Publications by authors named "Daniel Swarr"

21 Publications

  • Page 1 of 1

Beyond diagnostic yield: prenatal exome sequencing results in maternal, neonatal, and familial clinical management changes.

Genet Med 2021 Jan 13. Epub 2021 Jan 13.

Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.

Purpose: Previous studies have reported that prenatal exome sequencing (pES) can detect monogenic diseases in fetuses with congenital anomalies with diagnostic yields ranging from 6% to 81%, but there are few reports of its clinical utility.

Methods: We conducted a retrospective chart review of patients who had pES to determine whether results led to clinical management changes.

Results: Of 20 patients, 8 (40%) received a definitive diagnosis. Seven patients (35%) had medical management changes based on the pES results, including alterations to their delivery plan and neonatal management (such as use of targeted medications, subspecialty referrals, additional imaging and/or procedures). All patients who received a definitive diagnosis and one who received a likely pathogenic variant (n = 9; 45%) received specific counseling about recurrence risk and the medical/developmental prognosis for the baby. In five (25%) cases, the result facilitated a diagnosis in parents and/or siblings.

Conclusion: pES results can have significant impacts on clinical management, some of which would not be possible if testing is deferred until after birth. To maximize the clinical utility, pES should be prioritized in cases where multiple care options are available and the imaging findings alone are not sufficient to guide parental decision-making, or where postnatal testing will not be feasible.
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http://dx.doi.org/10.1038/s41436-020-01067-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804210PMC
January 2021

"PIK"ing Out New Epigenetic Markers in Lung Disease.

Am J Respir Crit Care Med 2020 05;201(9):1029-1030

Cincinnati Children's HospitalUniversity of Cincinnati School of MedicineCincinnati, Ohioand.

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http://dx.doi.org/10.1164/rccm.202002-0295EDDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193860PMC
May 2020

Making a Genetic Diagnosis in a Level IV Neonatal Intensive Care Unit Population: Who, When, How, and at What Cost?

J Pediatr 2019 10 27;213:211-217.e4. Epub 2019 Jun 27.

Division of Pulmonary Biology, Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH. Electronic address:

Objective: To investigate the prevalence of genetic disease and its economic impact in a level IV neonatal intensive care unit (NICU) by identifying and describing diseases diagnosed, genetic testing methodologies used, timing of diagnosis, length of NICU stay, and charges for NICU care.

Study Design: A retrospective chart review of patients admitted to a level IV NICU from 2013 to 2014 (n = 1327) was undertaken and data collected up to 2 years of age from the electronic medical record.

Results: In total, 117 patients (9%) received 120 genetic diagnoses using a variety of methodologies. A significant minority of diagnoses, 36%, were made after NICU discharge and 41% were made after 28 days of age. Patients receiving a genetic diagnosis had significantly longer mean lengths of stay (46 days vs 29.1 days; P < .01) and costlier mean charges ($598 712 vs $352 102; P < .01) for their NICU care. The NICU stay charge difference to care for a newborn with a genetic condition was on average $246 610 in excess of that for a patient without a genetic diagnosis, resulting in more than $28 000 000 in excess charges to care for all patients with genetic conditions in a single NICU over a 2-year period.

Conclusions: Given the high prevalence of genetic disease in this population and the documented higher cost of care, shortening the time to diagnosis and targeting therapeutic interventions for this population could make a significant impact on neonatal care in level IV NICUs.
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http://dx.doi.org/10.1016/j.jpeds.2019.05.054DOI Listing
October 2019

The long noncoding RNA Falcor regulates Foxa2 expression to maintain lung epithelial homeostasis and promote regeneration.

Genes Dev 2019 06 28;33(11-12):656-668. Epub 2019 Mar 28.

Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.

Transcription factors (TFs) are dosage-sensitive master regulators of gene expression, with haploinsufficiency frequently leading to life-threatening disease. Numerous mechanisms have evolved to tightly regulate the expression and activity of TFs at the transcriptional, translational, and posttranslational levels. A subset of long noncoding RNAs (lncRNAs) is spatially correlated with transcription factors in the genome, but the regulatory relationship between these lncRNAs and their neighboring TFs is unclear. We identified a regulatory feedback loop between the TF Foxa2 and a downstream lncRNA, Falcor (Foxa2-adjacent long noncoding RNA). Foxa2 directly represses Falcor expression by binding to its promoter, while Falcor functions in to positively regulate the expression of Foxa2. In the lung, loss of Falcor is sufficient to lead to chronic inflammatory changes and defective repair after airway epithelial injury. Moreover, disruption of the Falcor-Foxa2 regulatory feedback loop leads to altered cell adhesion and migration, in turn resulting in chronic peribronchial airway inflammation and goblet cell metaplasia. These data reveal that the lncRNA Falcor functions within a regulatory feedback loop to fine-tune the expression of Foxa2, maintain airway epithelial homeostasis, and promote regeneration.
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http://dx.doi.org/10.1101/gad.320523.118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6546060PMC
June 2019

Novel Molecular and Phenotypic Insights into Congenital Lung Malformations.

Am J Respir Crit Care Med 2018 05;197(10):1328-1339

6 Penn Center for Pulmonary Biology, and.

Rationale: Disruption of normal pulmonary development is a leading cause of morbidity and mortality in infants. Congenital lung malformations are a unique model to study the molecular pathogenesis of isolated structural birth defects, as they are often surgically resected.

Objectives: To provide insight into the molecular pathogenesis of congenital lung malformations through analysis of cell-type and gene expression changes in these lesions.

Methods: Clinical data, and lung tissue for DNA, RNA, and histology, were obtained from 58 infants undergoing surgical resection of a congenital lung lesion. Transcriptome-wide gene expression analysis was performed on paired affected and unaffected samples from a subset of infants (n = 14). A three-dimensional organoid culture model was used to assess isolated congenital lung malformation epithelium (n = 3).

Measurements And Main Results: Congenital lung lesions express higher levels of airway epithelial related genes, and dysregulated expression of genes related to the Ras and PI3K-AKT-mTOR (phosphatidylinositol 3-kinase-AKT-mammalian target of rapamycin) signaling pathways. Immunofluorescence confirmed differentiated airway epithelial cell types throughout all major subtypes of congenital lung lesions, and three-dimensional cell culture demonstrated a cell-autonomous defect in the epithelium of these lesions.

Conclusions: This study provides the first comprehensive analysis of the congenital lung malformation transcriptome and suggests that disruptions in Ras or PI3K-AKT-mTOR signaling may contribute to the pathology through an epithelial cell-autonomous defect.
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http://dx.doi.org/10.1164/rccm.201706-1243OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5955056PMC
May 2018

Congenital Cystic Lung Lesions: Redefining the Natural Distribution of Subtypes and Assessing the Risk of Malignancy.

Am J Surg Pathol 2019 01;43(1):47-55

Surgery, Children's Hospital of Philadelphia, Philadelphia, PA.

Asymptomatic cystic lung lesions-congenital pulmonary airway malformations (CPAMs), sequestrations, and bronchogenic cysts-are commonly diagnosed prenatally. Indications to resect are to eliminate risk of malignancy or infection. CPAMs consist of a spectrum of malformations, with type 1 historically considered the most common. Mucinous cell clusters, seen almost exclusively in type 1, are premalignant lesions at risk for progression to mucinous adenocarcinoma. We reviewed and classified 2.5 years of consecutive, prenatally diagnosed lesions as extralobar sequestration, intralobar sequestration, type 1 CPAM, type 2 CPAM/bronchial atresia, or "other" to determine the distribution of lesion types and risk of malignancy. One hundred eighty-four lesions in 174 patients showed type 1 CPAM to be least common subtype. Type 1 CPAMs had more severe presentation, infrequently had features of obstruction, and usually had cysts ≥2 cm. Fifteen of eighteen type 1 CPAMs had mucinous cell clusters (total risk, 8%), with mucous cells outside main cyst in 12/15. No pleuropulmonary blastomas were identified. Additional historic cases were reviewed to further evaluate risk of malignancy. Over 14 years, 28 infants with fetal/type 1 lesions were identified, with clusters of mucinous cells in 75% of cases. A total of 9 pleuropulmonary blastomas were diagnosed in 6 patients over 16 years. Contrary to historical studies, type 1 CPAMs are much less common than type 2, likely related to detection of asymptomatic lesions prenatally. A majority of type 1 CPAMs contain mucinous cell clusters. This data is useful in management of patients in centers that do not resect asymptomatic lesions.
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http://dx.doi.org/10.1097/PAS.0000000000000992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6816050PMC
January 2019

Systematic Review and Meta-analysis: Gene Association Studies in Neonatal Sepsis.

Am J Perinatol 2017 06 13;34(7):684-692. Epub 2016 Dec 13.

Division of Neonatology, Department of Pediatrics, The Children's Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.

 Association studies of various gene variants in neonatal sepsis show conflicting results.  We performed a systematic review of candidate gene association studies in neonatal sepsis to provide pooled estimates of risk for selected gene variants.  We performed a search using MeSH terms "infection," "sepsis," "infant," "genetic variation," "polymorphism," and "genetic association studies." We included studies evaluating associations between neonatal sepsis and genetic variants (2000-2015). We excluded case reports/series, commentaries, narrative reviews, and nonhuman research. We assessed quality of studies using STREGA guidelines. Following estimation of odds ratios (ORs), data were pooled using random effects models.  Twenty eight of 1,404 identified studies were included. Meta-analyses were performed for interleukin (IL)-6, tumor necrosis factor-α (TNF-α), and IL-10 as these gene variants were tested in multiple studies. TNF-α 308GG genotype demonstrated trends toward increased sepsis risk in the primary analysis of culture-proven sepsis (OR 1.18, 95% confidence interval [CI] 0.97-1.44). IL-10 1082GG genotype was associated with lower sepsis odds in very low-birth-weight (VLBW) infants (OR 0.51, 95% CI 0.29-0.91).  We uncovered an association between IL-10 1082 gene variation and sepsis in VLBW infants but did not identify associations between neonatal sepsis and TNF-α 308 or IL-6 gene variation. Larger cohort replication studies are required to validate these findings.
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http://dx.doi.org/10.1055/s-0036-1597132DOI Listing
June 2017

Accelerating Scientific Advancement for Pediatric Rare Lung Disease Research. Report from a National Institutes of Health-NHLBI Workshop, September 3 and 4, 2015.

Ann Am Thorac Soc 2016 12;13(12):385-393

8 Division of Lung Diseases, National Heart, Lung, and Blood Institute, Bethesda, Maryland.

Pediatric rare lung disease (PRLD) is a term that refers to a heterogeneous group of rare disorders in children. In recent years, this field has experienced significant progress marked by scientific discoveries, multicenter and interdisciplinary collaborations, and efforts of patient advocates. Although genetic mechanisms underlie many PRLDs, pathogenesis remains uncertain for many of these disorders. Furthermore, epidemiology and natural history are insufficiently defined, and therapies are limited. To develop strategies to accelerate scientific advancement for PRLD research, the NHLBI of the National Institutes of Health convened a strategic planning workshop on September 3 and 4, 2015. The workshop brought together a group of scientific experts, intramural and extramural investigators, and advocacy groups with the following objectives: (1) to discuss the current state of PRLD research; (2) to identify scientific gaps and barriers to increasing research and improving outcomes for PRLDs; (3) to identify technologies, tools, and reagents that could be leveraged to accelerate advancement of research in this field; and (4) to develop priorities for research aimed at improving patient outcomes and quality of life. This report summarizes the workshop discussion and provides specific recommendations to guide future research in PRLD.
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http://dx.doi.org/10.1513/AnnalsATS.201605-402OTDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5291498PMC
December 2016

Lung endoderm morphogenesis: gasping for form and function.

Annu Rev Cell Dev Biol 2015 10;31:553-73. Epub 2015 Sep 10.

The respiratory endoderm develops from a small cluster of cells located on the ventral anterior foregut. This population of progenitors generates the myriad epithelial lineages required for proper lung function in adults through a complex and delicately balanced series of developmental events controlled by many critical signaling and transcription factor pathways. In the past decade, understanding of this process has grown enormously, helped in part by cell lineage fate analysis and deep sequencing of the transcriptomes of various progenitors and differentiated cell types. This review explores how these new techniques, coupled with more traditional approaches, have provided a detailed picture of development of the epithelial lineages in the lung and insight into how aberrant development can lead to lung disease.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5051950PMC
http://dx.doi.org/10.1146/annurev-cellbio-100814-125249DOI Listing
September 2016

Detection of mutually exclusive mosaicism in a girl with genotype-phenotype discrepancies.

Am J Med Genet A 2015 Dec 21;167A(12):3091-5. Epub 2015 Jul 21.

Department of Pathology & Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

Discordance between clinical phenotype and genotype has multiple causes, including mosaicism. Phenotypes can be modified due to tissue distribution, or the presence of multiple abnormal cell lines with different genomic contributions. We have studied a 20-month-old female whose main phenotypes were failure to thrive, developmental delay, and patchy skin pigmentation. Initial chromosome and SNP microarray analysis of her blood revealed a non-mosaic ∼24 Mb duplication of 15q25.1q26.3 resulting from the unbalanced translocation of terminal 15q to the short arm of chromosome 15. The most common feature associated with distal trisomy 15q is prenatal and postnatal overgrowth, which was not consistent with this patient's phenotype. The phenotypic discordance, in combination with the patchy skin pigmentation, suggested the presence of mosaicism. Further analysis of skin biopsies from both hyper- and hypopigmented regions confirmed the presence of an additional cell line with the short arm of chromosome X deleted and replaced by the entire long arm of chromosome 15. The Xp deletion, consistent with a variant Turner Syndrome diagnosis, better explained the patient's phenotype. Parental studies revealed that the alterations in both cell lines were de novo and the duplicated distal 15q and the deleted Xp were from different parental origins, suggesting a mitotic event. The possible mechanism for the occurrence of two mutually exclusive structural rearrangements with both involving the long arm of chromosome 15 is discussed.
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http://dx.doi.org/10.1002/ajmg.a.37261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4715567PMC
December 2015

Mutations in SPECC1L, encoding sperm antigen with calponin homology and coiled-coil domains 1-like, are found in some cases of autosomal dominant Opitz G/BBB syndrome.

J Med Genet 2015 Feb 20;52(2):104-10. Epub 2014 Nov 20.

Division of Human Genetics, The Children's Hospital of Philadelphia, Clinical Genetics Center, and the Perelman School of Medicine of the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Background: Opitz G/BBB syndrome is a heterogeneous disorder characterised by variable expression of midline defects including cleft lip and palate, hypertelorism, laryngealtracheoesophageal anomalies, congenital heart defects, and hypospadias. The X-linked form of the condition has been associated with mutations in the MID1 gene on Xp22. The autosomal dominant form has been linked to chromosome 22q11.2, although the causative gene has yet to be elucidated.

Methods And Results: In this study, we performed whole exome sequencing on DNA samples from a three-generation family with characteristics of Opitz G/BBB syndrome with negative MID1 sequencing. We identified a heterozygous missense mutation c.1189A>C (p.Thr397Pro) in SPECC1L, located at chromosome 22q11.23. Mutation screening of an additional 19 patients with features of autosomal dominant Opitz G/BBB syndrome identified a c.3247G>A (p.Gly1083Ser) mutation segregating with the phenotype in another three-generation family.

Conclusions: Previously, SPECC1L was shown to be required for proper facial morphogenesis with disruptions identified in two patients with oblique facial clefts. Collectively, these data demonstrate that SPECC1L mutations can cause syndromic forms of facial clefting including some cases of autosomal dominant Opitz G/BBB syndrome and support the original linkage to chromosome 22q11.2.
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http://dx.doi.org/10.1136/jmedgenet-2014-102677DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4393015PMC
February 2015

Long noncoding RNAs are spatially correlated with transcription factors and regulate lung development.

Genes Dev 2014 Jun;28(12):1363-79

Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Department of Medicine, Institute for Regenerative Medicine, Cardiovascular Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.

Long noncoding RNAs (lncRNAs) are thought to play important roles in regulating gene transcription, but few have well-defined expression patterns or known biological functions during mammalian development. Using a conservative pipeline to identify lncRNAs that have important biological functions, we identified 363 lncRNAs in the lung and foregut endoderm. Importantly, we show that these lncRNAs are spatially correlated with transcription factors across the genome. In-depth expression analyses of lncRNAs with genomic loci adjacent to the critical transcription factors Nkx2.1, Gata6, Foxa2 (forkhead box a2), and Foxf1 mimic the expression patterns of their protein-coding neighbor. Loss-of-function analysis demonstrates that two lncRNAs, LL18/NANCI (Nkx2.1-associated noncoding intergenic RNA) and LL34, play distinct roles in endoderm development by controlling expression of critical developmental transcription factors and pathways, including retinoic acid signaling. In particular, we show that LL18/NANCI acts upstream of Nkx2.1 and downstream from Wnt signaling to regulate lung endoderm gene expression. These studies reveal that lncRNAs play an important role in foregut and lung endoderm development by regulating multiple aspects of gene transcription, often through regulation of transcription factor expression.
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http://dx.doi.org/10.1101/gad.238782.114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4066405PMC
June 2014

Clinical features of three girls with mosaic genome-wide paternal uniparental isodisomy.

Am J Med Genet A 2013 Aug 26;161A(8):1929-39. Epub 2013 Jun 26.

The Division of Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.

Here we describe three subjects with mosaic genome-wide paternal uniparental isodisomy (GWpUPD) each of whom presented initially with overgrowth, hemihyperplasia (HH), and hyperinsulinism (HI). Due to the severity of findings and the presence of additional features, SNP array testing was performed, which demonstrated mosaic GWpUPD. Comparing these individuals to 10 other live-born subjects reported in the literature, the predominant phenotype is that of pUPD11 and notable for a very high incidence of tumor development. Our subjects developed non-metastatic tumors of the adrenal gland, kidney, and/or liver. All three subjects had pancreatic hyperplasia resulting in HI. Notably, our subjects to date display minimal features of other diseases associated with paternal UPD loci. Both children who survived the neonatal period have displayed near-normal cognitive development, likely due to a favorable tissue distribution of the mosaicism. To understand the range of UPD mosaicism levels, we studied multiple tissues using SNP array analysis and detected levels of 5-95%, roughly correlating with the extent of tissue involvement. Given the rapidity of tumor growth and the difficulty distinguishing malignant and benign tumors in these GWpUPD subjects, we have utilized increased frequency of ultrasound (US) and alpha-fetoprotein (AFP) screening in the first years of life. Because of a later age of onset of additional tumors, continued tumor surveillance into adolescence may need to be considered in these rare patients.
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http://dx.doi.org/10.1002/ajmg.a.36045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4082120PMC
August 2013

Expanding the differential diagnosis of fetal hydrops: an unusual prenatal presentation of megalencephaly-capillary malformation syndrome.

Prenat Diagn 2013 Oct 23;33(10):1010-2. Epub 2013 Jul 23.

Division of Human Genetics, Department of Pediatrics, University of Pennsylvania School of Medicine and The Children's Hospital of Philadelphia, Philadelphia, PA, USA; Division of Neonatology, Department of Pediatrics, University of Pennsylvania School of Medicine and The Children's Hospital of Philadelphia, Philadelphia, PA, USA.

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http://dx.doi.org/10.1002/pd.4178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3962827PMC
October 2013

Novel FOXF1 mutations in sporadic and familial cases of alveolar capillary dysplasia with misaligned pulmonary veins imply a role for its DNA binding domain.

Hum Mutat 2013 Jun 12;34(6):801-11. Epub 2013 Apr 12.

Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA.

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare and lethal developmental disorder of the lung defined by a constellation of characteristic histopathological features. Nonpulmonary anomalies involving organs of gastrointestinal, cardiovascular, and genitourinary systems have been identified in approximately 80% of patients with ACD/MPV. We have collected DNA and pathological samples from more than 90 infants with ACD/MPV and their family members. Since the publication of our initial report of four point mutations and 10 deletions, we have identified an additional 38 novel nonsynonymous mutations of FOXF1 (nine nonsense, seven frameshift, one inframe deletion, 20 missense, and one no stop). This report represents an up to date list of all known FOXF1 mutations to the best of our knowledge. Majority of the cases are sporadic. We report four familial cases of which three show maternal inheritance, consistent with paternal imprinting of the gene. Twenty five mutations (60%) are located within the putative DNA-binding domain, indicating its plausible role in FOXF1 function. Five mutations map to the second exon. We identified two additional genic and eight genomic deletions upstream to FOXF1. These results corroborate and extend our previous observations and further establish involvement of FOXF1 in ACD/MPV and lung organogenesis.
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http://dx.doi.org/10.1002/humu.22313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3663886PMC
June 2013

Unusual cardiac "masses" in a newborn with infantile pompe disease.

JIMD Rep 2012 13;5:17-20. Epub 2011 Dec 13.

Department of Pediatrics, Section of Biochemical Genetics, The Children's Hospital of Philadelphia, 34th St & Civic Center Blvd, Philadelphia, PA, 19104, USA.

Glycogen storage disease type II (OMIM #232300), or Pompe disease, may present in the newborn period with moderate-to-severe biventricular hypertrophy with or without left ventricular outflow tract obstruction that typically leads to death from cardiorespiratory failure in the first year of life. Glycogen deposition tends to be uniform, and is only occasionally accompanied by patchy areas of fibrosis. Here, we present an infant identified with biventricular hypertrophy and cardiac masses by prenatal ultrasound. Postnatal molecular studies did not support the diagnosis of tuberous sclerosis in this case. Additional evaluation for infantile hypertrophic cardiomyopathy confirmed the diagnosis of Pompe disease. We discuss whether the "cardiac masses," which brought this infant to medical attention and facilitated an early diagnosis of Pompe disease, may represent an unusual manifestation of GSD type II or the coincidental occurrence of an unrelated disease process.
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http://dx.doi.org/10.1007/8904_2011_85DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3509919PMC
February 2013

Novel FREM1 mutations expand the phenotypic spectrum associated with Manitoba-oculo-tricho-anal (MOTA) syndrome and bifid nose renal agenesis anorectal malformations (BNAR) syndrome.

Am J Med Genet A 2013 Mar 8;161A(3):473-8. Epub 2013 Feb 8.

Division of Genetics, Department of Pediatrics, University of California, San Francisco, California 94143-0748, USA.

Loss of function mutations in FREM1 have been demonstrated in Manitoba-oculo-tricho-anal (MOTA) syndrome and Bifid Nose Renal Agenesis and Anorectal malformations (BNAR) syndrome, but the wider phenotypic spectrum that is associated with FREM1 mutations remains to be defined. We screened three probands with phenotypic features of MOTA syndrome. In one severely affected infant who was diagnosed with MOTA syndrome because of bilateral eyelid colobomas, a bifid nasal tip, hydrometrocolpos and vaginal atresia, we found two nonsense mutations that likely result in complete loss of FREM1 function. This infant also had renal dysplasia, a finding more consistent with BNAR syndrome. Another male who was homozygous for a novel stop mutation had an extensive eyelid colobomas, corneopalpebral synechiae, and unilateral renal agenesis. A third male child diagnosed with MOTA syndrome because of corneopalpebral synechiae and eyelid colobomas had a homozygous splice site mutation in FREM1. These cases illustrate that disruption of the FREM1 gene can produce a spectrum of clinical manifestations encompassing the previously described MOTA and BNAR syndromes, and that features of both syndromes may be seen in the same individual. The phenotype of FREM1-related disorders is thus more pleiotropic than for MOTA and BNAR syndrome alone and more closely resembles the widespread clinical involvement seen with Fraser syndrome. Moreover, our first case demonstrates that vaginal atresia may be a feature of FREM1-related disorders.
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http://dx.doi.org/10.1002/ajmg.a.35736DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3581754PMC
March 2013

Unraveling the complex genetic underpinnings of asthma and allergic disorders.

Curr Opin Allergy Clin Immunol 2010 Oct;10(5):434-42

Department of Pediatrics, Baylor College of Medicine & Texas Children's Hospital, Texas, USA.

Purpose Of Review: Asthma and other allergic diseases are complex genetic disorders that result from interactions between multiple genes and environmental factors. In this review, we summarize findings from candidate gene analyses, discuss the recent success of genome-wide association (GWA) studies, and outline challenges facing the field.

Recent Findings: In the past year, five GWA studies have been reported for asthma, one for atopic dermatitis, and four for intermediate phenotypes using quantitative trait loci. These results have in general been more robust to replication than prior candidate gene studies, and have allowed the identification of novel loci for both asthma (i.e. 1q31, 9q21.31) and atopic dermatitis (11q13).

Summary: The integration of results from recent GWA studies with careful analyses of candidate gene associations studies has confirmed the importance of immune detection and TH2-cell mediated immune responses in the pathogenesis of allergic disease, and has raised new interest in the role of epithelial barrier function and tissue-level responses. GWA studies appear to provide a robust way to identify novel gene loci contributing to disease susceptibility. Dissecting gene-gene and gene-environment interactions, and exploring the contribution of epigenetic phenomena to allergic disease susceptibility remain important challenges to understanding the complex nature of asthma and other allergic diseases.
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http://dx.doi.org/10.1097/ACI.0b013e32833da71dDOI Listing
October 2010

Potocki-Shaffer syndrome: comprehensive clinical assessment, review of the literature, and proposals for medical management.

Am J Med Genet A 2010 Mar;152A(3):565-72

Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA.

Potocki-Shaffer syndrome is a rare contiguous gene deletion syndrome due to haploinsufficiency of the 11p11.2p12 region and is characterized by craniofacial abnormalities, developmental delay, intellectual disability, multiple exostoses, and biparietal foramina. In this study, six patients with the Potocki-Shaffer syndrome were identified and evaluated using a multidisciplinary protocol that included assessments by a geneticist, ophthalmologist, otolaryngologist, orthopedist, nephrologist, audiologist, and neuropsychologist. Diagnostic studies included skeletal survey, magnetic resonance imaging of the brain, renal ultrasound, complete blood count, comprehensive metabolic panel, thyroid studies, and urinalysis. Using array comparative genomic hybridization, we further characterized the deletion in five of these patients. The results of these evaluations were combined with a comprehensive review of reported cases. Our data highlight the characteristic facial features, biparietal foramina, moderate-to-severe developmental delay and intellectual disability, myopia and strabismus, and multiple exostoses seen with this disorder. We also identify for the first time an association of Potocki-Shaffer syndrome with sensorineural hearing loss and autistic behaviors. Finally, we provide recommendations for the health maintenance of patients with Potocki-Shaffer syndrome.
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http://dx.doi.org/10.1002/ajmg.a.33245DOI Listing
March 2010

Fate of the residual distal and proximal aorta after acute type a dissection repair using a contemporary surgical reconstruction algorithm.

Ann Thorac Surg 2007 Dec;84(6):1955-64; discussion 1955-64

Division of Cardiothoracic Surgery, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania, USA.

Background: In this study, we evaluated the long-term results of our contemporary, standardized surgical management algorithm for repair of acute type A aortic dissections. Prior reports have analyzed heterogeneous techniques and populations.

Methods: From 1993 to 2004, 221 consecutive patients underwent repair of acute type A aortic dissection at our aortic center. Hemiarch repair was performed in 97.7% (216 of 221), and total arch in 2.3% (5 of 221). Of these, 72.9% (161 of 221) underwent aortic valve resuspension, and 27.1% (60 of 221) had aortic root replacement.

Results: In-hospital mortality for a primary operation was 12.7% (28 of 221). Actuarial survival was 79.2% at 1 year, 62.8% at 5 years, and 46.3% at 10 years. Significant risk factors for decreased survival included prior stroke, cerebral malperfusion, and length of cardiopulmonary bypass. Freedom from proximal reoperation after aortic valve resuspension was 94.6% at 5 years and 76.8% at 10 years, with cardiac malperfusion as the main risk factor. Freedom from distal reoperation was 87.6% at 5 years and 76.4% at 10 years, with Marfan syndrome, age, and extent of dissection as significant risk factors for reoperation. In-hospital mortality was 18.2% (2 of 11) after proximal reoperation and 31.2% (5 of 16) after distal reoperation.

Conclusions: We report improved long-term durability of our proximal root repair, with cardiac malperfusion as a significant risk factor. Marfan disease, younger age, and DeBakey type I dissection are risk factors for distal reoperation. To further improve long-term outcome, means to prevent progression of distal aortic disease need to be developed.
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http://dx.doi.org/10.1016/j.athoracsur.2007.07.017DOI Listing
December 2007