Angela Scheuerle

Phenotypic spectrum and genotype–phenotype correlations of NRXN1 exon deletions

Copy number variants (CNVs) and intragenic rearrangements of the NRXN1 (neurexin 1) gene are associated with a wide spectrum of developmental and neuropsychiatric disorders, including intellectual disability, speech delay, autism spectrum disorders (ASDs), hypotonia and schizophrenia. We performed a detailed clinical and molecular characterization of 24 patients who underwent clinical microarray analysis and had intragenic deletions of NRXN1. Seventeen of these deletions involved exons of NRXN1, whereas seven deleted intronic sequences only. The patients with exonic deletions manifested developmental delay/intellectual disability (93%), infantile hypotonia (59%) and ASDs (56%). Congenital malformations and dysmorphic features appeared infrequently and inconsistently among this population of patients with NRXN1 deletions. The more C-terminal deletions, including those affecting the β isoform of neurexin 1, manifested increased head size and a high frequency of seizure disorder (88%) when compared with N-terminal deletions of NRXN1.

The Xolair Pregnancy Registry (EXPECT): The safety of omalizumab use during pregnancy

BACKGROUND For many asthma medications, pregnancy safety data remains insufficient. OBJECTIVE The omalizumab pregnancy registry, EXPECT, evaluates maternal, pregnancy, and infant outcomes after exposure to omalizumab, including incidence of congenital anomalies. METHODS EXPECT is a prospective, observational study of pregnant women exposed to ≥1 dose of omalizumab within 8 weeks prior to conception or at any time during pregnancy. Primary outcome measures include rates of live births, elective terminations, stillbirths, and congenital anomalies. Data were collected at enrollment, each trimester, birth, and every 6 months up to 18 months post-delivery. RESULTS As of November 2012, 188 of 191 pregnant women were exposed to omalizumab during their first trimester. Of 169 pregnancies with known outcomes (median exposure during pregnancy, 8.8 months), there were 156 live births of 160 infants (4 twin pairs), 1 fetal death/stillbirth, 11 spontaneous abortions, and 1 elective termination. Among 152 singleton infants, 22 (14.5%) were born prematurely. Of 147 singleton infants with weight data, 16 (10.9%) were small for gestational age. Among 125 singleton full-term infants, 4 (3.2%) had low birth weights. Overall, 20 infants had congenital anomalies confirmed, 7 (4.4%) of whom had 1 major defect. No pattern of anomalies was observed. CONCLUSIONS To date, proportions of major congenital anomalies, prematurity, low birth weight, and small size for gestational age observed in the EXPECT registry are not inconsistent with findings from other studies in this asthma population. Recognizing the small sample size available, no apparent increased birth prevalence of major anomalies or patterns of major anomalies has been observed.

Loss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large fontanelle and X-linked inheritance

Cornelia de Lange syndrome (CdLS) is a multisystem genetic disorder with distinct facies, growth failure, intellectual disability, distal limb anomalies, gastrointestinal and neurological disease. Mutations in NIPBL, encoding a cohesin regulatory protein, account for >80% of cases with typical facies. Mutations in the core cohesin complex proteins, encoded by the SMC1A, SMC3 and RAD21 genes, together account for ∼5% of subjects, often with atypical CdLS features. Recently, we identified mutations in the X-linked gene HDAC8 as the cause of a small number of CdLS cases. Here, we report a cohort of 38 individuals with an emerging spectrum of features caused by HDAC8 mutations. For several individuals, the diagnosis of CdLS was not considered prior to genomic testing. Most mutations identified are missense and de novo. Many cases are heterozygous females, each with marked skewing of X-inactivation in peripheral blood DNA. We also identified eight hemizygous males who are more severely affected. The craniofacial appearance caused by HDAC8 mutations overlaps that of typical CdLS but often displays delayed anterior fontanelle closure, ocular hypertelorism, hooding of the eyelids, a broader nose and dental anomalies, which may be useful discriminating features. HDAC8 encodes the lysine deacetylase for the cohesin subunit SMC3 and analysis of the functional consequences of the missense mutations indicates that all cause a loss of enzymatic function. These data demonstrate that loss-of-function mutations in HDAC8 cause a range of overlapping human developmental phenotypes, including a phenotypically distinct subgroup of CdLS.

Insight into IKBKG/NEMO Locus: Report of New Mutations and Complex Genomic Rearrangements Leading to Incontinentia Pigmenti Disease

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.

Frequency of Prenatal Diagnosis of Birth Defects in Houston, Galveston and the Lower Rio Grande Valley, Texas 1995

Background: Estimates of the proportion of birth defects diagnosed before birth exist for only a few types of birth defects and for a few geographic regions in the United States. This population-based study examines rates of prenatal diagnosis for previously unstudied birth defects in a new geographic region. Methods: Active surveillance of 23 categories of birth defects among 111,902 infants born in 77 birthing hospitals in Texas in 1995 identified 852 infants or fetuses with major birth defects. Surveillance was conducted by the Texas Birth Defects Monitoring Program of the Texas Department of Health. Two regions were covered, the Houston/Galveston metropolitan area as well as the Lower Rio Grande Valley of Texas. Rates of prenatal diagnosis were evaluated for 23 different types of birth defects, using proportions and 95% confidence intervals. Results: One third of the 852 infants or fetuses with birth defects were prenatally diagnosed. Diagnosis rates varied greatly depending on the type of birth defects and were lower among infants born to Black and Hispanic women. More than 60% of anencephaly, encephalocele, gastroschisis and trisomies 13 and 18 were diagnosed antenatally. Many of the fetuses that were electively terminated had birth defects or combinations of birth defects that were potentially lethal. Prevalence rates for birth defects generally do not include fetuses that die or are electively terminated before 20 weeks of gestation. Thus, 36% of anencephaly, 21% of omphalocele, 15% of encephalocele and between 7 and 10% of spina bifida, hydrocephaly, renal agenesis, and trisomies 13, 18, and 21 were not included in our published rates. Conclusions: Published rates for specific types of birth defects are spuriously low. This should be considered when investigating alleged clusters and comparing rates of birth defects across geographic areas. Since many elective abortions are for lethal or potentially lethal birth defects, a major effect of prenatal diagnosis is the resultant decrease in infant mortality attributable to birth defects.

High Incidence of Noonan Syndrome Features Including Short Stature and Pulmonic Stenosis in Patients carrying NF1 Missense Mutations Affecting p.Arg1809: Genotype–Phenotype Correlation

Neurofibromatosis type 1 (NF1) is one of the most frequent genetic disorders, affecting 1:3,000 worldwide. Identification of genotype–phenotype correlations is challenging because of the wide range clinical variability, the progressive nature of the disorder, and extreme diversity of the mutational spectrum. We report 136 individuals with a distinct phenotype carrying one of five different NF1 missense mutations affecting p.Arg1809. Patients presented with multiple café‐au‐lait macules (CALM) with or without freckling and Lisch nodules, but no externally visible plexiform neurofibromas or clear cutaneous neurofibromas were found. About 25% of the individuals had Noonan‐like features. Pulmonic stenosis and short stature were significantly more prevalent compared with classic cohorts (P < 0.0001). Developmental delays and/or learning disabilities were reported in over 50% of patients. Melanocytes cultured from a CALM in a segmental NF1‐patient showed two different somatic NF1 mutations, p.Arg1809Cys and a multi‐exon deletion, providing genetic evidence that p.Arg1809Cys is a loss‐of‐function mutation in the melanocytes and causes a pigmentary phenotype. Constitutional missense mutations at p.Arg1809 affect 1.23% of unrelated NF1 probands in the UAB cohort, therefore this specific NF1 genotype–phenotype correlation will affect counseling and management of a significant number of patients.

PARK2 copy number aberrations in two children presenting with autism spectrum disorder: further support of an association and possible evidence for a new microdeletion/microduplication syndrome.

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.

The prevalence and predictors of anencephaly and spina bifida in Texas

Texas shares a 1255-mile border with Mexico and encompasses a variety of ecosystems, industries and other potential environmental exposures. The Texas Birth Defects Registry is an active surveillance system which covers all pregnancy outcomes (livebirths, fetal deaths and elective pregnancy terminations). This study describes the occurrence and the predictors of neural tube defects (anencephaly and spina bifida) in Texas between 1999 and 2003. Birth prevalence, crude and adjusted prevalence ratios and 95% confidence intervals were calculated using Poisson regression, for each defect, by fetal/infant sex, delivery year and maternal sociodemographic characteristics. Among approximately 1.8 million livebirths, a total of 1157 neural tube defects cases were ascertained by the Registry, resulting in an overall prevalence of 6.33 cases per 10 000 livebirths. The prevalences of anencephaly and spina bifida were 2.81 and 3.52 per 10 000 livebirths respectively. Prevalences of both defects were highest in Hispanics, among mothers living along the border with Mexico, among women of higher parity and among mothers who were 40+ years of age. In addition, the prevalence of each defect was higher among women with no record of prenatal care and among women with less than 7 years of education. Hispanic ethnicity was an important predictor for anencephaly, along with sex, maternal age, parity and border residence. However, only border residence and delivery year were significant predictors for spina bifida.

Use of Oral Contraceptives in Pregnancy and Major Structural Birth Defects in Offspring

Background: Oral contraceptives (OCs) are the most commonly used reversible contraceptive method among US women. Although the majority of previous studies have reported no association between OC use during pregnancy and birth defects, some studies have reported increased occurrence of neural tube defects, limb reduction defects, and urinary tract anomalies. Methods: We assessed OC use among mothers who participated in the multisite, case-control, National Birth Defects Prevention Study. Mothers of 9986 infants with 32 types of birth defects and 4000 infants without birth defects were included. Results: Maternal OC use during the first 3 months of pregnancy was associated with an increased odds ratio for 2 of 32 birth defects: hypoplastic left heart syndrome (adjusted odds ratio = 2.3 [95% confidence interval = 1.3–4.3) and gastroschisis (1.8 [1.3–2.7]). Conclusion: Previous reports of associations between OC use and specific types of anomalies were not corroborated. Given that associations were assessed for 32 types of birth defects, our findings of 2 increased associations between OC use and gastroschisis and hypoplastic left heart syndrome should be interpreted as hypotheses until they can be evaluated further. Overall, our findings are consistent with the majority of previous studies that found women who use OCs during early pregnancy have no increased risk for most types of major congenital malformations.

Maternal residential proximity to waste sites and industrial facilities and conotruncal heart defects in offspring

Most studies of the relationship between maternal residential proximity to sources of environmental pollution and congenital cardiovascular malformations have combined heart defects into one group or broad subgroups. The current case-control study examined whether risk of conotruncal heart defects, including subsets of specific defects, was associated with maternal residential proximity to hazardous waste sites and industrial facilities with recorded air emissions. Texas Birth Defects Registry cases were linked to their birth or fetal death certificate. Controls without birth defects were randomly selected from birth certificates. Distances from maternal addresses at delivery to National Priority List (NPL) waste sites, state superfund waste sites, and Toxic Release Inventory (TRI) facilities were determined for 1244 cases (89.5% of those eligible) and 4368 controls (88.0%). Living within 1 mile of a hazardous waste site was not associated with risk of conotruncal heart defects [adjusted odds ratio (aOR) = 0.83, 95% confidence interval (CI) = 0.54, 1.27]. This was true whether looking at most types of defects or waste sites. Only truncus arteriosus showed statistically elevated ORs with any waste site (crude OR: 2.80, 95% CI 1.19, 6.54) and with NPL sites (crude OR: 4.63, 95% CI 1.18, 13.15; aOR 4.99, 95% CI 1.26, 14.51), but the latter was based on only four exposed cases. There was minimal association between conotruncal heart defects and proximity to TRI facilities (aOR = 1.10, 95% CI = 0.91, 1.33). Stratification by maternal age or race/ethnic group made little difference in effect estimates for waste sites or industrial facilities. In this study population, maternal residential proximity to waste sites or industries with reported air emissions was not associated with conotruncal heart defects or its subtypes in offspring, with the exception of truncus arteriosus.