Prenatal diagnosis of Baraitser – Winter syndrome using exome sequencing: Clinical report and review of literature

Baraitser – Winter Cerebrofrontofacial Syndrome (BWCFF) is a rare disorder characterized by facial dysmorphism and mental retardation of varying grades. The clinical phenotype of BWCFF indicates variable phenotypic expression involving various congenital malformations such as cardiac, renal and musculoskeletal abnormalities. Nevertheless, the prenatal presentation of BWCFF is rarely described, making prenatal diagnosis challenging. This report describes a prenatal diagnosis of BWCFF syndrome to date; a case of a fetus with intrauterine growth restriction, increased nuchal fold, bilateral hydronerphosis, rocker bottom foot and clubfoot detected on Anomaly Scan is outlined. Molecular karyotype failed to detect any abnormality. Assessment with Next Generation Sequencing was then performed, revealing a heterozygous de novo mutation in ACTB gene setting the diagnosis of BWCFF.     

Further delineation of putative ACTB loss‐of‐function variants: A 4‐patient series

ACTB encodes β‐cytoplasmic actin, an essential component of the cytoskeleton. Based on chromosome 7p22.1 deletions that include the ACTB locus and on rare truncating ACTB variants, a phenotype resulting from ACTB haploinsufficiency was recently proposed. We report putative ACTB loss‐of‐function variants in four patients. To the best of our knowledge, we report the first 7p22.1 microdeletion confined to ACTB and the second ACTB frameshifting mutation that predicts mRNA decay. A de‐novo ACTB p.(Gly302Ala) mutation affects β‐cytoplasmic actin distribution. All four patients share a facial gestalt that is distinct from that of individuals with dominant‐negative ACTB variants in Baraitser‐Winter cerebrofrontofacial syndrome. Two of our patients had strikingly thin and sparse scalp hair. One patient had sagittal craniosynostosis and hypospadias. All three affected male children have attention deficits and mild global developmental delay. Mild intellectual disability was present in only one patient. Heterozygous ACTB deletion can allow for normal psychomotor function.     

Severe forms of Baraitser–Winter syndrome are caused by ACTB mutations rather than ACTG1 mutations

ACTB and ACTG1 mutations have recently been reported to cause Baraitser–Winter syndrome (BRWS) – a rare condition characterized by ptosis, colobomata, neuronal migration disorder, distinct facial anomalies and intellectual disability. One of the patients carrying an ACTB mutation was previously diagnosed with Fryns–Aftimos syndrome (FAS), which is a rare and severe, multiple congenital anomaly (MCA) syndrome whose symptoms partially overlap with that of BRWS. However, several patients with Fryns–Aftimos were considered not to fit into the ACTB and ACTG1 spectrum because of their severe impairment and additional malformations. We report on three patients who had been diagnosed with FAS. All three patients carry a mutation in the ACTB gene. On the basis of the ACTB mutations and analysis of the clinical findings, we reclassify the diagnosis of these patients as severe BRWS. We suggest that mutations in ACTB cause a distinctly more severe phenotype than ACTG1 mutations, despite the structural similarity of beta- and gamma-actins and their overlapping expression pattern. We expand the spectrum of BRWS and confirm that FAS is not a separate entity but an early and severe manifestation of BRWS.     

An Emerging Female Phenotype with Loss‐of‐Function Mutations in the Aristaless‐Related Homeodomain Transcription Factor ARX

The devastating clinical presentation of X‐linked lissencephaly with abnormal genitalia (XLAG) is invariably caused by loss‐of‐function mutations in the Aristaless‐related homeobox (ARX) gene. Mutations in this X‐chromosome gene contribute to intellectual disability (ID) with co‐morbidities including seizures and movement disorders such as dystonia in affected males. The detection of affected females with mutations in ARX is increasing. We present a family with multiple affected individuals, including two females. Two male siblings presenting with XLAG were deceased prior to full‐term gestation or within the first few weeks of life. Of the two female siblings, one presented with behavioral disturbances, mild ID, a seizure disorder, and complete agenesis of the corpus callosum (ACC), similar to the mother's phenotype. A novel insertion mutation in Exon 2 of ARX was identified, c.982delCinsTTT predicted to cause a frameshift at p.(Q328Ffs^*37). Our finding is consistent with loss‐of‐function mutations in ARX causing XLAG in hemizygous males and extends the findings of ID and seizures in heterozygous females. We review the reported phenotypes of females with mutations in ARX and highlight the importance of screening ARX in male and female patients with ID, seizures, and in particular with complete ACC.     

Functional Analysis of a De Novo ACTB Mutation in a Patient with Atypical Baraitser–Winter Syndrome

Exome sequence analysis can be instrumental in identifying the genetic etiology behind atypical disease. We report a patient presenting with microcephaly, dysmorphic features, and intellectual disability with a tentative diagnosis of Dubowitz syndrome. Exome analysis was performed on the patient and both parents. A de novo missense variant was identified in ACTB, c.349G>A, p.E117K. Recent work in Baraitser–Winter syndrome has identified ACTB and ACTG1 mutations in a cohort of individuals, and we rediagnosed the patient with atypical Baraitser–Winter syndrome. We performed functional characterization of the variant actin and show that it alters cell adhesion and polymer formation supporting its role in disease. We present the clinical findings in the patient, comparison of this patient to other patients with ACTB/ACTG1 mutations, and results from actin functional studies that demonstrate novel functional attributes of this mutant protein.     

A Clinical and Molecular Analysis of Branchio‐Oculo‐Facial Syndrome Patients in Russia Revealed New Mutations in TFAP2A

Branchio‐oculo‐facial syndrome (BOFS, OMIM# 113620) is a rare autosomal dominant disorder characterised by branchial cleft sinus defects, ocular anomalies and facial dysmorphisms, including lip or palate cleft or pseudocleft, and is associated with mutations in the TFAP2A gene. Here, we performed clinical analysis and mutation diagnostics in seven BOFS patients in Russia. The phenotypic presentation of BOFS observed in three patients showed high heterogeneity, including variation in its main clinical manifestations (linear loci of cervical cutaneous aplasia, ocular anomalies and orofacial cleft). In certain other cases, isolated ocular anomalies, or an orofacial cleft with accessory BOFS symptoms, were observed. In five BOFS patients, conductive hearing loss was diagnosed. Direct sequencing of the coding region of the TFAP2A gene revealed missense mutations in four BOFS patients. One patient was observed to have a previously described mutation (p.Arg251Gly), while three patients from two families were found to have novel mutations: p.Arg213Ser and p.Val210Asp. These novel mutations were not present in healthy members of the same family and therefore should be classified as de novo.     

ORIGINAL ARTICLE: Enhanced Maternal Anti‐Fetal Immunity Contributes to the Severity of Hypertensive Disorder Complicating Pregnancy

Citation Liu L‐P, Huang W, Lu Y‐C, Liao A‐H. Enhanced maternal anti‐fetal immunity contributes to the severity of hypertensive disorder complicating pregnancy. Am J Reprod Immunol 2010 Problem The aim of this study was to evaluate how fetal monocyte activation and maternal anti‐fetal antigen‐specific antibody‐secreting cells (ASC) affect the severity of hypertensive disorder complicating pregnancy (HDCP). Method of study Forty‐six healthy third‐trimester pregnant women and 20 patients with gestational hypertension, 20 with mild pre‐ecalmpsia and another 20 with severe pre‐eclampsia were included in the study. Interleukin‐6 (IL‐6) release from cord blood monocytes was examined by intracellular cytokine staining and flow cytometric analysis. Moreover, the maternal anti‐fetal antigen‐specific ASC were detected by enzyme‐linked immunospot assay. Results A significantly increased percentage of IL‐6‐positive monocytes were detected in the cord blood of study groups compared with the controls (P < 0.01). The percentage of IL‐6‐positive monocytes was increased as the disease progressed (P < 0.05). There were more anti‐fetal antigen‐specific ASC in the study groups than those in the controls (P < 0.001). Furthermore, the anti‐fetal antigen‐specific ASC showed difference in gestational hypertensive and severe pre‐eclamptic groups (P < 0.05). Conclusion We conclude that the fetal monocyte activation and the increase in maternal anti‐fetal antigen‐specific ASC were related to the incidence and severity of HDCP. These results provide both indirect and direct evidence for the occurrence of exaggerated maternal humoral immunity against the fetal antigens in HDCP.     

Smith‐Lemli‐Opitz (RHS) syndrome: holoprosencephaly and homozygous IVS8‐1G→C genotype

Smith‐Lemli‐Opitz syndrome (RHS) (SLOS, OMIM 270400) is an autosomal recessive disorder of cholesterol biosynthesis caused by mutations of the 3β‐hydroxysterol Δ⁷‐Δ⁸‐reductase gene, DHCR7. We report a fetus with holoprosencephaly and multiple congenital anomalies who was homozygous for the IVS8‐1G→C mutation. Following termination of pregnancy, both the elevated amniotic fluid 7‐dehydrocholesterol level and the DHCR7 mutations were demonstrated. Two other newborn infants with IVS8‐1G→C/IVS8‐1G→C genotype are described. This report illustrates a severe phenotypic extreme of SLOS associated with a null genotype, underscores the complex relationship between SLOS and holoprosencephaly, and discusses the possible pathogenetic mechanisms of the development of holoprosencephaly in SLOS. © 2001 Wiley‐Liss, Inc.     

Neonatal outcomes in offspring of women with anxiety and depression during pregnancy

Summary Background: The presence of mental disorder during pregnancy could affect the offspring.Aims: To examine the effects of anxiety disorder and depression in pregnant women on neonatal outcomes, and to compare neonatal outcomes between offspring of attendees and non-attendees in a general population-based health survey.Method: Pregnant women (n = 680) were identified from the population-based health study of Nord-TrØndelag County (HUNT-2) by linkage with the Medical Birth Registry of Norway. The women rated themselves on the Hospital Anxiety and Depression Rating Scale (HADS). Outcome variables were gestational length, birth weight, and Apgar scores.Results: HADS-defined anxiety disorder during pregnancy was associated with lower Apgar score at one minute (score < 8; odds ratio = 2.27; p = .03) and five minutes (score < 8; odds ratio = 4.49; p = .016). No confounders were identified. Anxiety disorder and depression during pregnancy was not associated with low birth weight or preterm delivery. Offspring of non-attendees had a lower birth weight (77 g; t = 3.27; p = 0.001) and a shorter gestational length (1.8 days; t = 2.76; p = 0.006) than that of offspring of attendees, a difference that may be explained by a higher load of psychosocial risk factors among the non-attendees.Conclusion: In our study that may be biased towards the healthier among pregnant women, anxiety disorder or depression during pregnancy were not strong risk factors for adverse neonatal outcomes although low Apgar score in offspring of women with anxiety disorder may indicate poor neonatal adaptation.     

The new neuromuscular disease related with defects in the ASC‐1 complex: report of a second case confirms ASCC1 involvement

Next‐generation sequencing technology aided the identification of the underlying genetic cause in a female newborn with a severe neuromuscular disorder. The patient presented generalized hypotonia, congenital bone fractures, lack of spontaneous movements and poor respiratory effort. She died within the first days of life. Karyotyping and screening for several genes related with neuromuscular diseases all tested negative. A male sibling was subsequently born with the same clinical presentation. Whole‐exome sequencing was performed with variant filtering assuming a recessive disease model. Analysis focused on genes known to be related firstly with congenital myopathies, extended to muscle diseases and finally to other neuromuscular disorders. No disease‐causing variants were identified. A similar disorder was described in patients with recessive variants in two genes: TRIP4 (three families) and ASCC1 (one family), both encoding subunits of the nuclear activating signal cointegrator 1 (ASC‐1) complex. Our patient was also found to have a homozygous frameshift variant (c.157dupG, p.Glu53Glyfs*19) in ASCC1 , thereby representing the second known case. This confirms ASCC1 involvement in a severe neuromuscular disease lying within the spinal muscular atrophy or primary muscle disease spectra.     

FBXL4 defects are common in patients with congenital lactic acidemia and encephalomyopathic mitochondrial DNA depletion syndrome

Mutations in FBXL4 have recently been recognized to cause a mitochondrial disorder, with clinical features including early onset lactic acidosis, hypotonia, and developmental delay. FBXL4 sequence analysis was performed in 808 subjects suspected to have a mitochondrial disorder. In addition, 28 samples from patients with early onset of lactic acidosis, but without identifiable mutations in 192 genes known to cause mitochondrial diseases, were examined for FBXL4 mutations. Definitive diagnosis was made in 10 new subjects with a total of 7 novel deleterious variants; 5 null and 2 missense substitutions. All patients exhibited congenital lactic acidemia, most of them with severe encephalopathic presentation, and global developmental delay. Overall, FBXL4 defects account for at least 0.7% (6 out of 808) of subjects suspected to have a mitochondrial disorder, and as high as 14.3% (4 out of 28) in young children with congenital lactic acidosis and clinical features of mitochondrial disease. Including FBLX4 in the mitochondrial diseases panel should be particularly important for patients with congenital lactic acidosis.     

Microparticles of pregnant women and preeclamptic patients activate endothelial cells in the presence of monocytes

Citation Lok CAR, Snijder KS, Nieuwland R, Van Der Post JAM, de Vos P, Faas MM. Microparticles of pregnant women and preeclamptic patients activate endothelial cells in the presence of monocytes. Am J Reprod Immunol 2012; 67: 206–215 Problem Preeclampsia is a pregnancy‐specific disorder that may result from an adverse maternal response to circulating placenta‐derived factors, causing a systemic inflammation including endothelial activation. Plasma from preeclamptic patients was shown to induce endothelial activation in the presence of monocytes. We investigated whether microparticles (MP) are the plasma factors causing this activation of endothelial cells. Method of study Monocultures and co‐cultures of monocytes and endothelial cells were incubated with plasma, MP‐poor plasma or isolated MP from non‐pregnant and pregnant women and preeclamptic patients (each n = 8). ICAM‐1 expression was analyzed with flow cytometry. Results The expression of ICAM‐1 was significantly increased in monocytes and endothelial cells in co‐cultures after the addition of isolated MP from preeclamptic patients (P = 0.017) and to a lesser extent in pregnant women (P = 0.012) compared to non‐pregnant controls. Conclusions Microparticles from preeclamptic patients activate endothelial cells in the presence of monocytes. Whether all MP have the same effect on monocytes and endothelial cells or only a specific subgroup is the focus of future research.     

Segmental duplications in genome-wide significant loci and housekeeping genes; warning for GAPDH and ACTB

Normalizing quantitative polymerase chain reaction (qPCR) data to a housekeeping gene is a critical step in qPCR analyses. Our bioinformatics analysis of 1978 housekeeping genes revealed that 348 of them, including GAPDH and ACTB, are not reliable normalizers for qPCR validation of genomic copy number variants because they overlap highly homologous segmental duplications. For RNA-based qPCR, it is also critical to ensure that the cDNA is not contaminated with genomic DNA if GAPDH or ACTB is used as an endogenous control. Furthermore, we observed that 138 significant single nucleotide polymorphisms (SNPs) reported in 134 published genome-wide association studies (GWAS) (out of 1093 GWAS) are mapped to regions affected by segmental duplications. This observation is important, because these SNPs could potentially tag copy number variations that might explain the GWAS signal. However, it is essential to ensure that the association between disease and such a SNP is not a false positive finding (due to incorrect genotype calls) or the result of an association with another homologous genomic region.     

Biallelic variants in TUBGCP6 result in microcephaly and chorioretinopathy 1: Report of four cases and a literature review

Autosomal recessive microcephaly and chorioretinopathy-1 (MCCRP1) is a rare Mendelian disorder resulting from biallelic loss of function variants in Tubulin-Gamma Complex Associated Protein 6 (TUBGCP6, MIM#610053). Clinical features of this disorder include microcephaly, cognitive impairment, dysmorphic features, and variable ophthalmological anomalies including chorioretinopathy. Microcephaly can be recognized prenatally and visual impairment becomes evident during the first year of life. The clinical presentation resembles the findings in some acquired conditions such as congenital toxoplasmosis and cytomegalovirus infections; thus, it is important to recognize and diagnose this syndrome in view of its impact on patient health management and familial reproductive plans. To date, only seven molecularly confirmed patients from five unrelated families have been reported. We report an additional four unrelated patients with TUBGCP6 variants including one prenatal diagnosis and review the clinical phenotypes and genotypes of all the known cases. This report expands the molecular and phenotypic spectrum of TUBGCP6 and includes additional prenatal findings associated with MCCRP1.     

Anxiety, depression and saliva cortisol in women with a medical disorder during pregnancy

Anxiety and depression during pregnancy increase the risk for an adverse pregnancy outcome and neurodevelopmental problems in the child. The aim of this study was to investigate anxiety and depression in women with a medical disorder of pregnancy compared with control antenatal women, and any association with saliva cortisol. One hundred and twenty pregnant women (60 with a known medical disorder and 60 without, mean gestation 32 weeks) completed five self-rating questionnaires (Spielberger State and Trait Anxiety, Edinburgh Postnatal Depression Scale (EPDS), the Adult Wellbeing Scale and a Life Events Questionnaire). Diurnal saliva samples were obtained from 39 women with a medical disorder and 50 controls for cortisol analysis. The medical disorders group were significantly more anxious and depressed than the controls (mean (SD)) state anxiety 40.0 (11.5) vs. 31.6 (8.8), p = 0.00; trait anxiety 39.4 (9.5) vs. 35.2 (9.2), p = 0.02; adult wellbeing 15.9 (7.5) vs. 12.3 (7.5) p = 0.01; and EPDS 9.6 (5.4) vs. 5.9 (4.8), p = 0.00). There was no difference in the life events scores between the groups. The subgroup of women suffering from hyperemesis gravidarum had particularly high EPDS scores, (16.2 (3), n = 5, p = 0.00) compared with controls. There were no significant differences in the cortisol levels between the groups. Some women with a medical disorder during pregnancy showed considerably elevated levels of anxiety and depression. Health professionals need to be aware that these women need extra psychological support.     

Anxiety disorders among Nigerian women in late pregnancy: a controlled study

Summary This study aimed to investigate the rate and type of anxiety disorders among Nigerian women in late pregnancy. Women in late pregnancy (n = 172) and a non-pregnant control group were assessed for DSM-IV anxiety disorders. The rate of any anxiety disorder in the pregnant women was 39.0% compared with 16.3% in the non-pregnant population (p < 0.001). Although all the anxiety disorders were more common, only the rate of social anxiety disorder was significantly higher among the pregnant than non-pregnant population. Correlates of anxiety disorder in the pregnant population include age less than 25 years (OR 4.62, 95% CI 2.39–8.92), primiparity (OR 3.90, 95% CI 2.00–7.59) and presence of medical conditions (OR 3.60, 95% CI 1.28–10.12). More research is needed in this field to ascertain the specific association between pregnancy and anxiety disorders.     

Bipolar and ADHD Comorbidity: Both Artifact and Outgrowth of Shared Mechanisms

[Clin Psychol Sci Prac 17: 350–359, 2010] Published rates of comorbidity between pediatric bipolar disorder (PBD) and attention‐deficit/hyperactivity disorder (ADHD) have been higher than would be expected if they were independent conditions, but also dramatically different across different studies. This review examines processes that could artificially create the appearance of comorbidity or substantially bias estimates of the PBD‐ADHD comorbidity rate, including categorization of dimensional constructs, overlap among diagnostic criteria, over‐splitting, developmental sequencing, and referral or surveillance biases. Evidence also suggests some mechanisms for “true” PBD‐ADHD comorbidity, including shared risk factors, distinct subtypes, and weak causal relationships. Keys to differential diagnosis include focusing on episodic presentation and nonoverlapping symptoms unique to mania.     

Emerging psychiatric disorders in Kleine‐Levin syndrome

In Kleine‐Levin syndrome (KLS), episodes of hypersomnia and cognitive, psychiatric and behavioural disturbances alternate with asymptomatic periods in adolescents. We evaluated whether psychiatric disorders would emerge during asymptomatic periods in a naturalistic, uncontrolled clinical cohort. Patients with primary KLS underwent psychiatric interviews at diagnosis and every year for 1–10 years, leading to diagnosis of former and present comorbid psychiatric disorders. Among the 115 patients (65.2% male and aged 16.1 ± 4.8 years at KLS onset), 19 (16.5%) had a history of psychiatric disorder prior to KLS onset, which persisted afterwards in 10. Twenty‐five (21%) patients developed a new, comorbid psychiatric disorder 1–6 years after KLS onset, during ‘asymptomatic’ periods, including mood disorders (n = 14; including major depressive episodes, n = 8; recurrent depressive episodes, n = 2; bipolar I disorder, n = 1; dysthymic disorder, n = 1; adjustment disorder with depressive mood, n = 1; and mood disorder not otherwise specified, n = 1), anxiety disorders (n = 7), eating disorders (n = 2), psychotic disorders not otherwise specified (n = 2), schizoaffective disorder (n = 1) and cannabis dependence (n = 1). Six patients attempted suicide: two before and two after KLS onset, and two during episodes. Female sex, longer disease course, longer time incapacitated (356 ± 223 versus 155 ± 186 days) and more frequent psychiatric symptoms during episodes (but no family or personal history of psychiatric disorders) were associated with emerging psychiatric disorders. Contrary to the alleged benignity of KLS and normality between episodes, one KLS patient in five suffers from emerging psychiatric disorders. These disorders may depend on personal vulnerability and, most probably, on psychiatric symptoms during episodes.