Genetic Analysis of 1p36 Deletions for Six Aborted Fetuses.

Context: Chromosomal abnormalities in embryos are the most common cause of early spontaneous abortions. Chromosome 1p36 deletion syndrome (OMIM 607872) is the most common subtelomeric, terminal microdeletion syndrome. Objective: The study intended to analyze miscarriage samples using chromosomal microarray analysis (CMA), to explore the mechanism of chromosomal aberrations, and to identify the recurrence risk and a prenatal diagnostic strategy for couples experiencing spontaneous abortions. Design: The research team performed a narrative review by searching PubMed databases. The search used the keywords 1p36 deletion, CMA, karyotype analysis, FISH and aborted fetus. The team also conducted case studies using genetic analyses. Setting: The study took place at Wuxi Maternity and Child Health Care Hospital in Wuxi, Jiangsu, PR China. Participants: Out of 673 abortion samples, six had 1p36 deletions (0.89%). Participants were the six families who had had those spontaneous abortions. Outcome Measures: The research team evaluated the fetal samples using: (1) CMA, (2) karyotype analysis, and (3) novel fluorescence in-situ hybridization (FISH). Results: The CMA showed that: (1) fetus 1 had a 1.75 MB microdeletion at the 1p36.32p36.31 band, which testing didn't detect in fetus 1's parents, but the research team couldn't exclude the possibility that one of the parents was a carrier of a chromosomal insertional translocation; and (2) fetus 2 had a 5.10 MB microdeletion at the 1p36.13p36.12 segment, and fetus 3 had a 9.21 MB deletion at the 1p36.33p36.22 band, and the high-resolution karyotype analysis and FISH of the parents of both fetuses appeared normal, indicating that the chromosomal abnormalities were de novo; (3) fetus 4 had a 9.28 MB deletion at 1p36.33p36.22, although the high-resolution karyotype analysis of fetus 4's parent was normal; (4) fetuses 5 and 6 had a 7.64 MB microdeletion at 1p36.33p36.23 and a 4.45 MB deletion at 1p36.33p36.32, respectively, although the parents of both fetuses waived further testing. Conclusions: This study provides the first report of recurrent spontaneous and sporadic abortions with 1p36 deletion syndrome. The CMA combined with a reasonable family-pedigree investigation can detect cryptic chromosomal aberrations in miscarriages and can determine the mechanism of the chromosomal variations. It thus is invaluable in assessing recurrence risk and providing appropriate prenatal diagnostic strategies for affected families.

Zinc deficiency and supplementation in autism spectrum disorder and Phelan-McDermid syndrome.

Approximately 1 in 36 children are diagnosed with autism spectrum disorder (ASD). The disorder is four times more common in males than in females. Zinc deficiency and mutations in SHANK2 and SHANK3 (members of a family of excitatory postsynaptic scaffolding proteins) are all risk factors that may contribute to the pathophysiology of the disease. The presence of shankopathies (loss of one copy of the SHANK3 gene) can lead to the development of Phelan-McDermid syndrome (PMDS)-a rare genetic disorder characterized by developmental delay, intellectual disability, poor motor tone, and ASD-like symptoms. We reviewed the relationship between zinc, ASD, and PMDS as well as the effect of zinc supplementation in improving symptoms of ASD and PMDS based on 22 studies published within 6 years (2015-2020). Zinc deficiency (assessed by either dietary intake, blood, hair, or tooth matrix) was shown to be highly prevalent in ASD and PMDS patients as well as in preclinical models of ASD and PMDS. Zinc supplements improved the behavioral deficits in animal models of ASD and PMDS. Clinical trials are still needed to validate the beneficial therapeutic effects of zinc supplements in ASD and PMDS patients.

Lymphedema complicated by protein-losing enteropathy with a 22q13.3 deletion and the potential role of CELSR1: A case report.

INTRODUCTION: 22q13.3 deletion syndrome is a well-known syndrome characterized by typical clinical findings including neonatal hypotonia, absent or severely delayed speech, intellectual disability, and other various features, and detection of a heterozygous deletion of chromosome 22q13.3 with the involvement of at least part of SHANK3. It is reported that 10% to 29% of patients with 22q13.3 deletion syndrome present lymphedema. Protein-losing enteropathy (PLE) has never been reported in 22q13.3 deletion syndrome. PATIENT CONCERNS: The patient presented to our institution for refractory hypoalbuminemia and chronic lymphedema in both legs. DIAGNOSIS: The patient manifested intellectual disability, absent speech, tooth grinding, dysmorphic face, and abnormal hands and toenails. Copy-number variation sequencing confirmed the maternal deletion in 22q13.31-q13.33 (chr22:46285592-51244566, hg19). The patient was genetically diagnosed with 22q13.3 deletion syndrome. INTERVENTIONS: Low-fat diets and medium-chain triglycerides supplements were prescribed. The patient was recommended to wear compression garments and elevate legs. OUTCOMES: The symptom of diarrhea was resolved, but hypoalbuminemia persisted. Lower extremities lymphedema was gradually becoming severe. CONCLUSIONS: Primary lymphedema and PLE can occur simultaneously in a patient with 22q13.3 deletion syndrome. The 2 phenotypes could share the same genetic etiology of congenital lymphatic abnormalities. CELSR1 deletion may play a role in lymphatic dysplasia. The case also provides additional proof of the pathogenic effect of CELSR1 on hereditary lymphedema.

Yin-yang actions of histone methylation regulatory complexes in the brain.

Dysregulation of histone methylation has emerged as a major driver of neurodevelopmental disorders including intellectual disabilities and autism spectrum disorders. Histone methyl writer and eraser enzymes generally act within multisubunit complexes rather than in isolation. However, it remains largely elusive how such complexes cooperate to achieve the precise spatiotemporal gene expression in the developing brain. Histone H3K4 methylation (H3K4me) is a chromatin signature associated with active gene-regulatory elements. We review a body of literature that supports a model in which the RAI1-containing H3K4me writer complex counterbalances the LSD1-containing H3K4me eraser complex to ensure normal brain development. This model predicts H3K4me as the nexus of previously unrelated neurodevelopmental disorders.

Auditory Evoked M100 Response Latency is Delayed in Children with 16p11.2 Deletion but not 16p11.2 Duplication.

Individuals with the 16p11.2 BP4-BP5 copy number variant (CNV) exhibit a range of behavioral phenotypes that may include mild impairment in cognition and clinical diagnoses of autism spectrum disorder (ASD). To better understand auditory processing impairments in populations with this chromosomal variation, auditory evoked responses were examined in children with the 16p11.2 deletion, 16p11.2 duplication, and age-matched controls. Stimuli consisted of sinusoidal binaural tones presented passively while children underwent recording with magnetoencephalography (MEG). The primary indicator of auditory processing impairment was the latency of the ∼100-ms "M100" auditory response detected by MEG, with the 16p11.2 deletion population exhibiting profoundly delayed M100 latencies relative to controls. This delay remained even after controlling for potential confounds such as age and cognitive ability. No significant difference in M100 latency was observed between 16p11.2 duplication carriers and controls. Additionally, children meeting diagnostic criteria for ASD (16p11.2 deletion carriers) exhibited nonsignificant latency delays when compared with the corresponding CNV carriers not meeting criteria for ASD. Present results indicate that 16p11.2 deletion is associated with auditory processing delays analogous to (but substantially more pronounced than) those previously reported in "idiopathic" ASD.

Growth hormone deficiency and pituitary malformation in a recurrent Cat-Eye syndrome: a family report.

Growth hormone deficiency affects roughly between one in 3000 and one in 4000 children with most instances of growth hormone deficiency being idiopathic. Growth hormone deficiency can also be associated with genetic diseases or chromosome abnormalities. Association of growth hormone deficiency together with hypothalamic-pituitary axis malformation and Cat-Eye syndrome is a very rare condition. We report a family with two brothers presenting with growth delay due to a growth hormone deficiency associated with a polymalformation syndrome. They both displayed pre-auricular pits and tags, imperforate anus and Duane retraction syndrome. Both parents and a third unaffected son displayed normal growth pattern. Cerebral MRI showed a hypothalamic-pituitary axis malformation in the two affected brothers. Cytogenetic studies revealed a type I small supernumerary marker chromosome derived from chromosome 22 resulting in a tetrasomy 22pter-22q11.21 characteristic of the Cat-Eye syndrome. The small supernumerary marker chromosome was present in the two affected sons and the mother in a mosaic state. Patients with short stature due to growth hormone deficiency should be evaluated for chromosomal abnormality. Family study should not be underestimated.

Enfermedad de Hirschsprung asociada al síndrome de Mowat-Wilson: a propósito de un caso / Hirschsprung disease associated with mowat-wilson syndrome: report of a case

Introducción: La enfermedad de Hirschsprung (EH) o megacolon agangliónico es un trastorno congénito que se caracteriza por la ausencia de células ganglionares intramurales de los plexos mioentéricos submucosos (de Auerbach y Meissner, respectivamente) en tramos distales del intestino, debido al fracaso de la migración de los precursores de estas células desde la cresta neural durante el desarrollo embrionario y asociada a otras anomalías en el 18% restante de los casos, en ocasiones formando parte de síndromes polimalformativos específicos. Objetivo: Este artículo tiene como objetivo presentar la evolución clínica y nutricional de un paciente pediátrico de 14 meses diagnosticado de EH al nacer asociado a MWS, así como evaluar los resultados clínicos de este paciente. Métodos: A través de la revisión de la historia clínica, se estudió la evolución de los datos antropométricos (peso y talla) así como los parámetros analíticos para su valoración. Adicionalmente, se evaluaron las complicaciones asociadas al soporte nutricional y la estrategia terapéutica en el contexto multidisciplinar. Resultados: Paciente de 14 meses, sexo masculino, hijo de padres sanos no consanguíneos inmigrantes de Colombia acude al servicio de urgencias de nuestro hospital por presentar distensión abdominal y vómitos con ausencia de deposiciones espontáneas. Descripción de la composición de la nutrición parenteral recibida durante los 28 días que duró su ingreso hospitalario. Conclusión: La asociación de la enfermedad de Hirschsprung y el síndrome de Mowat-Wilson puede conducir a la necesidad de nutrición parenteral de manera prolongada y presentar con mayor frecuencia desvío del estoma produciéndose un mayor número de complicaciones postoperatorias en estos pacientes, tal y como es el caso de nuestro paciente (AU)

Introduction: Hirschsprung’s disease (HD) or aganglionic megacolon is a congenital disorder characterized by the absence of ganglion intramural cells of the submucosal myenteric plexus (namely Auerbach and Meissner, respectively) in distal sections of the intestine. This is due to a failure in the migration of the precursors of these cells from the neural chalk during the embryonic development and also due to other abnormalities associated (18 % of cases), in some cases involving specific polymalformation syndromes. Objectives: The aim of the work is to present the clinical and nutritional evolution of a 14 months aged pediatric patient who was diagnosed with HD since was born associated with Mowat- Wilson syndrome (MWS). In addition, it is also targeted to evaluate the clinical results from this patient. Methods: Reviewing the medical history of the patient, the evolution of the anthropometric data (weight and height) as well as the analytical parameters for further studies were carried out. In addition, the upcoming issues associated with nutritional support and therapeutic strategies in the multidisciplinary context were evaluated. Results: A male, 14 months aged patient, son of not consanguineous healthy immigrants parents from Colombia went to the emergency department of our hospital suffering abdominal distension and vomiting with no spontaneous bowels. A detailed description of the composition of parenteral nutrition administered within the period of 28 days of hospital admission. Conclusion: As observed in this patient, the association of HD and MWS can lead to the need of prolonged parenteral nutrition and frequently present diverting stoma leading to a greater number of postoperative complications in this population (AU)

Two cases of recurrent abortion in which isodicentric chromosome 15 was observed in the husbands.

We report two cases of women positive for anticardiolipin antibodies who experienced recurrent abortion whose husbands had isodicentric chromosome 15 aberrations who eventually had successful pregnancies. Two women were referred to our hospital due to their medical history of recurrent abortion. Both were diagnosed as being positive for anticardiolipin antibodies and their husbands with isodicentric chromosome 15. After both patients were treated with a Japanese herbal medicine (Sairei-to) and low-dose aspirin for the positive anticardiolipin antibodies, they delivered appropriate-for-date infants at term gestation. Although both husbands were revealed to have isodicentric chromosome 15, and coincidentally both wives were positive for anticardiolipin antibodies, their next pregnancies continued uneventfully as a result of the treatment.

Effects of Jatropha curcas oil in Lactuca sativa root tip bioassays.

Jatropha curcas L. (Euphorbiaceae) is important for biofuel production and as a feed ingredient for animal. However, the presence of phorbol esters in the oil and cake renders the seeds toxic. The toxicity of J. curcas oil is currently assessed by testing in animals, leading to their death. The identification of toxic and nontoxic improved varieties is important for the safe use of J. curcas seeds and byproducts to avoid their environmental toxicity. Hence, the aim of this study was to propose a short-term bioassay using a plant as a model to screen the toxicity of J. curcas oil without the need to sacrifice any animals. The toxicity of J. curcas oil was evident in germination, root elongation and chromosomal aberration tests in Lactuca sativa. It was demonstrated that J. curcas seeds contain natural compounds that exert phyto-, cyto- and genotoxic effects on lettuce, and that phorbol esters act as aneugenic agents, leading to the formation of sticky chromosomes and c-metaphase cells. In conclusion, the tests applied have shown reproducibility, which is important to verify the extent of detoxification and to determine toxic doses, thus reducing the numbers of animals that would be used for toxicity tests.

Neuroendocrine phenotypes in a boy with 5q14 deletion syndrome implicate the regulatory roles of myocyte-specific enhancer factor 2C in the postnatal hypothalamus.

The 5q14.3 deletion syndrome is a rare chromosomal disorder characterized by moderate to severe intellectual disability, seizures and dysmorphic features. We report a 14-year-old boy with 5q14.3 deletion syndrome who carried a heterozygous deletion of the myocyte-specific enhancer factor 2c (MEF2C) gene. In addition to the typical neurodevelopmental features of 5q14.3 deletion syndrome, he showed recurrent hypoglycemia, appetite loss and hypothermia. Hormonal loading tests using insulin, arginine and growth hormone-releasing factor revealed that growth hormone was insufficiently released into serum in response to these stimuli, thus disclosing the hypothalamic dysfunction in the present case. To uncover the biological roles of MEF2C in the hypothalamus, we studied its expression in the postnatal mouse brain. Notably, neuropeptide Y (NPY)-positive interneurons in the hypothalamic arcuate nuclei highly expressed MEF2C. In contrast, the Rett syndrome-associated protein, Methyl-CpG binding Protein 2 (MECP2) was barely expressed in these neurons. MEF2C knockdown or overexpression experiments using Neuro2a cells revealed that MEF2C activated the endogenous transcription of NPY. Conversely, siRNA-mediated knockdown of MECP2 led to derepression of the Npy gene. These data support the concept that MEF2C and MECP2 share common molecular pathways regulating the homeostatic expression of NPY in the adult hypothalamus. We propose that individuals with 5q14.3 deletion syndrome may exhibit neuroendocrine phenotypes through the functional loss of MEF2C in the postnatal hypothalamus.

Anticlastogenic activity of flavonoid rich extract of Cassia auriculata Linn. on experimental animal [corrected].

OBJECTIVE: To determine antimutagenic activity of Cassia auriculata Linn. on chromosomal damage induced by cyclophosphamide (CP). MATERIAL AND METHODS: In the present investigation, four groups of six Swiss albino mice in each group were used. Excepting for the first group all the remaining groups were treated with CP (50 mg/kg). Mice of third and fourth group were treated with ethyl acetate extract of C. auriculata Linn. at 100 mg/kg and 200 mg/kg with CP. Metaphase of bone marrow cells of all animals were analyzed for qualitative and quantitative chromosomal aberrations. Break, fragment, deletion, Polyploidy, pulverized, ring and total aberration were observed. RESULTS: Flavonoids rich extracts of root of C. auriculata Linn. provided significant protection (P < 0.05) against CP induced chromosomal aberration. Total chromosomal aberration was found to be 12.16 and 7.33% in 100 and 200 mg/kg of extract treated animals respectively. CONCLUSION: From the present study it can was observed that ethyl acetate extract of C. auriculata Linn possess significant anti-mutagenic potential against CP induced chromosomal aberration.

Maternal age-based prenatal screening for chromosomal disorders: attitudes of women and health care providers toward changes.

OBJECTIVE: To explore views of women and health care providers (HCPs) about the changing recommendations regarding maternal age-based prenatal screening. DESIGN: Mixed-methods design. SETTING: Ontario. PARTICIPANTS: A sample of women who had given birth within the previous 2 years and who had attended a family medicine centre, midwifery practice, or baby and mother wellness program (n = 42); and a random sample of family physicians (n = 1600), and all Ontario obstetricians (n = 694) and midwives (n = 334) who provided prenatal care. METHODS: We used focus groups (FGs) to explore women's views. Content analysis was used to uncover themes and delineate meaning. To explore HCPs' views, we conducted a cross-sectional self-completion survey. MAIN FINDINGS: All FG participants (42 women in 6 FGs) expressed the importance of individual choice of prenatal screening modality, regardless of age. They described their perception that society considers women older than 35 to be at high obstetric risk and raised concerns that change in the maternal age-related screening policy would require education. The HCP survey response rate was 40%. Results showed 24% of HCPs agreed that women of any age should be eligible for invasive diagnostic testing regardless of prenatal screening results; 15% agreed that the age for diagnostic testing should be increased to 40 years, 14% agreed that diagnostic testing should be reserved for women with positive prenatal screening results, and 45% agreed that prenatal screening should remain unchanged. CONCLUSION: Maternity care organizations have recommended that maternal age-based prenatal screening is no longer appropriate. Informed choice is of paramount importance to women and should be part of any change. Health care providers need to be engaged in and educated about any change to screening guidelines to offer women informed choices.

Integrated and first trimester prenatal screening in California: program implementation and patient choice for follow-up services.

OBJECTIVES: The California Prenatal Screening Program serves over 350,000 women annually. This study examines utilization rates for the various screening options and patient choices regarding follow-up services. METHODS: The study tracked patients with first trimester positive results for Down syndrome to examine patient decisions regarding follow-up services and/or additional screening and to identify determinants of patient decisions. For first trimester screen positive women who elected further screening, second trimester integrated screening results were analyzed. The Genetic Disease Screening Program Chromosome Registry was used to identify Down syndrome cases. RESULTS: Ethnicity, but not age, was a strong predictor of acceptance of prenatal diagnosis. Approximately 47% of first trimester screen positive women opted for further screening. Among these women, 46% percent received an integrated screen negative result. All but one confirmed Down syndrome case in this cohort were still screen positive. CONCLUSIONS: Data from the California Prenatal Screening Program indicate that all of the major screening modalities continue to be utilized. The wide range of choices made by women with screen positive results demonstrate the importance of including multiple options within the Program. Providing integrated screening to first trimester Down syndrome screen positive women reduced the number of unnecessary invasive procedures.

Dietary docosahexaenoic acid supplementation prevents age-related functional losses and A2E accumulation in the retina.

PURPOSE: With age, retina function progressively declines and A2E, a constituent of the toxin lipofuscin, accumulates in retinal pigment epithelial (RPE) cells. Both events are typically exacerbated in age-related retina diseases. We studied the effect of dietary docosahexaenoic acid (DHA, C22:6n-3) supplementation on these events, using a transgenic mouse model (mutant human ELOVL4; E4) displaying extensive age-related retina dysfunction and massive A2E accumulation. METHODS: Retina function was assessed with the electroretinogram (ERG) and A2E levels were measured in E4 and wildtype (WT) mice. Dietary DHA was manipulated from 1 to 3, 1 to 6, 6 to 12, and 12 to 18 months: 1% DHA over total fatty acids (E4+, WT+) or similar diet without DHA (E4-, WT-). RESULTS: Increased omega-3/6 ratios (DHA/arachidonic acid) in E4+ and WT+ retinas were confirmed for the 1- to 3-month and 1- to 6-month trials. Although 1- to 3-month intervention had no effects, when prolonged to 1 to 6 months, RPE function (ERG c-wave) was preserved in E4+ and WT+. Intervention from 6 to 12 months led to maintained outer and inner retina function (ERG a- and b-wave, respectively) in E4+. At 12 to 18 months, a similar beneficial effect on retina function occurred in WT+; A2E levels were reduced in E4+ and WT+. CONCLUSIONS: DHA supplementation was associated with: preserved retina function at mid-degenerative stages in E4 mice; prevention of age-related functional losses in WT mice; and reduced A2E levels in E4 and WT mice at the oldest age examined. These findings imply that dietary DHA could have broad preventative therapeutic applications (acting on pathologic and normal age-related ocular processes).

Supplemental dietary folic acid has no effect on chromosome damage in erythrocyte progenitor cells of mice.

Folate deficiency can cause chromosome damage, which could result from reduced de novo thymidylate synthesis or DNA hypomethylation. High folic acid intake has been hypothesized to inhibit folate-dependent one-carbon metabolism, which could also lead to DNA damage. A large proportion of the general population may have high folic acid intakes. In this study, 2 experiments were conducted to examine the effects of folate on chromosome damage. First, male mice were fed folic acid-deficient (D) (0 mg folic acid/kg diet), control (C) (2 mg/kg), or folic acid-supplemented (S) (6 mg folic acid/kg diet) diets from weaning to maturity. Second, female mice were fed the D, C, or S diet throughout pregnancy, lactation, and breeding for 3 generations; male mice from the F3 generation were fed the same diet as their mothers from weaning, producing D, C, and S F3 male mice. RBC micronucleus frequencies, a measure of chromosome damage or aneuploidy, were determined for both experimental groups. In mice fed diets from weaning to maturity, erythrocyte micronucleus frequency was 24% greater in D compared with C mice. F3 mice fed diet D had 260% and 174% greater reticulocyte and erythrocyte micronucleus frequencies compared with F3 C mice, respectively. The S diets did not affect micronucleus frequency, suggesting that excess folic acid at this level does not promote or protect against chromosome damage. The results suggest that chronic exposure to folic acid at the levels similar to those achieved through fortification is unlikely to be clastogenic or aneugenic.

Effect of Buchanania lanzan Spreng. bark extract on cyclophosphamide induced genotoxicity and oxidative stress in mice.

OBJECTIVE: To elucidate the effect of ethanolic extract of Buchanania lanzan Spreng. (B. lanan) bark against cyclophosphamide induced genotoxicity and oxidative stress in mice. METHODS: The prevalence of micronuclei in bone marrow, the extent of lipid peroxidation, reduced glutathione and the status of the antioxidant enzymes, superoxide dismutase and catalase in liver of mice were used as intermediate biomarkers for chemoprotection. Lipid peroxidation and associated compromised antioxidant defenses in cyclophosphamide treated mice were observed in the liver. RESULTS: Pre-treatment with B. lanzan 250, 500 and 1,000 mg/kg, p.o., daily for 7 days significantly reduced the chromosomal damage and lipid peroxidation with concomitant changes in antioxidants and detoxification systems. CONCLUSIONS: These results point out the presence of chemopreventive phytoconstituents in the crude extract offering protection against cyclophosphamide induced genotoxicity and oxidative stress in mice.

Effect of Buchanania lanzan Spreng. bark extract on cyclophosphamide induced genotoxicity and oxidative stress in mice

OBJECTIVE@#To elucidate the effect of ethanolic extract of Buchanania lanzan Spreng. (B. lanan) bark against cyclophosphamide induced genotoxicity and oxidative stress in mice.@*METHODS@#The prevalence of micronuclei in bone marrow, the extent of lipid peroxidation, reduced glutathione and the status of the antioxidant enzymes, superoxide dismutase and catalase in liver of mice were used as intermediate biomarkers for chemoprotection. Lipid peroxidation and associated compromised antioxidant defenses in cyclophosphamide treated mice were observed in the liver.@*RESULTS@#Pre-treatment with B. lanzan 250, 500 and 1,000 mg/kg, p.o., daily for 7 days significantly reduced the chromosomal damage and lipid peroxidation with concomitant changes in antioxidants and detoxification systems.@*CONCLUSIONS@#These results point out the presence of chemopreventive phytoconstituents in the crude extract offering protection against cyclophosphamide induced genotoxicity and oxidative stress in mice.