Utilization of genomic sequencing for population screening of immunodeficiencies in the newborn.

PurposeImmunodeficiency screening has been added to many state-directed newborn screening programs. The current methodology is limited to screening for severe T-cell lymphopenia disorders. We evaluated the potential of genomic sequencing to augment current newborn screening for immunodeficiency, including identification of non-T cell disorders.MethodsWe analyzed whole-genome sequencing (WGS) and clinical data from a cohort of 1,349 newborn-parent trios by genotype-first and phenotype-first approaches. For the genotype-first approach, we analyzed predicted protein-impacting variants in 329 immunodeficiency-related genes in the WGS data. As a phenotype-first approach, electronic health records were used to identify children with clinical features suggestive of immunodeficiency. Genomes of these children and their parents were analyzed using a separate pipeline for identification of candidate pathogenic variants for rare Mendelian disorders.ResultsWGS provides adequate coverage for most known immunodeficiency-related genes. 13,476 distinct variants and 8,502 distinct predicted protein-impacting variants were identified in this cohort; five individuals carried potentially pathogenic variants requiring expert clinical correlation. One clinically asymptomatic individual was found genomically to have complement component 9 deficiency. Of the symptomatic children, one was molecularly identified as having an immunodeficiency condition and two were found to have other molecular diagnoses.ConclusionNeonatal genomic sequencing can potentially augment newborn screening for immunodeficiency.

X-Linked Candidate Genes for a Ciliopathy-Like Disorder.

The ability to interrogate the genome via chromosomal microarray and sequencing-based technologies has accelerated the ability to rapidly and accurately define etiologies as well as new candidate genes related to genetic conditions. We describe a male patient with a lethal presentation of a multiple congenital anomaly syndrome that appeared consistent with a ciliopathy phenotype. The patient was found to have a novel maternally inherited 1.9-Mb X chromosome deletion including 4 known genes. Presently, the biological functions of these genes are not well delineated. However, at least one of these genes may be a promising candidate gene for this pattern of anomalies based on the function of related genes and information from publicly available copy number variant databases of control and affected individuals. These genes would bear further scrutiny in larger cohorts of patients with similar phenotypes.

Intimate partner violence increases adverse outcomes at birth and in early infancy.

OBJECTIVE: To determine the effect of intimate partner violence (IPV) on birth outcomes and infant hospitalization. STUDY DESIGN: Hospitalization records for the first 4 months of life for infants born in the Military Health System in 2006-2007 were linked to Family Advocacy Program-substantiated cases of IPV among military parents. Adverse outcomes were identified using International Classification of Diseases, Ninth Revision codes. Logistic regression modeling calculated the OR of children exposed to IPV experiencing adverse outcomes. RESULTS: A total of 204,546 infants were born during the study period. Among these, 173,026 infants (85%) were linked to active duty military parents. 31,603 infants (18%) experienced adverse outcomes, and 3059 infants (1.8%) were born into families with IPV. The infants exposed to IPV had a 31% increased odds of experiencing adverse outcomes compared with infants without known IPV exposure. IPV exposure increased the odds of the following outcomes: prematurity (OR, 1.45; 95% CI, 1.29-1.62), low birth weight (OR, 1.57; 95% CI, 1.25-1.97), respiratory problems (OR, 1.17; 95% CI, 1.04-1.32), neonatal hospitalization (OR, 1.39; 95% CI, 1.20-1.61), and postneonatal hospitalization (OR, 1.52; 95% CI, 1.29-1.81). After controlling for prematurity and demographic variables, IPV exposure was associated with low birth weight (OR, 1.52; 95% CI, 1.16-1.99), neonatal hospitalization (OR, 1.24; 95% CI, 1.02-1.49), and postneonatal hospitalization (OR, 1.27; 95% CI, 1.03-1.56). CONCLUSION: Infants exposed to IPV are more likely to experience adverse birth outcomes and infant hospitalization. Routinely addressing IPV during prenatal and early pediatric visits may potentially prevent these adverse outcomes.