Functional Confirmation of DNA Repair Defect in Ataxia Telangiectasia (AT) Infants Identified by Newborn Screening for Severe Combined Immunodeficiency (NBS SCID)

Barmettler, Sara; Coffey, Kara; Smith, Matthew J.; Chong, Hey; Pozos, Tamara C.; Seroogy, Christine M.; Walter, Jolán E.; Abraham, Roshini S.

doi:10.1016/j.jaip.2020.08.008

Cited by 10 publications

(4 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…While SCID is the primary NBS target, other conditions have been reported as part of the clinical follow-up after an abnormal TREC screening result for SCID: confirmation of the DNA repair defect in newborns with ataxia telangiectasia [ 61 ]; identifications of newborns having in utero exposure to immunosuppressive medications (a case series on natural history and management) [ 62 ]; diagnosis of cartilage-hair hypoplasia (an autosomal recessive, short-limb skeletal dysplasia with a variable immunologic phenotype) in an Amish cohort [ 63 ]; identification of Omenn using high-throughput DNA sequencing [ 64 ]; a case-based review of positive TREC results when the diagnosis was not SCID (e.g., prematurity, variants of T-cell lymphopenia (TCL) [ 65 ]; a case review of neonatal abstinence syndrome [ 66 ]; and a study characterizing the history and genetic findings of infants with non-SCID TCL [ 67 ].…”

Section: Resultsmentioning

confidence: 99%

Current Status of Newborn Bloodspot Screening Worldwide 2024: A Comprehensive Review of Recent Activities (2020–2023)

Therrell,

Padilla,

Borrajo

et al. 2024

IJNS

View full text Add to dashboard Cite

Newborn bloodspot screening (NBS) began in the early 1960s based on the work of Dr. Robert “Bob” Guthrie in Buffalo, NY, USA. His development of a screening test for phenylketonuria on blood absorbed onto a special filter paper and transported to a remote testing laboratory began it all. Expansion of NBS to large numbers of asymptomatic congenital conditions flourishes in many settings while it has not yet been realized in others. The need for NBS as an efficient and effective public health prevention strategy that contributes to lowered morbidity and mortality wherever it is sustained is well known in the medical field but not necessarily by political policy makers. Acknowledging the value of national NBS reports published in 2007, the authors collaborated to create a worldwide NBS update in 2015. In a continuing attempt to review the progress of NBS globally, and to move towards a more harmonized and equitable screening system, we have updated our 2015 report with information available at the beginning of 2024. Reports on sub-Saharan Africa and the Caribbean, missing in 2015, have been included. Tables popular in the previous report have been updated with an eye towards harmonized comparisons. To emphasize areas needing attention globally, we have used regional tables containing similar listings of conditions screened, numbers of screening laboratories, and time at which specimen collection is recommended. Discussions are limited to bloodspot screening.

show abstract

Section: Resultsmentioning

confidence: 99%

Current Status of Newborn Bloodspot Screening Worldwide 2024: A Comprehensive Review of Recent Activities (2020–2023)

Therrell,

Padilla,

Borrajo

et al. 2024

IJNS

View full text Add to dashboard Cite

show abstract

“…ATM is a critical initiator of the DNA-damage response by the process of phosphorylation of the key substrates involved in several critical cellular processes, such as DNA damage repair, apoptosis, and cell cycle ( Phan and Rezaeian, 2021 ). Recently, the Nationwide Children’s Hospital, Columbus, Ohio, has launched the clinical test DDRFL (DNA Damage Repair Assessment in Lymphocytes in Blood by Flow Cytometry) to assess the non-homologous end joining (NHEJ) DNA double-strand break (DSBs) repair pathway in patients’ lymphocytes ( Barmettler et al, 2021 ). The DDRFL clinical test for further functional assessment with respect to ATM was approved by the local institution for the proband.…”

Section: Resultsmentioning

confidence: 99%

Case Report: Biallelic Loss of Function ATM due to Pathogenic Synonymous and Novel Deep Intronic Variant c.1803-270T > G Identified by Genome Sequencing in a Child With Ataxia–Telangiectasia

et al. 2022

View full text Add to dashboard Cite

Ataxia–telangiectasia (AT) is a complex neurodegenerative disease with an increased risk for bone marrow failure and malignancy. AT is caused by biallelic loss of function variants in ATM, which encodes a phosphatidylinositol 3-kinase that responds to DNA damage. Herein, we report a child with progressive ataxia, chorea, and genome instability, highly suggestive of AT. The clinical ataxia gene panel identified a maternal heterozygous synonymous variant (NM_000051.3: c.2250G > A), previously described to result in exon 14 skipping. Subsequently, trio genome sequencing led to the identification of a novel deep intronic variant [NG_009830.1(NM_000051.3): c.1803-270T > G] inherited from the father. Transcript analyses revealed that c.1803-270T > G results in aberrant inclusion of 56 base pairs of intron 11. In silico tests predicted a premature stop codon as a consequence, suggesting non-functional ATM; and DNA repair analyses confirmed functional loss of ATM. Our findings highlight the power of genome sequencing, considering deep intronic variants in undiagnosed rare disease patients.

show abstract

“…To establish the functional significance of the variants, a flow cytometric assay assessing DNA repair defects demonstrated completely absent ATM phosphorylation along with decreased gamma-H2AX (Figs. 1A and 1B), one hour after induction of DNA double-strand breaks, which is typically when maximal phosphorylation is expected [11][12][13] . This result revealed a functional defect in the ATM protein, indicating that the VUS is pathogenic.…”

Section: Resultsmentioning

confidence: 99%

Ataxia-Telangiectasia and Refractory Peripheral T-cell Lymphoma: Considerations for Therapy and Role of Bone Marrow Transplantation

Kaviany

Kitko

Rueda

et al. 2020

Preprint

View full text Add to dashboard Cite

Certain patients with inborn errors of immunity have defects in DNA damage response, predisposing them to malignancy. Subsequent cancer therapy may require substantial attenuation given defective DNA repair; however, this carries risk of incomplete disease control. We describe a 5-year-old boy with peripheral T-Cell lymphoma with ataxia-telangiectasia (A-T).After incomplete chemotherapeutic response, he underwent allogenic hematopoietic cell transplantation (allo-HCT) with an attenuated preparative regimen, but developed graft rejection and relapse. Following remission with salvage chemotherapy, second allo-HCT with reduced intensity conditioning (RIC) resulted in minimal toxicity and short-term disease control. HCT with RIC can be considered in patients with A-T.

show abstract

Functional Confirmation of DNA Repair Defect in Ataxia Telangiectasia (AT) Infants Identified by Newborn Screening for Severe Combined Immunodeficiency (NBS SCID)

Cited by 10 publications

References 57 publications

Current Status of Newborn Bloodspot Screening Worldwide 2024: A Comprehensive Review of Recent Activities (2020–2023)

Current Status of Newborn Bloodspot Screening Worldwide 2024: A Comprehensive Review of Recent Activities (2020–2023)

Case Report: Biallelic Loss of Function ATM due to Pathogenic Synonymous and Novel Deep Intronic Variant c.1803-270T > G Identified by Genome Sequencing in a Child With Ataxia–Telangiectasia

Ataxia-Telangiectasia and Refractory Peripheral T-cell Lymphoma: Considerations for Therapy and Role of Bone Marrow Transplantation

Contact Info

Product

Resources

About