Background: Severe combined immunodeficiency (SCID) is a life-threatening genetic disorder caused by critical defects of the immune system. Almost all cases are lethal if not treated within the first two years of life. Early diagnosis and intervention are thus essential for improving patient outcomes. In 2013, Ontario became the first Canadian province to perform newborn screening (NBS) for SCID by T cell receptor excision circles (TRECs) analysis, a surrogate marker of thymic function and lymphocyte maturation. Methods: This retrospective study reports on nearly 10 years of NBS for SCID at a quaternary referral centre. Results: From August 2013 to April 2023, our centre’s densely populated catchment area flagged 162 newborns with low TRECs levels, including 10 cases with SCID. Follow-up revealed other causes of low TRECs, including non-SCID T cell lymphopenia (secondary/reversible or idiopathic causes, and syndromic conditions) and prematurity. A small number of cases with normal repeat TRECs levels and/or T cell subsets were also flagged. Province-wide data from around this period revealed at least 24 diagnosed cases of SCID or Leaky SCID. Conclusions: This is the first report of NBS outcomes in a Canadian province describing the causative genetic defects, and the non-SCID causes of a positive NBS for SCID.
The use of next-generation sequencing technologies such as genomic sequencing in newborn screening (NBS) could enable the detection of a broader range of conditions. We explored parental preferences and attitudes towards screening for conditions for which varying types of treatment exist with a cross-sectional survey completed by 100 parents of newborns who received NBS in Ontario, Canada. The survey included four vignettes illustrative of hypothetical screening targets, followed by questions assessing parental attitudes. Chi-square tests were used to compare frequency distributions of preferences. Results show that most parents supported NBS for conditions for which only supportive interventions are available, but to a significantly lesser degree than those with disease-specific treatments (99% vs. 82–87%, p ≤ 0.01). For conditions without an effective treatment, the type of supportive care and age of onset of the condition did not significantly alter parent perceptions of risks and benefits. Parents are interested in expanded NBS for conditions with only supportive interventions in childhood, despite lower levels of perceived benefit for the child and greater anticipated anxiety from screen-positive results. These preferences suggest that the expansion of NBS may require ongoing deliberation of perceived benefits and risks and enhanced approaches to education, consent, and support.
Background: The T cell receptor (TCR)-α chain plays a key role in TCR structure and function. Biallelic mutations in TRAC, encoding the constant region of the TCR-α chain, obliterates TCR expression and results in immunodeficiency. TCR-α chain deficiency presents at infancy or childhood with repeated viral and bacterial infections, enlarged liver, spleen, and lymph nodes as well as autoimmune features and lymphoma (OMIM #615387). Aim: To broaden the genotypic and phenotypic spectrum of TCR-α chain deficiency. Methods: We present a case report of a patient with severe combined immunodeficiency (SCID) due to a novel autosomal recessive mutation in TRAC. Results: Our patient was identified at 13 days of life due to abnormal T cell receptor excision circle levels detected by newborn screening (NBS). Immune evaluation revealed profound lymphopenia, depressed responses to the mitogen PHA and a skewed T cell repertoire, all consistent with SCID. The patient was found to carry a novel homozygous mutation in the TRAC gene. Conclusion: A novel homozygous mutation in the TRAC gene caused profound T cell lymphopenia and aberrant in vitro mitogenic response, the hallmarks of SCID. Statement of Novelty: TCR-α chain deficiency is a rare and relatively new condition and not very well defined. We herein report a novel mutation in TRAC resulting in SCID.
Introduction: DiGeorge syndrome is a heterogenous disorder with various clinical presentations. Common features include thymic hypoplasia, T cell lymphopenia, conotruncal heart defects, facial dysmorphism, cleft palate, developmental delay, and hypoparathyroidism. The severity of this condition varies, however typical presentation includes congenital heart defects and characteristic facial features. Isolated hypocalcemia in DiGeorge syndrome is rarely seen in neonates but rather as the sole manifestation in older teenagers or adults. Aim: To report a case of an atypical presentation of DiGeorge syndrome. Results: We report here a case of an infant who was diagnosed with DiGeorge syndrome, with seizures being the only clinical manifestation displayed by the patient. He was found to have low T cell receptor excision circle levels on a newborn screen (NBS) for severe combined immunodeficiency (SCID). He did not have facial dysmorphism nor cardiac defect. Conclusion: Our case shows that severe hypocalcemia can be the only presenting symptom in DiGeorge syndrome. Based on this case, we recommend physicians test for calcium levels and PTH at the first encounter with a patient who screened positive during NBS for SCID. Statement of Novelty: We describe an infant with DiGeorge syndrome who presented with severe hypocalcemia.
Genome-wide sequencing (GWS) is a standard of care for diagnosis of suspected genetic disorders, but the proportion of patients found to have pathogenic or likely pathogenic variants ranges from less than 30% to more than 60% in reported studies. It has been suggested that the diagnostic rate can be improved by interpreting genomic variants in the context of each affected individual's full clinical picture and by regular follow-up and reinterpretation of GWS laboratory results. Trio exome sequencing was performed in 415 families and trio genome sequencing in 85 families in the CAUSES study. The variants observed were interpreted by a multidisciplinary team including laboratory geneticists, bioinformaticians, clinical geneticists, genetic counselors, pediatric subspecialists, and the referring physician, and independently by a clinical laboratory using standard American College of Medical Genetics and Genomics (ACMG) criteria. Individuals were followed for an average of 5.1 years after testing, with clinical reassessment and reinterpretation of the GWS results as necessary. The multidisciplinary team established a diagnosis of genetic disease in 43.0% of the families at the time of initial GWS interpretation, and longitudinal follow-up and reinterpretation of GWS results produced new diagnoses in 17.2% of families whose initial GWS interpretation was uninformative or uncertain. Reinterpretation also resulted in rescinding a diagnosis in four families (1.9%). Of the families studied, 33.6% had ACMG pathogenic or likely pathogenic variants related to the clinical indication. Close collaboration among clinical geneticists, genetic counselors, laboratory geneticists, bioinformaticians, and individuals' primary physicians, with ongoing follow-up, reanalysis, and reinterpretation over time, can improve the clinical value of GWS.
Forkhead box protein N1 (FOXN1) transcription factor plays an essential role in the development of thymic epithelial cells, required for T-cell differentiation, maturation, and function. Biallelic pathogenic variants in
Background: Forkhead-box protein N1 (FOXN1) plays a critical role in the proper development and function of thymic epithelial cells, required for T cell ontogeny. Homozygous variants in the FOXN1 gene, encoding FOXN1, cause severe combined immunodeficiency (SCID), whereas heterozygous mutations are associated with variable presentations and over time, improving T cell function. Aim: To highlight the importance of broader genetic investigations to attain a definitive molecular diagnosis following abnormal newborn screening for SCID. Methods: Case report of a patient with immunodeficiency due to a novel de novo FOXN1 mutation. Results: The patient was identified following abnormal newborn screening for SCID in which T cell receptor excision circles were absent/very low. Initial immune investigations revealed severe T cell lymphopenia and poor lymphocyte function and she was diagnosed with T-B+NK+SCID. During work-up for hematopoietic stem cell transplantation, extensive genetic investigations identified a novel heterozygous mutation in FOXN1. A more conservative management approach was taken, and over the following months, the patient’s immune parameters improved. Conclusion: Newborn screening for SCID has facilitated the detection of SCID, as well as other T cell immunodeficiencies, before infectious complications and organ damage occur. Heterozygous mutations in FOXN1 are associated with more variable presentations including improving immune indices with age. Here, results of genetic investigations were essential for informing the management of this case. Statement of Novelty: We report a novel heterozygous mutation in FOXN1, presenting initially as T-B+NK+ SCID with gradual improvement of immune parameters over time.
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