated metabolite repair for normal tissue function and implicate innate immune processes in the pathogenesis of NAXD deficiency.

Both DNA damage response and methylation play a crucial role in antigen receptor recombination by creating a diverse repertoire in developing lymphocytes, but how their defects relate to T cell repertoire and phenotypic heterogeneity of immunodeficiency remains obscure. We studied the TCR repertoire in patients with the mutation in different genes (ATM, DNMT3B, ZBTB24, RAG1, DCLRE1C, and JAK3) and uncovered distinct characteristics of repertoire diversity. We propose that early aberrancies in thymus T cell development predispose to the heterogeneous phenotypes of the immunodeficiency spectrum. Shorter CDR3 lengths in ATM-deficient patients, resulting from a decreased number of nucleotide insertions during VDJ recombination in the pre-selected TCR repertoire, as well as the increment of CDR3 tyrosine residues, lead to the enrichment of pathology-associated TCRs, which may contribute to the phenotypes of ATM deficiency. Furthermore, patients with DNMT3B and ZBTB24 mutations who exhibit discrepant phenotypes present longer CDR3 lengths and reduced number of known pathology-associated TCRs.

Background: The aim of this study is to investigate potentially curable or treatable medical conditions in unselected newborns using genomic sequencing(GS). Methods: 321 newborns from a cohort of pregnant women from Qingdao, China, underwent high-depth GS (average 47.42 fold), with the approval of the ethics committee. 61 Mendelian Diseases, 151 Primary Immunodeficiency Diseases(PID) and 5 DPWG recommeded Essential pharmacogenetic(PGx) genes were analyzed. Results: 121 Mendelian pathogenic or likely pathogenic variants associated with 31 inherited diseases were detected, among these hearing loss, congenital hypothyroidism, methylmalonic acidemia, methylmalonic acidemia with homocystinuria, phenylketonuria(PKU) and benign hyperphenylalaninemia accounted for half of the carrier variants. Three children with compound heterozygous variants at GJB2 and PAH were confirmed by Sanger sequencing. Follow-up of the three families confirmed that one child was diagnosed with PKU and two children with GJB2 variants were scheduled to undergo hearing loss testing every six months after genetic counceling due to the nature of incomplete penetrance of hearing loss. 11 heterozygous pathogenic/ likely pathogenic variants in eight PID genes were identified in 11 infants. All 321 newborns carried at least one variant at the five DPGW recommended PGx genes. Codeine and clopidogrel require more attention in giving prescription for 25% and 8% of newborns have a decreased function of CYP2D6 and CYP2C19 enzymes respectively. Conclusions: Our study is the largest to date using GS to sequence unselected newborns. The results suggest that using GS may be a suitable method for screening newborns for variants in a large number of disease associated genes.

A novel allele HLA-C*08:80 differs from HLA-C*08:01:01:01 by one nucleotide substitution at position 142.