title: Newborn screening for SCID identifies patients with ataxia telangiectasia.
abstract: OBJECTIVE
  Severe combined immunodeficiency (SCID) is characterized by failure of T lymphocyte development and absent or very low T cell receptor excision circles (TRECs), DNA byproducts of T cell maturation. Newborn screening for TRECs to identify SCID is now performed in several states using PCR of DNA from universally collected dried blood spots (DBS). In addition to infants with typical SCID, TREC screening identifies infants with T lymphocytopenia who appear healthy and in whom a SCID diagnosis cannot be confirmed. Deep sequencing was employed to find causes of T lymphocytopenia in such infants.
  
  
  METHODS
  Whole exome sequencing and analysis were performed in infants and their parents. Upon finding deleterious mutations in the ataxia telangiectasia mutated (ATM) gene, we confirmed the diagnosis of ataxia telangiectasia (AT) in two infants and then tested archival newborn DBS of additional AT patients for TREC copy number.
  
  
  RESULTS
  Exome sequencing and analysis led to 2 unsuspected gene diagnoses of AT. Of 13 older AT patients for whom newborn DBS had been stored, 7 samples tested positive for SCID under the criteria of California's newborn screening program. AT children with low neonatal TRECs had low CD4 T cell counts subsequently detected (R = 0.64).
  
  
  CONCLUSIONS
  T lymphocytopenia in newborns can be a feature of AT, as revealed by TREC screening and exome sequencing. Although there is no current cure for the progressive neurological impairment of AT, early detection permits avoidance of infectious complications, while providing information for families regarding reproductive recurrence risks and increased cancer risks in patients and carriers.
authors.affiliation: Department of Pediatrics, University of California San Francisco, San Francisco, CA 94143-0519, USA.
authors.forename: Jacob
authors.initials: J
authors.lastname: Mallott
authors.forename: Antonia
authors.initials: A
authors.lastname: Kwan
authors.forename: Joseph
authors.initials: J
authors.lastname: Church
authors.forename: Diana
authors.initials: D
authors.lastname: Gonzalez-Espinosa
authors.forename: Fred
authors.initials: F
authors.lastname: Lorey
authors.forename: Ling Fung
authors.initials: LF
authors.lastname: Tang
authors.forename: Uma
authors.initials: U
authors.lastname: Sunderam
authors.forename: Sadhna
authors.initials: S
authors.lastname: Rana
authors.forename: Rajgopal
authors.initials: R
authors.lastname: Srinivasan
authors.forename: Steven E
authors.initials: SE
authors.lastname: Brenner
authors.forename: Jennifer
authors.initials: J
authors.lastname: Puck
mesh_terms: D000595:Amino Acid Sequence; D001260:Ataxia Telangiectasia / Q000150:complications / Q000175:diagnosis* / Q000235:genetics; D064007:Ataxia Telangiectasia Mutated Proteins; D001483:Base Sequence; D018797:Cell Cycle Proteins / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D004268:DNA-Binding Proteins / Q000235:genetics; D059472:Exome; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008231:Lymphopenia / Q000235:genetics; D008297:Male; D009154:Mutation; D015997:Neonatal Screening; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D016511:Severe Combined Immunodeficiency / Q000150:complications / Q000175:diagnosis* / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases