Aug 2026· Diagnostics· Vol 16· 0 citations· 17 references
Medicine
Abstract
Background and Clinical Significance: Sideroblastic anemia with immunodeficiency, fevers, and developmental delay (SIFD) syndrome is a rare autosomal recessive disorder caused by biallelic variants in the TRNT1 gene, which encodes tRNA nucleotidyltransferase 1. The disease typically presents early in life with microcytic anemia, recurrent febrile episodes, developmental delay, and immune dysfunction. Because of its rarity and variable clinical expression, diagnosis may be challenging, and broad genetic testing can identify additional variants whose clinical significance requires careful interpretation. Case Presentation: We report a 4-month-old male infant with recurrent febrile episodes, severe recurrent microcytic anemia, recurrent infections, mild psychomotor developmental delay, and multisystem involvement. Genetic analysis identified two heterozygous TRNT1 variants inherited from different parents and confirmed to be in trans: a maternally inherited pathogenic frameshift variant, c.428_431del, p.(Asp143Glyfs12), and a paternally inherited missense variant, c.1246A>G, p.(Lys416Glu), initially classified as a variant of uncertain significance and subsequently interpreted as likely pathogenic in the context of the clinical phenotype and segregation findings. These findings supported the diagnosis of TRNT1-related SIFD syndrome. An additional heterozygous pathogenic C7 variant, c.633_643del, p.(Ser212Hisfs4), was identified. No second pathogenic C7 allele was detected, and functional complement testing was not performed; therefore, complement component 7 deficiency could not be established. Conclusions: This case highlights the importance of early genetic evaluation in infants with recurrent fever, microcytic anemia, immune abnormalities, and multisystem involvement. It also emphasizes the need for cautious interpretation of additional monoallelic pathogenic variants detected by broad genetic panels when functional confirmation and a compatible inheritance pattern are lacking.
Sideroblastic Anemia with B-cell Immunodeficiency, Periodic Fever and Developmental Delay (SIFD) is a rare autosomal recessive disorder caused by biallelic pathogenic variants in the
TRNT1
gene, encoding tRNA nucleotidyltransferase 1, an enzyme essential for mitochondrial and cytosolic protein translation. The disease is characterized by a wide phenotypic spectrum, ranging from isolated hematological involvement to multisystem inflammatory disease. Herein, we report a pediatric patient with early-onset sideroblastic anemia, recurrent inflammatory episodes, B-cell immunodeficiency, immune dysregulation (cytopenia refractory to conventional treatment, splenomegaly and chronic interstitial lung disease), ectodermal dysplasia, mild developmental delay with white-matter hypomyelination, and progressive multisystem involvement. Genetic testing identified two biallelic
TRNT1
variants, the novel c.841G>C variant and the previously reported pathogenic c.1252dupA variant, inherited from the father and mother, respectively, confirming the diagnosis of SIFD. The patient required immunoglobulin replacement therapy and immunomodulatory treatment, including rituximab, with partial control of infectious and immune dysregulation manifestations. This case expands the clinical, immunological, and genetic spectrum of TRNT1-related disease and highlights that immune dysregulation may dominate the clinical course. SIFD should be considered in children presenting with sideroblastic anemia associated with recurrent unexplained inflammation, B-cell immunodeficiency, cytopenias, and multisystem involvement. Early genetic diagnosis is essential to guide monitoring, therapeutic decisions, and prognostic stratification.
Francesco Delle Cave, Ivan Taietti, Annalisa Agostini et al.· Frontiers in Immunology· 0 citations
The novel NR2F1 variant was classified as likely pathogenic according to ACMG guidelines, confirming the diagnosis of BBSOAS and the ARF3 variant, identified as a secondary finding of uncertain clinical significance, is unlikely to account for the patient's phenotype.
Sina Babaei, Haneieh Honarmand, Mortaza Bonyadi et al.· Molecular Biology Reports· 0 citations
CACNA1C-related disorder (CRD), a severe multisystem disorder caused by variants of CACNA1C gene, presents significant diagnostic and management challenges due to its rarity and variable expressivity. This study leverages a detailed longitudinal case report and comprehensive literature review to expand the phenotypic spectrum of CRD with Timothy syndrome (TS) features associated with the CACNA1C NM_001129830.1: c.3061 T > C (p.Cys1021Arg) variant. We describe an individual with CRD exhibiting a severe multisystem phenotype including classic features like syndactyly, profound neurological symptoms, and cardiac arrhythmias. Critically, our detailed clinical and genetic analysis identified previously undocumented features for this specific variant: cerebral infarction, as well as a combined T-cell and B-cell immunodeficiency characterized by specific lymphocyte dysregulation. These novel findings necessitate refined diagnostic protocols and tailored management strategies. By redefining CRD with TS features as a profoundly multisystem disorder, this expanded understanding facilitates improved prognostication, genetic counseling, and targeted therapeutic interventions, aiming to transform management from unpredictable complications into predictable, preventable components, ultimately enhancing quality of life and survival.
Congshan Jiang, Yafei Zhou, Siyu Zhang et al.· Molecular Genetics and Metab...· 0 citations
Pathogenic variants in KIF11 are linked to autosomal dominant syndromes with microcephaly, chorioretinopathy, lymphedema, and intellectual disability (MCLID), though adult presentations remain underreported. We report a 42-year-old female presenting with a de novo single-amino acid in-frame deletion in the KIF11 gene (c.1294_1296del; p.Glu432del), who exhibited severe intellectual disability, microcephaly, hypotonia, seizures, and self-injurious behavior. There was evidence of developmental delays, ophthalmologic findings, and impairments in speech and adaptive functioning in her clinical history. Trio whole exome sequencing identified a diagnostic pathogenic variant in KIF11 and a maternally inherited SCN3A variant of uncertain significance. The presentation of the case offers an unusual longitudinal perspective of over four decades, illustrating the variable expressivity and long-term outcome of KIF11 disorders. This report calls for the consideration of KIF11 variants in the differential diagnosis of syndromic developmental delay and microcephaly in adults and underlines the diagnostic as well as the prognostic importance of detailed genetic and phenotypic analysis, particularly in cases with de novo variants.
Thrishna Chathurvedula, Juvy L. Rabelas, Kareem Touleimat et al.· American Journal of Medical...· 0 citations
Background Phenotypic variability in PTEN hamartoma tumor syndrome (PHTS) remains incompletely understood, and the contribution of additional rare genetic variants has rarely been functionally investigated. Case presentation We report a 9-year-old girl with macrocephaly, gastrointestinal manifestations, hypogammaglobulinemia, and lymphocyte abnormalities. Thyroid function and biochemical screening for SDHB-associated tumors were normal. Trio-based whole-exome sequencing identified a de novo pathogenic PTEN variant, c.464A > G (p.Tyr155Cys), together with a de novo SDHB variant, c.719T > C (p.Leu240Pro). Functional studies showed an increased succinate-to-fumarate ratio and reduced succinate dehydrogenase activity, consistent with impaired mitochondrial complex II function. Structural modeling further suggested that the p.Leu240Pro substitution may reduce SDHB protein stability. Functional evidence fulfilled ACMG/AMP PS3 criteria and supported the proposed reinterpretation of the SDHB variant from a variant of uncertain significance to likely pathogenic using the OddsPath framework. Conclusions This case expands the molecular spectrum of PHTS by describing the coexistence of pathogenic PTEN and functionally supported SDHB variants. Although the phenotype is largely attributable to PHTS, the potential contribution of SDHB dysfunction remains speculative and warrants further investigation. These findings underscore the importance of functional variant interpretation and genotype-informed longitudinal surveillance in rare genetic disorders.
Yaqin Zhang, Sooyeon Lee, Justin P. Annes et al.· Frontiers in Pediatrics· 0 citations
A Chinese patient presenting with classic hallmarks of MGORS7 alongside atypical clinical features, including hearing and visual impairments is reported, suggesting that growth hormone therapy may be beneficial for growth retardation in patients with MGORS7.
Ying Zhao, Yiyang Fu, Shuying Zhang et al.· Frontiers in Genetics· 0 citations
