Ebtissal Khouj

SLC25A4, solute carrier family 25 member 4, gene is a member of the mitochondrial carrier subfamily within the solute carrier protein family. Pathogenic variants in SLC25A4 are associated with a spectrum of mitochondrial disorders that exhibit variable inheritance patterns and clinical manifestations. Specifically, dominantly inherited variants are typically associated with progressive external ophthalmoplegia with mitochondrial DNA deletions, recessively inherited variants are linked to myopathy and cardiomyopathy, and de novo variants can result in early-onset fatal disease presentations. In this study, we aimed to identify and characterize the disease-causing mutation(s) in a nine-year-old female patient from a consanguineous Saudi family. The patient was asymptomatic until the age of 3 years, when she presented with cardiomyopathy and myopathy. Comprehensive genetic analysis inclusive of whole exome sequencing and segregation analysis using Sanger sequencing identified an SLC25A4 variant (NM_001151.4: exon 2: c.112-1G>C) as the most likely cause of the disease. To assess transcript-level effects, we performed RT-PCR on RNA extracted from the patient’s cultured lymphoblast cell lines (LCLs) and fibroblast cell lines (FCLs). RT-PCR analysis demonstrated that the variant causes aberrant splicing, resulting in a 6 bp in-frame deletion (p.Gln37_Val38del) in the ANT1 protein. Quantitative RT-PCR demonstrated reduced SLC25A4 transcript levels in both FCLs and LCLs. Quantitative PCR analysis of mitochondrial DNA demonstrated a trend toward increased mtDNA copy number in patient-derived FCLs compared with controls, suggesting a possible compensatory response to mitochondrial dysfunction. Furthermore, Seahorse assays revealed marked reductions in both oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) in patient-derived FCLs compared with controls. These findings expand the molecular and functional spectrum of SLC25A4-associated disease and may inform clinical practice, including genetic interventions such as preimplantation genetic diagnosis, premarital genetic screening, targeted genetic counseling, and cascade testing of at-risk family members.

Growth differentiation factor 2 ( GDF2 ), also known as bone morphogenetic protein‐9 ( BMP9 ), is a key member of the transforming growth factor‐beta (TGF‐β) superfamily, playing a pivotal role in pulmonary vascular regulation and remodeling. Dominant variants in GDF2 are known to cause hereditary hemorrhagic telangiectasia type 5 (HHT5), a condition characterized by telangiectases and arteriovenous malformations (AVMs). More recently, recessive variants in GDF2 have been reported to cause pulmonary arterial hypertension (PAH) with or without features of HHT5. In this study, we identified a founder variant in GDF2 that potentially causes semidominant PAH in a cohort of 13 patients ranging in age from pediatric to middle‐aged adults. Careful clinical evaluation revealed a wide range of ages of onset and disease severity. However, lack of HHT manifestations was a consistent clinical feature. Our results lend further support to GDF2 as a bona fide disease gene in the context of non‐syndromic PAH and demonstrate the power of founder variants to reveal the full spectrum of disease variability.

STEAP3 (Six‐transmembrane epithelial antigen of the prostate 3), a metalloreductase, plays a key role in various cell processes, including iron homeostasis, inflammation, and cancer promotion. Over a decade ago, researchers reported a single, heterozygous nonsense variant in STEAP3 linked to transfusion‐dependent severe hypochromic anemia. However, a later large population study on STEAP3 found no phenotypic red cell changes in heterozygous individuals. While the genotype and phenotype of STEAP3 are tentatively established for hypochromic microcytic anemia with autosomal dominant inheritance (MIM: 615234), we describe an autosomal recessive form of STEAP3 ‐related neonatal familial hemophagocytic lymphohistiocytosis (HLH). We expanded the phenotype to include cytopenia and neonatal HLH. Our report on two affected male siblings highlights the expanded phenotype, clarifies the phenotypic spectrum of STEAP3 , and broadens its genetic inheritance, ultimately providing a clinical and molecular workup for neonatal patients with unexplained HLH.

Background: Chromosomal aneuploidy, characterized by an abnormal number of chromosomes, represents a significant cause of genetic disorders. While karyotyping and chromosomal microarray analysis (CMA) are established diagnostic approaches, they are limited by cost and extended turnaround times. Advances in exome sequencing (ES) bioinformatics enable detection of chromosomal aneuploidy alongside single-nucleotide variant analysis. This study explores the utility of clinical ES for the detection of aneuploidies. Method: We analyzed exome sequencing data (2023–2024) from samples positive for Trisomy 21 (n = 27), Trisomy 18 (n = 4), Turner syndrome (n = 3), and Klinefelter syndrome (n = 2) from our clinical ES cohort (n = 10,000). Results: The results obtained were concordant with copy number variants (CNVs) identified by clinical testing. Conclusion: In conclusion, our findings suggest that exome sequencing offers a rapid and viable approach for the detection of chromosomal aneuploidy, potentially reducing turnaround time and associated costs.

Summary: Colony‐stimulating factor 3 (CSF3) is a key factor in neutrophil production and function, and recombinant forms have been used clinically for decades to treat congenital and acquired neutropenia. Although biallelic inactivation of its receptor CSF3R is a well‐established cause of severe congenital neutropenia (SCN), no corresponding Mendelian disease has been ascribed to date to CSF3. Here, we describe three patients from two families each segregating a different biallelic inactivating variant in CSF3 with SCN. Complete deficiency of CSF3 as a result of nonsense‐mediated decay (NMD) could be demonstrated on RT‐PCR using skin fibroblasts‐derived RNA. The phenotype observed in this cohort mirrors that documented in mouse and zebrafish models of CSF3 deficiency. Our results suggest that CSF3 deficiency in humans causes a novel autosomal recessive form of SCN.