CMR Characteristics, gene variants and long-term outcome in patients with left ventricular non-compaction cardiomyopathy

Background As the paucity of data focusing on evaluating cardiac structure and function in patients with or without gene mutation, this study was sought to investigate the correlation between genotype and cardiac magnetic resonance (CMR) phenotype in patients with left ventricular non-compaction cardiomyopathy (LVNC) and to explore prognostic relevance in this cohort if possible. Methods Patients with LVNC who underwent CMR and targeted gene sequencing between 2006 and 2016 were retrospectively evaluated. Demographic data, clinical presentation, genetic analysis, CMR data and follow-up data of all participants were collected. Results Compared to negative genotype (G−) group, patients with positive genotype (G+) had larger left atrial volume (LAV), and carriers of multiple variants had lower left ventricular (LV) ejection fraction and cardiac index, increased LV fibrosis, larger LA volume, reduced LV global circumferential strain, LA reservoir strain and booster pump strain (all p < 0.05). LA volume was able to discriminate patients with G + (all p < 0.05), as well as those with multiple genetic mutation (all p < 0.01). During a median follow-up of 5.1 years, Kaplan–Meier survival analysis revealed worse primary endpoint-free survival among carriers of multiple variants compared to G− group. Conclusions CMR feature tracking is a remarkable tool to evaluate implication, genetics cascade screen and predict outcome in LVNC population. LA volume is a sensitive and robust indicator for genetic mutational condition, of which facilities to guide clinical management and intensity of follow-up for patients and their relatives.

Circular RNAs in acute myeloid leukemia

Although mechanistic studies clarifying the molecular underpinnings of AML have facilitated the development of several novel targeted therapeutics, most AML patients still relapse. Thus, overcoming the inherent and acquired resistance to current therapies remains an unsolved clinical problem. While current diagnostic modalities are primarily defined by gross morphology, cytogenetics, and to an extent, by deep targeted gene sequencing, there is an ongoing demand to identify newer diagnostic, therapeutic and prognostic biomarkers for AML. Recent interest in exploring the role of circular RNA (circRNA) in elucidating AML biology and therapy resistance has been promising. This review discerns the circular RNAs’ evolving role on the same scientific premise and attempts to identify its potential in managing AML.

Accurate interpretation of genetic variants in sudden unexpected death in infancy by trio-targeted gene-sequencing panel analysis

In sudden unexpected death in infancy cases, postmortem genetic analysis with next-generation sequencing potentially can extract candidate genes associated with sudden death. However, it is difficult to accurately interpret the clinically significant genetic variants. The study aim was to conduct trio analysis of cases of sudden unexpected death in infancy and their parents to more accurately interpret the clinically significant disease-associated gene variants associated with cause of death. From the TruSight One panel targeting 4813 genes we extracted candidate genetic variants of 66 arrhythmia-, 63 inherited metabolic disease-, 81 mitochondrial disease-, and 6 salt-losing tubulopathy-related genes in 7 cases and determined if they were de novo or parental-derived variants. Thirty-four parental-derived variants and no de novo variants were found, but none appeared to be related to the cause of death. Using trio analysis and an in silico algorithm to analyze all 4813 genes, we identified OBSCN of compound heterozygous and HCCS of hemizygous variants as new candidate genetic variants related to cause of death. Genetic analysis of these deceased infants and their living parents can provide more accurate interpretation of the clinically significant genetic variants than previously possible and help confirm the cause of death.

Identification of a novel mutation in the PHKA2 gene in a child with liver cirrhosis

Objectives Glycogen storage diseases (GSDs) are heterogeneous disorders caused by various enzyme deficiencies. GSD type IX α2, the most common subtype of GSD IX, is due to a deficiency of hepatic phosphorylase kinase. Herein we will report a novel mutation in this disease with an unusual presentation. Case presentation we describe a 3-year-old boy who suffered from hepatomegaly, fatty liver disease, and liver cirrhosis. The cause of cirrhosis at a young age was unknown based on the laboratory data and liver biopsy, so we performed a targeted-gene sequencing (TGS) covering 450 genes involved in inborn metabolic diseases consisting of glycogen storage disorders genes with hepatic involvement. He was found out to have a rare novel pathogenic variant in the PHKA2 gene. Conclusions This novel variant c.2226+2T > C expands the mutational spectrum of the PHKA2 gene. Also, severe liver damage (cirrhosis) in patients with GSD- IX α2 has rarely been reported, which needs further discussion. We hypothesize that unidentified PHKA2 variants may be a rare cause of childhood liver cirrhosis.

Lethal variants in humans: lessons learned from a large molecular autopsy cohort

Background Molecular autopsy refers to DNA-based identification of the cause of death. Despite recent attempts to broaden its scope, the term remains typically reserved to sudden unexplained death in young adults. In this study, we aim to showcase the utility of molecular autopsy in defining lethal variants in humans. Methods We describe our experience with a cohort of 481 cases in whom the cause of premature death was investigated using DNA from the index or relatives (molecular autopsy by proxy). Molecular autopsy tool was typically exome sequencing although some were investigated using targeted approaches in the earlier stages of the study; these include positional mapping, targeted gene sequencing, chromosomal microarray, and gene panels. Results The study includes 449 cases from consanguineous families and 141 lacked family history (simplex). The age range was embryos to 18 years. A likely causal variant (pathogenic/likely pathogenic) was identified in 63.8% (307/481), a much higher yield compared to the general diagnostic yield (43%) from the same population. The predominance of recessive lethal alleles allowed us to implement molecular autopsy by proxy in 55 couples, and the yield was similarly high (63.6%). We also note the occurrence of biallelic lethal forms of typically non-lethal dominant disorders, sometimes representing a novel bona fide biallelic recessive disease trait. Forty-six disease genes with no OMIM phenotype were identified in the course of this study. The presented data support the candidacy of two other previously reported novel disease genes (FAAH2 and MSN). The focus on lethal phenotypes revealed many examples of interesting phenotypic expansion as well as remarkable variability in clinical presentation. Furthermore, important insights into population genetics and variant interpretation are highlighted based on the results. Conclusions Molecular autopsy, broadly defined, proved to be a helpful clinical approach that provides unique insights into lethal variants and the clinical annotation of the human genome.

Hearing loss in Africa: current genetic profile

Hearing impairment (HI) is highly heterogeneous with over 123 associated genes reported to date, mostly from studies among Europeans and Asians. Here, we performed a systematic review of literature on the genetic profile of HI in Africa. The study protocol was registered on PROSPERO, International Prospective Register of Systematic Reviews with the registration number “CRD42021240852”. Literature search was conducted on PubMed, Scopus, Africa-Wide Information, and Web of Science databases. A total of 89 full-text records was selected and retrieved for data extraction and analyses. We found reports from only 17/54 (31.5%) African countries. The majority (61/89; 68.5%) of articles were from North Africa, with few reports found from sub-Saharan Africa. The most common method used in these publications was targeted gene sequencing (n = 66/111; 59.5%), and only 13.5% (n = 15/111) used whole-exome sequencing. More than half of the studies were performed in families segregating HI (n = 51/89). GJB2 was the most investigated gene, with GJB2: p.(R143W) founder variant only reported in Ghana, while GJB2: c.35delG was common in North African countries. Variants in MYO15A were the second frequently reported in both North and Central Africa, followed by ATP6V1B1 only reported from North Africa. Usher syndrome was the main syndromic HI molecularly investigated, with variants in five genes reported: USH2A, USH1G, USH1C, MYO7A, and PCDH15. MYO7A: p.(P1780S) founder variant was reported as the common Usher syndrome variant among Black South Africans. This review provides the most comprehensive data on HI gene variants in the largely under-investigated African populations. Future exomes studies particularly in multiplex families will likely provide opportunities for the discovery of the next sets of novel HI genes, and well as unreported variants in known genes to further our understanding of HI pathobiology, globally.

Genetic profiles of subcutaneous panniculitis-like T-cell lymphoma and clinicopathological impact of HAVCR2 mutations

Recent studies identified germline mutations in HAVCR2 (encoding TIM-3) as a genetic factor that predisposes to subcutaneous panniculitis-like T-cell lymphoma (SPTCL). However, the differences between HAVCR2-mutated (HAVCR2MUT) and HAVCR2-wild-type (HAVCR2WT) SPTCLs remain unclear. A nationwide cohort of 53 SPTCL patients diagnosed at eight Korean institutions was established. Whole-exome sequencing (WES) and RNA-seq were performed on eight patients in the discovery set. In the validation set, targeted gene sequencing (TGS) or direct sequencing of HAVCR2 was performed. Of 49 patients with available HAVCR2 status, 24 (49.0%) were HAVCR2Y82C. HAVCR2Y82C was associated with younger age (p = 0.001), development of hemophagocytic lymphohistiocytosis (HLH) or HLH-like systemic illness (p &lt; 0.001), and short relapse-free survival (RFS) (p = 0.023). Most mutated genes in SPTCLs were involved in immune responses, epigenetic modifications, and cell signaling. Mutations in UNC13D, PIAS3, and KMT2D were more frequent in HAVCR2WT SPTCLs. At the gene expression level, HAVCR2Y82C SPTCLs were enriched in genes involved in IL6-JAK-STAT3 signaling and in TNF-α signaling via NF-κB. CCR4 was significantly upregulated in HAVCR2WT SPTCLs both at the mRNA and protein levels. We established a risk stratification system for SPTCL by integrating clinical and histopathological features, including age and HAVCR2 mutation status. This risk stratification system was strongly associated with RFS (p = 0.031). In conclusion, the HAVCR2Y82C mutation was common in Korean patients with SPTCL and was associated with unique clinicopathological and genetic features. Combining clinicopathological parameters could aid in predicting SPTCL patients' prognosis.

Chronic mucocutaneous Candidiasis caused by a novel STAT1 mutation: a report of 4 patients

Background: Chronic mucocutaneous Candidiasis (CMCC) is characterized by recurrent or persistent fungal infections of the skin, nails, and oral and genital mucosae. There are several underlying genetic causes for CMCC, with mutations in Signal Transducer and Activator of Transcription-1 (STAT1) accounting for the majority of cases. Aim: To broaden the genotypic spectrum of CMCC caused by STAT1 mutations. Methods: We evaluated a young patient and her family with CMCC. Immune workup and targeted gene sequencing were performed. Results: The proband presented at 7 years of age with persistent oral thrush. Immune evaluation revealed her cellular and humoral immunity to be within normal range. Given that her family history was significant for oral lesions in father, siblings, and paternal family members, STAT1 gene sequencing was performed. A novel heterozygous missense c.G799A, predicting a p.Ala267Thr amino acid change within the coiled-coil domain, was identified in our patient and 3 of her family members. Conclusion: Gain-of-function mutations in STAT1 have been associated with a variety of phenotypes, ranging from isolated CMCC to severe fatal combined immunodeficiency, mycobacterial infections, autoimmune disorders, as well as malignancy and aneurysms. Here, we describe a novel STAT1 mutation, c.G799A, resulting in a very mild phenotype of isolated CMCC in 4 members of one kindred. Statement of Novelty: We describe 4 patients with a mild phenotype of CMCC caused by a novel STAT1 heterozygous mutation.