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Dallas, TX, United States

Scheuerle A.,Tesserae Genetics | Wilson K.,Southwestern University
American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics | Year: 2011

Microdeletions of PARK2 have been reported previously in seven patients with autism spectrum disorder. There are no reports of PARK2 microduplications in this population. Presented are two patients, one with deletion and the other with duplication, both with autism spectrum disorder, though their syndromic phenotypes vary. The deletion patient is cognitively normal and ectomorphic: the duplication patient is cognitively impaired, underweight and short. Further, the microduplication patient has demonstrated adverse medication reactions to psychotropic medications active in the dopamine metabolic pathway: cyclopentolate, lisdexamfetamine, methylphenidate. These patients support an association between PARK2 mutations and autism spectrum disorder and suggest that duplications may be equally causative. It is hypothesized that the disparate patient phenotypes may represent a deletion/duplication syndrome and that the adverse medication reactions may be a pharmacogenetic phenomenon. © 2011 Wiley-Liss, Inc.

Case A.P.,Birth Defects Epidemiology and Surveillance Branch | Colpitts L.R.,Tesserae Genetics | Langlois P.H.,Birth Defects Epidemiology and Surveillance Branch | Scheuerle A.E.,Birth Defects Epidemiology and Surveillance Branch
Journal of Maternal-Fetal and Neonatal Medicine | Year: 2012

Objective.To describe the patterns of cesarean section (CS) and vaginal delivery by type of birth defect and determine whether prenatal diagnosis predicts a higher or lower likelihood of CS for selected defect categories. Methods.Data from a large population-based registry were analyzed to determine percentages of vaginal versus CS delivery for each of 49 categories of birth defects. Odds ratios and statistical significance were computed to determine if a record of prenatal diagnosis (PND) predicted delivery mode. Cases were liveborn children with any of these defects born in Texas between 1997 and 2005. Results.Forty-three percent of infants in the study were delivered by CS, with a range of 25.3% (aniridia) to 62.4% (spina bifida). A record of prenatal diagnosis of the primary assigned birth defect was found in 43.0% of all records but varied substantially by defect category. PND significantly predicted higher CS percentages for spina bifida without anencephaly, encephalocele, hydrocephaly, transposition of the great vessels, ventricular septal defect, pulmonary valve atresia/stenosis, craniosynostosis, diaphragmatic hernia, gastroschisis, and trisomy 21. Vaginal delivery was predicted by PND of anencephaly, agenesis, aplasia, or hypoplasia of the lung, renal agenesis or dysgenesis, and trisomy 18. Conclusion.Texas children with birth defects are more likely to have been delivered by CS than the population in general. For several types of defects, prenatal diagnosis is predictive of higher odds of CS; for others, especially fatal defects, PND predicts lower CS likelihood. © 2012 Informa UK, Ltd.

Simmons K.,University of Houston | Hashmi S.S.,University of Houston | Scheuerle A.,Tesserae Genetics | Canfield M.,Birth Defects Epidemiology and Surveillance Branch | Hecht J.T.,University of Houston
Birth Defects Research Part A - Clinical and Molecular Teratology | Year: 2014

BACKGROUND: Natural history studies performed 30 years ago identifying higher mortality among children born with achondroplasia, a genetic dwarfing condition, resulted in clinical recommendations aimed at improving mortality in childhood. The objective of this study was to determine if mortality rates have changed over the past few decades. METHODS: Children born with achondroplasia during 1996 to 2003 were ascertained from the Texas Birth Defects Registry and matched with death certificate data from the Bureau of Vital Statistics through 2007. Infant and overall mortality rates, both crude and standardized to the 2005 (SMR2005) and 1975 (SMR1975) U.S. populations, were calculated. RESULTS: 106 children born with achondroplasia were identified. Four deaths were reported, with all occurring in the first year of life (mortality rate: 41.4 /1000 live-births). Infant mortality was higher when standardized to the 2005 U.S. population (SMR2005:6.02, 95% CI:1.64-15.42) than the 1975 population (SMR1975:2.58, 95% CI:0.70-6.61). CONCLUSION: The higher SMR2005 compared with SMR1975, along with the fact that SMR1975 was nearly half that of a previous cohort reported 25 years ago (rate ratio: 0.53, 95% CI: 0.11-2.25), reflect a discrepancy in the changes in mortality in the overall population and in our cohort. Although an overall improvement in mortality, especially after the first year of life, is observed in our cohort, children with achondroplasia are still at a much higher risk of death compared with the general population. A longer follow-up is needed to elucidate whether evaluation/intervention changes have resulted in significant improvement in long-term survival among these patients. © 2014 Wiley Periodicals, Inc.

Moffitt K.B.,Birth Defects Epidemiology and Surveillance Branch | Abiri O.O.,Texas A&M University | Scheuerle A.E.,Tesserae Genetics | Langlois P.H.,Birth Defects Epidemiology and Surveillance Branch
Birth Defects Research Part A - Clinical and Molecular Teratology | Year: 2011

Background Few population-based studies exist on descriptive epidemiologic characteristics of rare heritable birth defects. The number of birth defect cases in the Texas Birth Defects Registry (one of the largest active birth defects surveillance systems in the world) enabled us to examine six different heritable disorders (aqueductal stenosis, infantile polycystic kidney disease, achondroplasia, thanatophoric dwarfism, chondrodysplasia/dwarfism not otherwise specified (NOS), and osteogenesis imperfecta) for a variety of descriptive demographic variables. Methods The Texas Birth Defects Registry was used to identify infants or fetuses with heritable birth defects. Crude prevalence rates were calculated and Poisson regression was used to test the association of each demographic variable (e.g., maternal age) with each of the selected genetic birth defects. Results White non-Hispanics exhibited higher rates of achondroplasia and osteogenesis imperfecta than other race/ethnic groups. Lower maternal education level and to a lesser extent, paternal education level, was associated with higher rates of several disorders. The birth prevalence rate for achondroplasia decreased from 1999 through 2006. Conclusion The use of a large birth defects registry provides a sufficient count of cases to perform some basic epidemiologic analysis on selected rare heritable birth defects. © 2011 Wiley Periodicals, Inc.

Conte M.I.,CNR Institute of Neuroscience | Pescatore A.,CNR Institute of Neuroscience | Paciolla M.,CNR Institute of Neuroscience | Esposito E.,CNR Institute of Neuroscience | And 19 more authors.
Human Mutation | Year: 2014

Incontinentia pigmenti (IP) is an X-linked-dominant Mendelian disorder caused by mutation in the IKBKG/NEMO gene, encoding for NEMO/IKKgamma, a regulatory protein of nuclear factor kappaB (NF-kB) signaling. In more than 80% of cases, IP is due to recurrent or nonrecurrent deletions causing loss-of-function (LoF) of NEMO/IKKgamma. We review how the local architecture of the IKBKG/NEMO locus with segmental duplication and a high frequency of repetitive elements favor de novo aberrant recombination through different mechanisms producing genomic microdeletion. We report here a new microindel (c.436_471delinsT, p.Val146X) arising through a DNA-replication-repair fork-stalling-and-template-switching and microhomology-mediated-end-joining mechanism in a sporadic IP case. The LoF mutations of IKBKG/NEMO leading to IP include small insertions/deletions (indel) causing frameshift and premature stop codons, which account for 10% of cases. We here present 21 point mutations previously unreported, which further extend the spectrum of pathologic variants: 14/21 predict LoF because of premature stop codon (6/14) or frameshift (8/14), whereas 7/21 predict a partial loss of NEMO/IKKgamma activity (two splicing and five missense). We review how the analysis of IP-associated IKBKG/NEMO hypomorphic mutants has contributed to the understanding of the pathophysiological mechanism of IP disease and has provided important information on affected NF-kB signaling. We built a locus-specific database listing all IKBKG/NEMO variants, accessible at http://IKBKG.lovd.nl. © 2013 WILEY PERIODICALS, INC.

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