Prevalence and clinical outcomes of germline variants among patients with myeloid neoplasms.

AIMS: Myeloid neoplasms (MNs) with germline predisposition have been recognised as a distinct entity. Emerging evidence suggests that sporadic myelodysplastic syndromes may also harbour undetected germline predispositions. We investigated germline alterations in a cohort of 122 adult Thai MNs. METHODS: MN patients were recruited and tested for germline variants using deep targeted next-generation sequencing. The germline variant was filtered using American College of Medical Genetics classifications and then evaluated for the association with clinical characteristics and outcomes. RESULTS: Our findings revealed pathogenic/likely pathogenic germline alterations in 12 (10%) of the patients. These germline lesions were commonly found in the DNA damage response pathway (n=6, 50%). We also identified novel deleterious FANCA A1219GfsTer59 variants in two patients diagnosed with secondary acute myeloid leukaemia (sAML) from aplastic anaemia and AML with myelodysplasia related. Among sAML, individuals with germline mutations had inferior overall survival compared with those with wild-type alleles (2 months vs 12 months) with HR 4.7 (95% CI 1.0 to 20), p=0.037. Therefore, the presence of pathogenic or likely pathogenic mutations may be linked to inferior survival outcomes. CONCLUSIONS: Our study highlighted that the prevalence of germline predisposition in Southeast Asian populations is comparable to that in Caucasians. This underscores the importance of germline genetic testing within the Asian population.

A LILRB1 variant with a decreased ability to phosphorylate SHP-1 leads to autoimmune diseases.

Inborn errors of immunity are known to cause not only immunodeficiencies and allergies but also autoimmunity. Leukocyte immunoglobulin-like receptor B1 (LILRB1) is a receptor on leukocytes playing a role in regulating immune responses. No phenotypes have been reported to be caused by germline mutations in LILRB1. We aimed to identify the causative variant in a three-generation family with nine members suffering from one of the three autoimmune diseases-Graves' disease, Hashimoto's thyroiditis, or systemic lupus erythematosus. Whole-genome linkage study revealed a locus on chromosome 19q13.4 with the maximum LOD score of 2.71. Whole-exome sequencing identified a heterozygous missense variant, c.479G > A (p. G160E) in LILRB1, located within the chromosomal-linked region, in all nine affected members. The variant has never been previously reported. Jurkat cells transfected with the mutant LILRB1, compared with those with the wild-type LILRB1, showed decreased phosphorylation of both LILRB1 and its downstream protein, SHP-1. Flow cytometry was used to study immunophenotype and revealed that LILRB1 was significantly lower on the surface of activated regulatory T lymphocytes (Treg) cells of patients. Single-cell RNA sequencing showed substantially increased M1-like monocytes in peripheral blood mononuclear cells of affected individuals. This study, for the first time, implicates LILRB1 as a new disease gene for autoimmunity.

Actionable secondary findings in the 73 ACMG-recommended genes in 1559 Thai exomes.

High-throughput DNA sequencing provides not only primary diagnosis but also makes available other genetic variants with potential health implications. the American College of Medical Genetics and Genomics (ACMG) has recommended a list of medically actionable genes since 2013 and very recently released an updated ACMG SF v3.0 list comprising 73 genes. Here, we analyzed exome data of 1559 unrelated Thai individuals to determine the frequency and spectrum of pathogenic (P) or likely pathogenic (LP) variants in the 73 genes. Based on the ACMG guidelines for the interpretation of sequence variants, 68 different P/LP variants in 26 genes associated with 18 diseases inherited in an autosomal-dominant manner of 186 individuals (11.9%; 186/1559) were identified. Of these, 22 P/LP variants in 15 genes associated with 13 diseases of 85 individuals (5.5%; 85/1559) were also reported as P/LP in the ClinVar archive. The majority harbored variants in genes related to cardiovascular diseases (4.7%; 74/1559), followed by cancer phenotypes (0.5%; 8/1559). None of the individuals in our cohort harbored biallelic variants in genes responsible for diseases inherited in an autosomal recessive manner. The results would serve as a basis for precision medicine practice at individual and population levels.