X-linked hypophosphatemia (XLH) is a rare inherited bone disorder and the most common form of hereditary rickets, caused by loss-of-function variants in the phosphate regulating endopeptidase homolog X-linked (PHEX) gene. Elevated fibroblast growth factor 23 (FGF23) results in renal phosphate wasting and impaired bone mineralization. Despite established clinical and biochemical diagnostic criteria, interpretation of novel missense variants remains challenging because of genetic heterogeneity and variable expressivity. A female pediatric patient clinically diagnosed with X-linked hypophosphatemia underwent exome sequencing, which identified a novel missense variant NM_000444.6:c.2119 A > C p.(Ile707Leu) in exon 21 of the PHEX transcript (accession number: PRJEB107180). Biochemical evaluation revealed hypophosphatemia, elevated alkaline phosphatase, elevated fibroblast growth factor 23 (FGF23), and reduced tubular maximum phosphate reabsorption per glomerular filtration rate (TmP/GFR), consistent with renal phosphate wasting. Targeted Sanger sequencing of the parents revealed the same variant in her mother with limited biochemical abnormalities, demonstrating intrafamilial phenotypic variability despite shared genotype. This report expands the mutational spectrum of PHEX and highlights the challenges of interpreting novel missense PHEX variants, particularly among heterozygous females. The findings emphasize the importance of integrating clinical, biochemical, molecular, and familial evidence for variant interpretation and highlight the importance of comprehensive genetic counseling in inherited disorders.
β-thalassemia is a prevalent hereditary blood disorder caused by over 300 mutations in the β-globin (HBB) gene, leading to reduced (β+) or absent (β0) β-globin chain synthesis. While point mutations are the most common cause, deletional mutations within the HBB gene, though rarer, can have profound functional consequences. This study reports the identification and molecular characterization of a novel 12-nucleotide deletion (HBB.326_337del) in exon 3 of the HBB gene. Molecular diagnostics and characterization were performed on genomic DNA extracted from four consanguineous patients and one fetus presenting with β-thalassemia phenotypes. Mutation screening, sequence analysis, and structural/functional prediction were utilized to determine the exact nature and consequences of the genetic variation. Genetic analysis identified a previously unreported 12-nucleotide deletion (HBB.326_337del, also corresponding to CD 108-112) in exon 3. This deletion causes a frameshift mutation resulting in a predicted premature termination codon (PTC). This molecular alteration is consistent with a β0 allele, may lead to a total loss of functional β-globin chain production and severe clinical manifestations among the affected individuals. The identification of the HBB.326_337del mutation broadens the known mutational spectrum of the HBB gene. These findings underscore the critical importance of comprehensive molecular diagnostics in thalassemic disorders and highlight the necessity for population-specific mutation screening strategies to improve prenatal diagnosis, genetic counseling, and clinical management.
Hypereosinophilia (HE) refers to an elevated eosinophil count that may arise from reactive, hereditary, primary/neoplastic, or undetermined causes. When HE is associated with eosinophil-related organ damage, it is classified as hypereosinophilic syndrome (HES). Recent advances in genomic technologies have refined the understanding of HE pathogenesis, revealing genetic abnormalities in cases previously considered idiopathic. We describe a young male patient with severe HES initially diagnosed as idiopathic in childhood. Early treatment achieved only partial disease control, and persistent hypereosinophilia eventually led, after several years, to severe cardiac, renal, digestive, and cutaneous involvement. The patient ultimately died from an eosinophil-rich left ventricular thrombus with multiple arterial embolic infarctions. Trio whole-exome sequencing (WES) identified presumed de novo germline variants in STAT5B (p.Asn642His) and RRAS (p.Gly39dup), both absent in the parents. The STAT5B p.Asn642His gain-of-function variant represents the strongest molecular candidate, with a possible additional contribution from RRAS. Although germline origin could not be formally confirmed, these findings provide a molecular basis for reclassifying the case from idiopathic HES toward a genetically defined form of HES and highlight the value of early genetic testing in severe unexplained or treatment-resistant HE, as molecular insights can lead to diagnostic reclassification and guide future targeted therapies.
CNTNAP2-related disorders comprise a clinically heterogeneous group of neurodevelopmental conditions characterized by variable combinations of developmental delay, intellectual disability, language impairment, autistic features, epilepsy, and craniofacial features. Although biallelic loss-of-function variants in CNTNAP2 have been associated with severe recessive neurodevelopmental presentations, the interpretation of rare biallelic missense variants remains considerably more challenging. We report a six-year-old girl of mixed Turkish Cypriot and Kazakh ancestry who presented with global developmental delay, mild intellectual disability, severe expressive language impairment, autistic features, mild generalized hypotonia, sleep disturbance, and mild craniofacial features, without a history of seizures. Trio-based whole-exome sequencing identified two rare missense variants in CNTNAP2, NM_014141.6:c.511 C > T (p.(Arg171Cys)) and NM_014141.6:c.2236G > A (p.(Asp746Asn)), inherited from different clinically unaffected parents. In gnomAD v2.1.1 exomes, c.511 C > T was observed in 10 of 251,440 alleles and c.2236G > A in 2 of 249,430 alleles; neither was homozygous. Both were classified as variants of uncertain significance under ACMG-AMP criteria. Their phase was inferred from parental inheritance rather than read-based phasing. The variants were not independently confirmed by Sanger sequencing, and no functional studies were performed. The phenotype overlaps the reported spectrum of biallelic CNTNAP2-associated neurodevelopmental disorders, but both variants remain variants of uncertain significance and cannot currently be considered diagnostic. This case documents a biallelic missense combination in a child who had not developed epilepsy by six years of age and supports continued clinical follow-up, functional investigation, and periodic variant reinterpretation.
Individuals carrying structural chromosomal rearrangements, particularly reciprocal translocations, face a heightened risk of recurrent spontaneous abortion (RSA) and the birth of offspring with genetic anomalies. In balanced translocations, no obvious genetic material is lost or gained; therefore, carriers typically exhibit a normal phenotype but often present with reproductive difficulties. Cytogenetic evaluation is of descriptive importance in couples experiencing recurrent miscarriages. This report describes reciprocal translocations identified in two couples with a history of RSA. The first case involved a 35‑year‑old man whose partner had experienced five recurrent miscarriages. Conventional cytogenetic analysis revealed a chromosomal defect in the male partner: 46, XY, t(4;6)(p10;p10). The second case involved a 29‑year‑old woman with three recurrent miscarriages, in whom the karyotype 46, XX, t(6;11)(q25.2;q24.2) was demonstrated. These findings underscore the necessity of cytogenetic assessment in couples with repeated pregnancy loss. Cytogenetic analysis is essential for couples with recurrent miscarriages to detect possible chromosomal aberrations. To the best of our knowledge, this is the first report of such translocations in Iran. A multidisciplinary approach should be offered to affected couples to assist them in achieving clinical pregnancy, lowering miscarriage risk, and increasing the likelihood of delivering healthy newborns. Preimplantation genetic diagnosis (PGD), along with other prenatal diagnostic strategies, was recommended to these patients.
