A cross-disorder dosage sensitivity map of the human genome.

Rare copy-number variants (rCNVs) include deletions and duplications that occur infrequently in the global human population and can confer substantial risk for disease. In this study, we aimed to quantify the properties of haploinsufficiency (i.e., deletion intolerance) and triplosensitivity (i.e., duplication intolerance) throughout the human genome. We harmonized and meta-analyzed rCNVs from nearly one million individuals to construct a genome-wide catalog of dosage sensitivity across 54 disorders, which defined 163 dosage sensitive segments associated with at least one disorder. These segments were typically gene dense and often harbored dominant dosage sensitive driver genes, which we were able to prioritize using statistical fine-mapping. Finally, we designed an ensemble machine-learning model to predict probabilities of dosage sensitivity (pHaplo & pTriplo) for all autosomal genes, which identified 2,987 haploinsufficient and 1,559 triplosensitive genes, including 648 that were uniquely triplosensitive. This dosage sensitivity resource will provide broad utility for human disease research and clinical genetics.

Nine is the New Ten of Apgar Scores: An Observational Retrospective Cohort Study.

Apgar scores of 10 were once common but are now rare. We aggregated scores from US term infants from 1978 to 2021. We found that scores of 10 decreased by logarithmic decay independent of demographic changes. We hypothesize that this trend was driven by improved appreciation of transitional physiology.

Genetic Disorders and their Association with Morbidity and Mortality in Early Preterm Small for Gestational Age Infants.

BACKGROUND: Early preterm (< 34 weeks gestation) small for gestational age infants (< 10th percentile birth weight for sex and gestational age) experience high rates of morbidity and mortality, the causes of which are poorly understood. Mounting evidence suggests that genetic disorders contribute. Scarce data exist regarding the prevalence of genetic disorders and their contribution to morbidity and mortality. OBJECTIVE: This study aimed to determine the proportion of genetic disorders in early preterm small for gestational age infants (with and without congenital anomalies) compared to early preterm appropriate for gestational age infants and the association of genetic disorders with morbidity or mortality. STUDY DESIGN: This is a retrospective cohort study of infants delivered at 23 and 0/7 to 33 and 6/7 weeks' gestation from 2000-2020 from the Pediatrix Clinical Data Warehouse. Data included diagnosed genetic disorders and congenital anomalies, baseline characteristics, and morbidity or mortality. We excluded cases of death in the delivery room before NICU admission, multiple gestations, and cases transferred after birth or before death or discharge. RESULTS: We identified 223,431 early preterm infants, including 21,180 small for gestational age. Genetic disorders were present in 441 (2.3%) of small for gestational age infants without congenital anomalies, in 194 (10.8%) of small for gestational age infants with congenital anomalies, and in 304 (4.5%) of small for gestational age infants that experienced morbidity or mortality (with or without congenital anomalies). Trisomies 13, 18, and 21 were the most prevalent genetic disorders in these groups, together accounting for 145 small for gestational age infants without congenital anomalies, 117 small for gestational age infants with congenital anomalies, and 166 small for gestational age infants with morbidity or mortality (with or without congenital anomalies). Less prevalent genetic disorders consisted of other aneuploidy (45, X and 47, XXY), copy number variants (13q14 deletion syndrome, cri du chat syndrome, DiGeorge syndrome) and single gene disorders (cystic fibrosis, Fanconi anemia, G6PD deficiency, hemophilia, hypophosphatasia, sickle cell disease, and thalassemia). Comparatively, genetic disorders were found in 1792 (1.0%) appropriate for gestational age infants without congenital anomalies, in 572 (5.8%) appropriate for gestational age infants with congenital anomalies, and 809 (2.0%) appropriate for gestational age infants that experienced morbidity or mortality (with or without congenital anomalies). Genetic disorders were associated with an adjusted odds ratio (95% confidence interval) of 2.10 (1.89-2.33) of isolated small for gestational age and 12.84 (11.47-14.35) of small for gestational age accompanied by congenital anomalies. Genetic disorders were associated with an adjusted odds ratio of 2.24 (1.83-2.74) of morbidity or mortality. CONCLUSIONS: These findings suggest that genetic disorders are more prevalent in early preterm small for gestational age infants, particularly those with congenital anomalies. These findings also suggest that genetic disorders are associated with increased morbidity and mortality. These associations were primarily driven by trisomies 13, 18, and 21. Genetic diagnoses in this cohort were made through routine clinical care, principally via karyotype, chromosomal microarray, and single gene-testing. These findings support evolving clinical guidelines for genetic testing of small for gestational age infants. Our study is limited due to the lack of prospective, genome-wide testing.

The Contribution of Commonly Diagnosed Genetic Disorders to Small for Gestational Age Birth and Subsequent Morbidity and Mortality in Preterm Infants.

Objective: Preterm infants born small, vs. appropriate for gestational age (SGA, AGA) are at greater risk for morbidity and mortality. The contribution of genetic disorders to preterm SGA birth, morbidity, and mortality is unknown. We sought to determine the association between genetic disorders and preterm SGA birth, and the association between genetic disorders and morbidity or mortality within preterm SGA infants. We hypothesized that genetic disorders were significantly associated with both. Study Design: This was a retrospective multicenter cohort study of 409 339 infants, born 23-33 weeks' gestation between 2000 and 2020. The odds of preterm SGA (vs AGA) birth, and the odds of severe morbidity or mortality within SGA preterm infants were determined for infants with genetic disorders, after adjusting for known risk factors. Results: Genetic disorders were present in 3.0 and 1.3% of SGA and AGA preterm infants respectively; genetic disorders conferred an aOR (95% CI) of 2.06 (1.92, 2.21) of SGA birth. Genetic disorders were present in 4.3 of preterm SGA infants with morbidity or mortality and 2.1% of preterm SGA infants that did not experience morbidity or mortality. Genetic disorders conferred an aOR (95% CI) of 2.12 (2.66, 3.08) of morbidity or mortality. Conclusions: Genetic disorders are strongly associated with preterm SGA birth, morbidity, and mortality. Clinicians should consider genetic testing of preterm SGA infants, particularly in the setting of other comorbidities or anomalies. Prospective, genomic research is needed to clarify the contribution of genetic disorders to disease in this population.

Prevalence and Clinical Significance of Commonly Diagnosed Genetic Disorders in Preterm Infants.

Background and Objectives: Preterm infants (<34 weeks' gestation) experience high rates of morbidity and mortality before hospital discharge. Genetic disorders substantially contribute to morbidity and mortality in related populations. The prevalence and clinical impact of genetic disorders is unknown in this population. We sought to determine the prevalence of commonly diagnosed genetic disorders in preterm infants, and to determine the association of disorders with morbidity and mortality. Methods: This was a retrospective multicenter cohort study of infants born from 23 to 33 weeks' gestation between 2000 and 2020. Genetic disorders were abstracted from diagnoses present in electronic health records. We excluded infants transferred from or to other health care facilities prior to discharge or death when analyzing clinical outcomes. We determined the adjusted odds of pre-discharge morbidity or mortality after adjusting for known risk factors. Results: Of 320,582 infants, 4196 (1.3%) had genetic disorders. Infants with trisomy 13, 18, 21, or cystic fibrosis had greater adjusted odds of severe morbidity or mortality. Of the 17,427 infants who died, 566 (3.2%) had genetic disorders. Of the 65,968 infants with a severe morbidity, 1319 (2.0%) had genetic disorders.ConclusionsGenetic disorders are prevalent in preterm infants, especially those with life-threatening morbidities. Clinicians should consider genetic testing for preterm infants with severe morbidity and maintain a higher index of suspicion for life-threatening morbidities in preterm infants with genetic disorders. Prospective genomic research is needed to clarify the prevalence of genetic disorders in this population, and the contribution of genetic disorders to preterm birth and subsequent morbidity and mortality. Article Summary: Genetic disorders were found in 1.3% of preterm infants and at a higher rate (2.0%) in infants who died or developed severe morbidity. What's Known on This Subject: Previous research described the prevalence and associated short-term morbidity and mortality of trisomy 13, 18, and 21 in preterm infants. The prevalence of other commonly diagnosed genetic disorders and associated short-term morbidity and mortality in preterm infants is unknown. What This Study Adds: In a multicenter, retrospective cohort of 320,582 preterm (<34 weeks' gestation) infants, we found that 1.3% had genetic disorders diagnosed through standard care. Multiple disorders were associated with increased adjusted odds of morbidities or mortality prior to hospital discharge. Contributors Statement Page: Selin S. Everett conceptualized and designed the study, conducted analyses, drafted the initial manuscript, and critically reviewed and revised the manuscript.Dr. Thomas Hays conceptualized and designed the study, drafted the initial manuscript, and critically reviewed and revised the manuscript.Miles Bomback conceptualized and designed the study and critically reviewed and revised the manuscript.Drs. Veeral N. Tolia and Reese H. Clark coordinated and supervised data collection and critically reviewed and revised the manuscript.Dr. Rakesh Sahni conceptualized and designed the study and critically reviewed and revised the manuscript.Dr. Alex Lyford conducted analyses and critically reviewed and revised the manuscript. Dr. Ronald J. Wapner reviewed and critically revised the manuscript.All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.