Clinical Presentations, Diagnosis, and Genetic Features of Hemophagocytic Lymphohistiocytosis: A Single Institutional Experience With the Saudi Population.

Background Hemophagocytic lymphohistiocytosis (HLH) is an uncommon, potentially fatal condition caused by high immune activation. The present study aimed to identify the clinical manifestations, geographic distribution, and associated pathogenic genetic mutations of HLH in Saudi Arabia. Method A retrospective cross-sectional study was conducted at King Fahad Medical City (KFMC), with a total of 59 patients diagnosed with HLH in the period between 2006 and 2018. All genetic results and clinical and biochemical data were retrieved and statistically analyzed using IBM SPSS Statistics for Windows, Version 25 (Released 2017; IBM Corp., Armonk, New York, United States). Results The results revealed that 48 patients (81.4%) had 15 pathogenic mutations of primary HLH whereas 8 (13.6%) patients had no genetic mutation. The most common variant mutation identified was c.1430C>T of the STXBP2 gene (42.4% of total patients), followed by c.1122G>A of the PRF1 gene (10.2% of patients), which demonstrated a distinctive geographic and tribal association. Patients with RAB27A mutation tend to present at an older age than the others with a median age of presentation of 5.5 months vs 2 months for patients with PRF1 mutations. No significant differences in clinical features were observed among the various groups. Conclusion This study highlights the incidence of genetic mutations among the Saudi population with HLH. The STXBP2 is the most common mutation followed by PRF1 mutations, many mutation variants are associated with a distinctive tribal and geographic association.

Hypomorphic GINS3 variants alter DNA replication and cause Meier-Gorlin syndrome.

The eukaryotic CDC45/MCM2-7/GINS (CMG) helicase unwinds the DNA double helix during DNA replication. The GINS subcomplex is required for helicase activity and is, therefore, essential for DNA replication and cell viability. Here, we report the identification of 7 individuals from 5 unrelated families presenting with a Meier-Gorlin syndrome-like (MGS-like) phenotype associated with hypomorphic variants of GINS3, a gene not previously associated with this syndrome. We found that MGS-associated GINS3 variants affecting aspartic acid 24 (D24) compromised cell proliferation and caused accumulation of cells in S phase. These variants shortened the protein half-life, altered key protein interactions at the replisome, and negatively influenced DNA replication fork progression. Yeast expressing MGS-associated variants of PSF3 (the yeast GINS3 ortholog) also displayed impaired growth, S phase progression defects, and decreased Psf3 protein stability. We further showed that mouse embryos homozygous for a D24 variant presented intrauterine growth retardation and did not survive to birth, and that fibroblasts derived from these embryos displayed accelerated cellular senescence. Taken together, our findings implicate GINS3 in the pathogenesis of MGS and support the notion that hypomorphic variants identified in this gene impaired cell and organismal growth by compromising DNA replication.

Exome sequencing in routine diagnostics: a generic test for 254 patients with primary immunodeficiencies.

BACKGROUND: Diagnosis of primary immunodeficiencies (PIDs) is complex and cumbersome yet important for the clinical management of the disease. Exome sequencing may provide a genetic diagnosis in a significant number of patients in a single genetic test. METHODS: In May 2013, we implemented exome sequencing in routine diagnostics for patients suffering from PIDs. This study reports the clinical utility and diagnostic yield for a heterogeneous group of 254 consecutively referred PID patients from 249 families. For the majority of patients, the clinical diagnosis was based on clinical criteria including rare and/or unusual severe bacterial, viral, or fungal infections, sometimes accompanied by autoimmune manifestations. Functional immune defects were interpreted in the context of aberrant immune cell populations, aberrant antibody levels, or combinations of these factors. RESULTS: For 62 patients (24%), exome sequencing identified pathogenic variants in well-established PID genes. An exome-wide analysis diagnosed 10 additional patients (4%), providing diagnoses for 72 patients (28%) from 68 families altogether. The genetic diagnosis directly indicated novel treatment options for 25 patients that received a diagnosis (34%). CONCLUSION: Exome sequencing as a first-tier test for PIDs granted a diagnosis for 28% of patients. Importantly, molecularly defined diagnoses indicated altered therapeutic options in 34% of cases. In addition, exome sequencing harbors advantages over gene panels as a truly generic test for all genetic diseases, including in silico extension of existing gene lists and re-analysis of existing data.