Genetics Copyright (c) 2013 University of Massachusetts Medical School All rights reserved. http://escholarship.umassmed.edu/peds_genetics Recent documents in Genetics en-us Wed, 13 Feb 2013 17:58:46 PST 3600 Cellular calibrators to quantitate T-cell receptor excision circles (TRECs) in clinical samples http://escholarship.umassmed.edu/peds_genetics/35 http://escholarship.umassmed.edu/peds_genetics/35 Wed, 23 Jan 2013 12:27:41 PST T-cell receptor excision circles (TRECs) are circular DNA molecules formed during rearrangement of the T-cell receptor (TCR) genes during lymphocyte development. Copy number of the junctional portion of the δRec-ψJα TREC, assessed by quantitative PCR (qPCR) using DNA from dried blood spots (DBS), is a biomarker for newly formed T cells and absent or low numbers of TRECs indicate SCID (severe combined immunodeficiency) or T lymphocytopenia. No quantitation standard for TRECs exists. To permit comparison of TREC qPCR results with a reliable method for counting TRECs across different laboratories, we sought to construct a stable cell line containing a normal human chromosomal constitution and a single copy of the TREC junction sequence. A human EBV (Epstein Barr virus)-transformed B-cell line was transduced with a lentivirus encoding mCherry fluorescence, puromycin resistance and the δRec-ψJα TREC sequence. A TREC-EBV cell line, with each cell carrying a single lentiviral insertion was established, expanded and shown to have one TREC copy per diploid genome. Graded numbers of TREC-EBV cells added to aliquots of T lymphocyte depleted blood showed TREC copy number proportional to TREC-EBV cell number. TREC-EBV cells, therefore, constitute a reproducible cellular calibrator for TREC assays, useful for both population-based screening for severe combined immunodeficiency and evaluation of naïve T-cell production in clinical settings.

]]> Divya Punwani et al. Genes, T-Cell Receptor Calibration Neonatal Screening Prevalence of a loss-of-function mutation in the proton-coupled folate transporter gene (PCFT-SLC46A1) causing hereditary folate malabsorption in Puerto Rico http://escholarship.umassmed.edu/peds_genetics/34 http://escholarship.umassmed.edu/peds_genetics/34 Tue, 10 Apr 2012 10:51:45 PDT OBJECTIVE: To determine whether subjects of Puerto Rican heritage are at increased risk for a specific mutation of the proton-coupled folate transporter (PCFT) causing hereditary folate malabsorption (HFM).

STUDY DESIGN: Three percent of the births in Puerto Rico in 2005, with additional regional oversampling, were screened for the prevalence of the c.1082G>A; p.Y362_G389 del PCFT gene mutation. Six new subjects of Puerto Rican heritage with the clinical diagnosis of HFM were also assessed for this mutation.

RESULTS: Six subjects of Puerto Rican heritage with the clinical diagnosis of HFM were all homozygous for the c.1082G>A; p.Y362_G389 del PCFT mutation. Three heterozygote carriers were identified from the 1582 newborn samples randomly selected from births in Puerto Rico in 2005. The carrier frequency for the mutated allele was 0.2% island-wide and 6.3% in Villalba.

CONCLUSION: These findings are consistent with a common mutation in the PCFT gene causing HFM that has disseminated to Puerto Ricans who have migrated to mainland United States. Because prompt diagnosis and treatment of infants with HFM can prevent the consequences of this disorder, newborn screening should be considered in high-risk populations and physicians should be aware of its prevalence in infants of Puerto Rican ancestry.

]]> Kris M. Mahadeo et al. Folic Acid Genetic Testing Heterozygote Detection Hispanic Americans Homozygote Humans Infant, Newborn Malabsorption Syndromes Mutation Proton-Coupled Folate Transporter Puerto Rico Newborn Screening Expansion: Massachusetts Research Models Encompass Public Health Service Responsibility http://escholarship.umassmed.edu/peds_genetics/32 http://escholarship.umassmed.edu/peds_genetics/32 Tue, 10 Apr 2012 10:51:41 PDT Introduction: Massachusetts has been at the forefront of incorporating a formal research component into its newborn screening programme to advance our understanding of disease, its prevention and the related necessary services available to populations. This chapter advocates that research be recognized as an integral component of any newborn screening programme and that the infrastructure required within the programme to support such research be promoted as a provision of public health responsibility.

Citation: Comeau AM. Newborn Screening Expansion: Massachusetts Research Models Encompass Public Health Service Responsibility. Knoppers, Martha Maria (Ed), in Genomics and Public Health: Socio-Ethical and Legal Perspectives. Leiden: Martinus Nijhoff International (Brill), 2007: pp 45-53.

A preview of this chapter is available via Google Books.

]]> Anne Marie Comeau Neonatal Screening Massachusetts Long-term follow-up to ensure quality care of individuals diagnosed with newborn screening conditions: early experience in New England http://escholarship.umassmed.edu/peds_genetics/31 http://escholarship.umassmed.edu/peds_genetics/31 Mon, 09 Apr 2012 12:39:32 PDT To fulfill the purpose of newborn screening, comprehensive newborn screening programs must ensure that infants and children with newborn screening conditions are not only diagnosed but also they maintain engagement in appropriate lifespan and family-centered care for best outcomes. To ensure success, monitoring and care-coordination requires a systems-based approach to streamline the significant surveillance activities, which must not overburden the critical core functions of newborn screening nor the health care delivery system. Furthermore, treatment and care can only be improved by translating reliable knowledge into changes in practice, a process that requires evaluations of outcomes that are confirmable at the local level and translatable into a larger, e.g., national data set. We describe a sustainable public health systems approach to long-term follow-up, built on existing comprehensive newborn screening infrastructure and compatible with national endeavors. We also describe early experience with implementation of a centralized public-health tracking model and show that a significant proportion of cases detected through newborn screening do not continue with subspecialty care as they get older.

]]> Inderneel Sahai et al. Child Evidence-Based Medicine Follow-Up Studies Genetic Diseases, Inborn *Health Plan Implementation Humans Infant Infant, Newborn *Neonatal Screening New England Public Health Practice *Quality Assurance, Health Care Guidelines for implementation of population-based newborn screening for severe combined immunodeficiency http://escholarship.umassmed.edu/peds_genetics/30 http://escholarship.umassmed.edu/peds_genetics/30 Mon, 09 Apr 2012 12:39:31 PDT Severe combined immunodeficiency (SCID) is a Primary Immune Deficiency that is under consideration for population-based newborn screening (NBS) by many NBS programs, and has recently been recommended for inclusion in the US uniform panel of newborn screening conditions. A marker of SCID, the T cell receptor excision circle (TREC), is detectable in the newborn dried blood spot using a unique molecular assay as a primary screen. The New England Newborn Screening Program developed and validated a multiplex TREC assay in which both the TREC analyte and an internal control are acquired from a single punch and run in the same reaction. Massachusetts then implemented a statewide pilot SCID NBS program. The authors describe the rationale for a pilot SCID NBS program, a comprehensive strategy for successful implementation, the screening test algorithm, the screening follow-up algorithm and preliminary experience based on statewide screening in the first year. The Massachusetts experience demonstrates that SCID NBS is a program that can be implemented on a population basis with reasonable rates of false positives.

]]> Anne Marie Comeau et al. Algorithms Blood Specimen Collection DNA False Positive Reactions Genes, T-Cell Receptor Humans Infant, Newborn Massachusetts *Neonatal Screening Pilot Projects Practice Guidelines as Topic Predictive Value of Tests Program Development Program Evaluation Quality Indicators, Health Care Reproducibility of Results Severe Combined Immunodeficiency A multiplex immunoassay using the Guthrie specimen to detect T-cell deficiencies including severe combined immunodeficiency disease http://escholarship.umassmed.edu/peds_genetics/29 http://escholarship.umassmed.edu/peds_genetics/29 Mon, 09 Apr 2012 12:39:30 PDT BACKGROUND: Severe combined immunodeficiency (SCID) fulfills many of the requirements for addition to a newborn screening panel. Two newborn screening SCID pilot studies are now underway using the T-cell receptor excision circle (TREC) assay, a molecular technique. Here we describe an immunoassay with CD3 as a marker for T cells and CD45 as a marker for total leukocytes that can be used with the Guthrie specimen.

METHODS: The multiplexing capabilities of the Luminex platform were used. Antibody pairs were used to capture and detect CD3 and CD45 from a single 3-mm punch of the Guthrie specimen. The assay for each biomarker was developed separately in identical buffers and then combined to create a multiplex assay.

RESULTS: Using calibrators made from known amounts of leukocytes, a detection limit of 0.25 x 10(6) cells/mL for CD3 and 0.125 x 10(6) cells/mL for CD45 was obtained. Affinity tests showed no cross-reactivity between the antibodies to CD3 and CD45. The multiplex assay was validated against 8 coded specimens of known clinical status and linked to results from the TREC assay that had identified them. All were correctly identified by the CD345 assay.

CONCLUSIONS: The performance parameters of the CD345 assay met the performance characteristics generally accepted for immunoassays. Our assay classifications of positive specimens concur with previous TREC results. This CD345 assay warrants evaluation as a viable alternative or complement to the TREC assay as a primary screening tool for detecting T-cell immunodeficiencies, including SCID, in Guthrie specimens.

]]> David K. Janik et al. Antigens, CD3 Antigens, CD45 Blood Specimen Collection Calibration Feasibility Studies Humans Immunoassay Immunologic Deficiency Syndromes Infant, Low Birth Weight Infant, Newborn Leukocytes Severe Combined Immunodeficiency T-Lymphocytes Identification of an infant with severe combined immunodeficiency by newborn screening http://escholarship.umassmed.edu/peds_genetics/28 http://escholarship.umassmed.edu/peds_genetics/28 Mon, 09 Apr 2012 12:39:29 PDT Jaime E. Hale et al. Hematologic Tests Humans Infant, Newborn Neonatal Screening Pilot Projects Receptors, Antigen, T-Cell Severe Combined Immunodeficiency Weighing the evidence for newborn screening for early-infantile Krabbe disease http://escholarship.umassmed.edu/peds_genetics/27 http://escholarship.umassmed.edu/peds_genetics/27 Mon, 09 Apr 2012 12:39:28 PDT PURPOSE: To summarize the evidence regarding screening, diagnosis, and treatment of early-infantile Krabbe disease in consideration of its addition to the core panel for newborn screening as has been done in New York state.

METHODS: Systematic review of articles indexed in MEDLINE and Embase published between January 1988 and July 2009. Thirteen articles describing studies related to screening, diagnosis, or treatment were included in this review.

RESULTS: Case series studies suggest that allogeneic hematopoietic stem-cell transplantation soon after the development of signs or symptoms of early-infantile Krabbe disease decreases early-childhood mortality and may improve neurodevelopment. However, limited data suggest there may be loss of motor function among some children who undergo transplantation. No long-term follow-up data are available from these case series. Of the approximately 550,000 newborns reported to have been screened in New York, 25 tested positive. None of these were clinically recognized to have Krabbe disease prior these results. Four were considered to be high risk for early-onset Krabbe disease. Two were subsequently diagnosed and underwent stem-cell transplantation, of whom one died from complications. No data are available regarding the impact on families of a positive newborn screen.

CONCLUSIONS: Although early treatment with hematopoietic stem-cell transplant seems to alter early-childhood mortality and some of the morbidity associated with early-infantile Krabbe disease, significant gaps in knowledge exist regarding the accuracy of screening, the strategy for establishing diagnosis, the affect of a positive screen on families, the benefits and harms of treatment, and long-term prognosis.

]]> Alex R. Kemper et al. DNA Mutational Analysis Humans Infant, Newborn Leukodystrophy, Globoid Cell Neonatal Screening New York Risk Risk Assessment United States An evidence development process for newborn screening http://escholarship.umassmed.edu/peds_genetics/26 http://escholarship.umassmed.edu/peds_genetics/26 Mon, 09 Apr 2012 12:39:27 PDT This article describes the background, development, and initial implementation of new procedures for the systematic review of key issues in newborn screening. Building on the work of other systematic review efforts, the Evidence Review Group described here has aimed to develop consistent and transparent strategies for evidence review. This process has helped to strengthen a complex analysis and decision system by providing balanced evidence, taking into account available high-quality data, expert opinion, and other levels of evidence, in a transparent manner. The methods developed and the identification of areas of missing data may also help investigators begin to standardize the clinical and laboratory data they collect pertaining to the newborn screening and diagnosis of rare disorders and their outcomes and focus future research efforts in the most needed areas.

]]> James M. Perrin et al. *Evidence-Based Medicine *Expert Testimony Health Plan Implementation Humans Infant, Newborn *Neonatal Screening Patient Advocacy Rare Diseases United States High-throughput multiplexed T-cell-receptor excision circle quantitative PCR assay with internal controls for detection of severe combined immunodeficiency in population-based newborn screening http://escholarship.umassmed.edu/peds_genetics/25 http://escholarship.umassmed.edu/peds_genetics/25 Mon, 09 Apr 2012 12:39:25 PDT BACKGROUND: Real-time quantitative PCR (qPCR) targeting a specific marker of functional T cells, the T-cell-receptor excision circle (TREC), detects the absence of functional T cells and has a demonstrated clinical validity for detecting severe combined immunodeficiency (SCID) in infants. There is need for a qPCR TREC assay with an internal control to monitor DNA quality and the relative cellular content of the particular dried blood spot punch sampled in each reaction. The utility of the qPCR TREC assay would also be far improved if more tests could be performed on the same newborn screening sample.

METHODS: We approached the multiplexing of qPCR for TREC by attenuating the reaction for the reference gene, with focus on maintaining tight quality assurance for reproducible slopes and for prevention of sample-to-sample cross contamination. Statewide newborn screening for SCID using the multiplexed assay was implemented, and quality-assurance data were recorded.

RESULTS: The multiplex qPCR TREC assay showed nearly 100% amplification efficiency for each of the TREC and reference sequences, clinical validity for multiple forms of SCID, and an analytic limit of detection consistent with prevention of contamination. The eluate and residual ghost from a 3.2-mm dried blood spot could be used as source material for multiplexed immunoassays and multiplexed DNA tests (Multiplex Plus), with no disruption to the multiplex TREC qPCR.

CONCLUSIONS: Population-based SCID newborn screening programs should consider multiplexing for quality assurance purposes. Potential benefits of using Multiplex Plus include the ability to perform multianalyte profiling.

]]> Jacalyn L. Gerstel-Thompson et al. Blood Specimen Collection Calibration DNA Feasibility Studies Gene Dosage Genes, T-Cell Receptor Humans Infant, Newborn Intensive Care Units *Neonatal Screening Polymerase Chain Reaction Quality Control Receptors, Antigen, T-Cell Regression Analysis Ribonucleases Severe Combined Immunodeficiency Reversible severe combined immunodeficiency phenotype secondary to a mutation of the proton-coupled folate transporter http://escholarship.umassmed.edu/peds_genetics/24 http://escholarship.umassmed.edu/peds_genetics/24 Mon, 09 Apr 2012 12:39:24 PDT Hereditary folate malabsorption is a rare inborn error of metabolism due to mutations in the proton-coupled folate transporter (PCFT). Clinical presentation of PCFT deficiency may mimic severe combined immune deficiency (SCID). We report a 4-month-old female who presented with failure to thrive, normocytic anemia, Pneumocystis jirovecii pneumonia and systemic cytomegalovirus infection. Immunological evaluation revealed hypogammaglobulinemia, absent antibody responses, and lack of mitogen-induced lymphocyte proliferative responses. However, the absolute number and distribution of lymphocyte subsets, including naive T cells and recent thymic emigrants, were normal, arguing against primary SCID. Serum and cerebrospinal fluid folate levels were undetectable. A homozygous 1082-1G>A mutation of the PCFT gene was found, resulting in skipping of exon 3. Parenteral folinic acid repletion resulted in normalization of anemia, humoral and cellular immunity, and full clinical recovery. PCFT mutations should be considered in infants with SCID-like phenotype, as the immunodeficiency is reversible with parenteral folinic acid repletion.

]]> Arturo Borzutzky et al. Base Sequence DNA Female Flow Cytometry Folic Acid Genetic Variation Humans Immunophenotyping Infant Intestinal Absorption Leucovorin Male Membrane Transport Proteins *Point Mutation Polymerase Chain Reaction Proton-Coupled Folate Transporter Severe Combined Immunodeficiency T-Lymphocytes BCOR analysis in patients with OFCD and Lenz microphthalmia syndromes, mental retardation with ocular anomalies, and cardiac laterality defects http://escholarship.umassmed.edu/peds_genetics/23 http://escholarship.umassmed.edu/peds_genetics/23 Mon, 09 Apr 2012 12:39:22 PDT Oculofaciocardiodental (OFCD) and Lenz microphthalmia syndromes form part of a spectrum of X-linked microphthalmia disorders characterized by ocular, dental, cardiac and skeletal anomalies and mental retardation. The two syndromes are allelic, caused by mutations in the BCL-6 corepressor gene (BCOR). To extend the series of phenotypes associated with pathogenic mutations in BCOR, we sequenced the BCOR gene in patients with (1) OFCD syndrome, (2) putative X-linked ('Lenz') microphthalmia syndrome, (3) isolated ocular defects and (4) laterality phenotypes. We present a new cohort of females with OFCD syndrome and null mutations in BCOR, supporting the hypothesis that BCOR is the sole molecular cause of this syndrome. We identify for the first time mosaic BCOR mutations in two females with OFCD syndrome and one apparently asymptomatic female. We present a female diagnosed with isolated ocular defects and identify minor features of OFCD syndrome, suggesting that OFCD syndrome may be mild and underdiagnosed. We have sequenced a cohort of males diagnosed with putative X-linked microphthalmia and found a mutation, p.P85L, in a single case, suggesting that BCOR mutations are not a major cause of X-linked microphthalmia in males. The absence of BCOR mutations in a panel of patients with non-specific laterality defects suggests that mutations in BCOR are not a major cause of isolated heart and laterality defects. Phenotypic analysis of OFCD and Lenz microphthalmia syndromes shows that in addition to the standard diagnostic criteria of congenital cataract, microphthalmia and radiculomegaly, patients should be examined for skeletal defects, particularly radioulnar synostosis, and cardiac/laterality defects.

]]> Emma Hilton et al. Adolescent Adult Aged Alleles Animals Child Child, Preschool Cohort Studies Eye Abnormalities Female Genetic Diseases, X-Linked Heart Diseases Humans Infant, Newborn Male Mental Retardation Microphthalmos Middle Aged Proto-Oncogene Proteins Repressor Proteins Syndrome Mosaic tetraploidy and transient GFI1 mutation in a patient with severe chronic neutropenia http://escholarship.umassmed.edu/peds_genetics/22 http://escholarship.umassmed.edu/peds_genetics/22 Mon, 09 Apr 2012 12:39:21 PDT This report presents the case of a 15-year-old male with severe chronic neutropenia, leukopenia, and persistent tetraploid mosaicism in the bone marrow and peripheral blood. His father had mild neutropenia and bone marrow tetraploidy. Flow cytometric analysis of DNA content peripheral blood showed tetraploidy in 20% of granulocytes and 15% of monocytes. Sequence analysis of the ELA2 gene was normal, but the GFI1 gene exhibited transient appearance of single base changes the coding region and promoter. We speculate that an underlying genetic defect, inherited in an autosomal dominant pattern, leads to both disordered mitosis and neutropenia in this kindred.

]]> Jessica C. Hochberg et al. Adolescent Adult Chronic Disease DNA-Binding Proteins Genes, Dominant Granulocytes Humans Leukemia Leukopenia Lymphoma, Follicular Male Mitosis Monocytes *Mosaicism Mutagenesis Neutropenia Paraproteinemias Pedigree *Polyploidy Transcription Factors Early HIV-1 diagnosis using in-house real-time PCR amplification on dried blood spots for infants in remote and resource-limited settings http://escholarship.umassmed.edu/peds_genetics/21 http://escholarship.umassmed.edu/peds_genetics/21 Mon, 09 Apr 2012 12:39:19 PDT BACKGROUND: In resource-limited settings, most perinatally HIV-1-infected infants do not receive timely antiretroviral therapy because early HIV-1 diagnosis is not available or affordable.

OBJECTIVE: To assess the performance of a low-cost in-house real-time polymerase chain reaction (PCR) assay to detect HIV-1 DNA in infant dried blood spots (DBS).

METHODS: One thousand three hundred nineteen DBS collected throughout Thailand from non-breast-fed infants born to HIV-1-infected mothers were shipped at room temperature to a central laboratory.In-house real-time DNA PCR results were compared with Roche Amplicor HIV-1 DNA test (Version 1.5) results. In addition, we verified the Roche test performance on DBS sampled from 1218 other infants using as reference HIV serology result at 18 months of age.

RESULTS: Real-time DNA PCR and Roche DNA PCR results were 100% concordant. Compared with HIV serology results, the Roche test sensitivity was 98.6% (95% confidence interval: 92.6% to 100.0%) and its specificity at 4 months of age was 99.7% (95% confidence interval: 99.2% to 99.9%).

CONCLUSIONS: In-house real-time PCR performed as well as the Roche test in detecting HIV-1 DNA on DBS in Thailand. Combined use of DBS and real-time PCR assays is a reliable and affordable tool to expand access to early HIV-1 diagnosis in remote and resource-limited settings, enabling timely treatment for HIV-1-infected infants.

]]> Nicole Pharm Ngo-Giang-Huong et al. DNA, Viral *Delivery of Health Care *Developing Countries HIV Infections *HIV-1 Humans Infant Infant Care Infectious Disease Transmission, Vertical Polymerase Chain Reaction Reproducibility of Results Sensitivity and Specificity Thailand Newborn screening showing decreasing incidence of cystic fibrosis http://escholarship.umassmed.edu/peds_genetics/20 http://escholarship.umassmed.edu/peds_genetics/20 Mon, 09 Apr 2012 12:39:18 PDT Jaime E. Hale et al. Cystic Fibrosis Genotype Humans Infant, Newborn Massachusetts *Neonatal Screening The phakomatoses: dermatologic clues to neurologic anomalies http://escholarship.umassmed.edu/peds_genetics/17 http://escholarship.umassmed.edu/peds_genetics/17 Mon, 09 Apr 2012 12:39:16 PDT The phakomatoses of particular interest to neurologists including Sturge-Weber syndrome, neurofibromatosis type 1, neurofibromatosis type 2, Bannayan-Riley-Ruvalcaba syndrome, and Proteus syndrome are presented. The physical manifestations required for clinical diagnosis, the neurologic features, and recommendations for management are given. The molecular etiology and genetic aspects of these disorders are briefly discussed as well as future implications of on-going research.

]]> Catherine Bearce Nowak Abnormalities, Multiple Hamartoma Syndrome, Multiple Humans Nervous System Diseases Neurocutaneous Syndromes Neurofibromatosis 1 Skin Diseases Sturge-Weber Syndrome Familial immunodeficiency with cutaneous vasculitis, myoclonus, and cognitive impairment http://escholarship.umassmed.edu/peds_genetics/16 http://escholarship.umassmed.edu/peds_genetics/16 Mon, 09 Apr 2012 12:39:15 PDT We report a family with five of six siblings (including identical male twins) with a novel constellation of immunologic and neurologic impairments. Affected subjects experienced severe dermatitis starting around 9 months of age, Stevens-Johnson syndrome in early childhood, and extreme elevations of IgE (9,400-43,000 IU/ml). The oldest sibling died at age 27 of respiratory failure following recurrent, severe pneumonias. All four surviving affected siblings have had chronic sinusitis or otitis, cutaneous vasculitis, and recurrent bacterial pneumonias leading to bronchiectasis. Neurologic features in all five siblings included oral motor deficits, dysarthria, low average IQ (70-80), and essential myoclonus. Four had documented ataxia and/or mild sensory loss with increased patellar but diminished ankle reflexes. The nonconsanguineous parents and one sibling had none of the above findings, consistent with autosomal recessive inheritance. This primary immunodeficiency with distinctive neurological impairments represents a new syndrome. Published 2003 Wiley-Liss, Inc.

]]> Beverly N. Hay et al. Adult Cognition Disorders Dermatitis Diseases in Twins Female Genes, Recessive Humans Immunologic Deficiency Syndromes Male Myoclonus Pedigree Siblings Syndrome Vasculitis Population-based newborn screening for severe combined immunodeficiency: steps toward implementation http://escholarship.umassmed.edu/peds_genetics/15 http://escholarship.umassmed.edu/peds_genetics/15 Mon, 09 Apr 2012 12:39:14 PDT Severe combined immune deficiency (SCID) has been identified as a disorder of high priority for population-based newborn screening. Most affected infants are not brought to medical attention until they develop serious infectious complications, and SCID is fatal if untreated. Effective treatment with allogeneic hematopoietic stem cell transplantation is widely established. The best outcome for SCID, as with many other conditions for which newborn screening is now done, is achieved if hematopoietic stem cell transplantation is performed in the first months of life, ideally before clinical presentation with infections and failure to thrive. A meeting in San Francisco in May 2007 brought together experts from newborn screening programs; the pediatric immunology community; pediatric transplant centers; and federal, state, and nongovernmental agencies to consider obstacles to and implications of developing newborn screening for SCID. Development of an appropriate low-cost, high-throughput screening algorithm has been a challenge, although absence of T-cell receptor gene excision circles is a sensitive marker of profound T lymphocytopenia and currently is the most developed screening method. A consensus was reached on several points: SCID newborn screening should be pursued with pilot studies in key locales, test methodologies need to be optimized, screening programs must be integrated with plans for definitive diagnosis and management, centralized specimen banks and registries are required to foster test validation and track outcomes that will guide future treatment, and SCID newborn screening will lead to important knowledge about human immune disorders as well as better care of patients.

]]> Jennifer M. Puck et al. Humans Infant Infant, Newborn *Neonatal Screening Severe Combined Immunodeficiency Gene therapy improves immune function in preadolescents with X-linked severe combined immunodeficiency http://escholarship.umassmed.edu/peds_genetics/14 http://escholarship.umassmed.edu/peds_genetics/14 Mon, 09 Apr 2012 12:39:12 PDT Retroviral gene therapy can restore immunity to infants with X-linked severe combined immunodeficiency (XSCID) caused by mutations in the IL2RG gene encoding the common gamma chain (gammac) of receptors for interleukins 2 (IL-2), -4, -7, -9, -15, and -21. We investigated the safety and efficacy of gene therapy as salvage treatment for older XSCID children with inadequate immune reconstitution despite prior bone marrow transplant from a parent. Subjects received retrovirus-transduced autologous peripherally mobilized CD34(+) hematopoietic cells. T-cell function significantly improved in the youngest subject (age 10 years), and multilineage retroviral marking occurred in all 3 children.

]]> Javier Chinen et al. Gene Therapy Hematopoietic Stem Cell Transplantation Humans Immunity Infant Mutation Receptors, Interleukin-2 Retroviridae T-Lymphocytes Transduction, Genetic Transplantation, Autologous X-Linked Combined Immunodeficiency Diseases Townes-Brocks syndrome: twenty novel SALL1 mutations in sporadic and familial cases and refinement of the SALL1 hot spot region http://escholarship.umassmed.edu/peds_genetics/13 http://escholarship.umassmed.edu/peds_genetics/13 Mon, 09 Apr 2012 12:39:11 PDT Townes-Brocks syndrome (TBS) is an autosomal dominant malformation syndrome characterized by renal, anal, ear, and thumb anomalies caused by SALL1 mutations. To date, 36 SALL1 mutations have been described in TBS patients. All but three of those, namely p.R276X, p.S372X, and c.1404dupG, have been found only in single families thereby preventing phenotype-genotype correlations. Here we present 20 novel mutations (12 short deletions, five short duplications, three nonsense mutations) in 20 unrelated families. We delineate the phenotypes and report previously unknown ocular manifestations, i.e. congenital cataracts with unilateral microphthalmia. We show that 46 out of the now 56 SALL1 mutations are located between the coding regions for the glutamine-rich domain mediating SALL protein interactions and 65 bp 3' of the coding region for the first double zinc finger domain, narrowing the SALL1 mutational hotspot region to a stretch of 802 bp within exon 2. Of note, only two SALL1 mutations would result in truncated proteins without the glutamine-rich domain, one of which is reported here. The latter is associated with anal, ear, hand, and renal manifestations, indicating that the glutamine-rich domain is not required for typical TBS.

]]> Elke M. Botzenhart et al. Abnormalities, Multiple Child, Preschool DNA Mutational Analysis Female Genotype Humans Infant Infant, Newborn Male Middle Aged *Mutation Pedigree Phenotype Syndrome Transcription Factors