Association between hereditary predisposition to common cancers and congenital multimalformations.

In a previous article we reported that mutations favoring cancer at adulthood seemed to improve fertility and limit miscarriages. Because spontaneous abortion may result from anomalies in embryo, we questioned if an increased frequency of congenital malformation could be evidenced among cancer-prone families. Oncogenetics database (≈193 000 members) of the comprehensive cancer center Jean Perrin was crossed with regional registry of congenital malformations (≈10 000). Among children born between 1986 and 2011, 176 children with malformation matched in both databases. In breast/ovaries cancer-prone families, the risk for malformations was multiplied by 2.4 [1.2-4.5] in case of a BRCA1 mutation. Frequencies of malformation in BRCA2 and MMR mutated families were similar to families without a cancer syndrome. In comparison to malformations concerning a unique anatomical system, multimalformations were significantly more frequent in case of BRCA or MMR mutations: compared to families without cancer syndrome, the risk of multimalformations was multiplied by 4.1 [0.8-21.7] for cancer-prone families but with no known deleterious mutation, by 6.9 [1.2-38.6] in families with a known mutation but an unknown parental mutational status and by 10.4 [2.3-46.0] when one parent carried the familial mutation. No association with the type of anatomical system was found, nor with multiple births. These results suggest that BRCA and MMR genes play an important role in human embryogenesis and that if their function is lowered because of heterozygote mutations, congenital malformations are either more likely (BRCA1 mutations) and/or more susceptible to concern several anatomical systems.

Moderate maternal folic acid supplementation ameliorates adverse embryonic and epigenetic outcomes associated with assisted reproduction in a mouse model.

STUDY QUESTION: Could clinically-relevant moderate and/or high dose maternal folic acid supplementation prevent aberrant developmental and epigenetic outcomes associated with assisted reproductive technologies (ART)? SUMMARY ANSWER: Our results demonstrate dose-dependent and sex-specific effects of folic acid supplementation in ART and provide evidence that moderate dose supplements may be optimal for both sexes. WHAT IS KNOWN ALREADY: Children conceived using ART are at an increased risk for growth and genomic imprinting disorders, often associated with DNA methylation defects. Folic acid supplementation is recommended during pregnancy to prevent adverse offspring outcomes; however, the effects of folic acid supplementation in ART remain unclear. STUDY DESIGN, SIZE, DURATION: Outbred female mice were fed three folic acid-supplemented diets, control (rodent daily recommended intake or DRI; CD), moderate (4-fold DRI; 4FASD) or high (10-fold DRI; 10FASD) dose, for six weeks prior to ART and throughout gestation. Mouse ART involved a combination of superovulation, in vitro fertilisation, embryo culture and embryo transfer. PARTICIPANTS/MATERIALS, SETTING, METHODS: Midgestation embryos and placentas (n = 74-99/group) were collected; embryos were assessed for developmental delay and gross morphological abnormalities and embryos and placentas were examined for epigenetic defects. We assessed methylation at four imprinted genes (Snrpn, Kcnq1ot1, Peg1 and H19) in matched midgestation embryos and placentas (n = 31-32/group) using bisulfite pyrosequencing. In addition, we examined genome-wide DNA methylation patterns in placentas (n = 6 normal placentas per sex/group) and embryos (n = 6 normal female embryos/group; n = 3 delayed female embryos/group) using reduced representation bisulfite sequencing (RRBS). MAIN RESULTS AND THE ROLE OF CHANCE: Moderate, but not high dose supplementation, was associated with a decrease in the proportion of developmentally delayed embryos. Although moderate dose folic acid supplementation reduced DNA methylation variance at certain imprinted genes in embryonic and placental tissues, high dose supplementation exacerbated the negative effects of ART at imprinted loci. Furthermore, folic acid supplements resolved female-biased aberrant imprinted gene methylation. Supplementation was more effective at correcting ART-induced genome-wide methylation defects in male versus female placentas; however, folic acid supplementation also led to additional methylation perturbations which were more pronounced in males. LARGE-SCALE DATA: The RRBS data from this study have been submitted to the NCBI Gene Expression Omnibus under the accession number GSE123143. LIMITATIONS REASONS FOR CAUTION: Although the combination of mouse ART utilised in this study consisted of techniques commonly used in human fertility clinics, there may be species differences. Therefore, human studies, designed to determine the optimal levels of folic acid supplementation for ART pregnancies, and taking into account foetal sex, are warranted. WIDER IMPLICATIONS OF THE FINDINGS: Taken together, our findings support moderation in the dose of folic acid supplements taken during ART. STUDY FUNDING/COMPETING INTEREST(S): This work was funded by the Canadian Institutes of Health Research (FDN-148425). The authors declare no conflict of interest.

NAD Deficiency, Congenital Malformations, and Niacin Supplementation.

BACKGROUND: Congenital malformations can be manifested as combinations of phenotypes that co-occur more often than expected by chance. In many such cases, it has proved difficult to identify a genetic cause. We sought the genetic cause of cardiac, vertebral, and renal defects, among others, in unrelated patients. METHODS: We used genomic sequencing to identify potentially pathogenic gene variants in families in which a person had multiple congenital malformations. We tested the function of the variant by using assays of in vitro enzyme activity and by quantifying metabolites in patient plasma. We engineered mouse models with similar variants using the CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 system. RESULTS: Variants were identified in two genes that encode enzymes of the kynurenine pathway, 3-hydroxyanthranilic acid 3,4-dioxygenase (HAAO) and kynureninase (KYNU). Three patients carried homozygous variants predicting loss-of-function changes in the HAAO or KYNU proteins (HAAO p.D162*, HAAO p.W186*, or KYNU p.V57Efs*21). Another patient carried heterozygous KYNU variants (p.Y156* and p.F349Kfs*4). The mutant enzymes had greatly reduced activity in vitro. Nicotinamide adenine dinucleotide (NAD) is synthesized de novo from tryptophan through the kynurenine pathway. The patients had reduced levels of circulating NAD. Defects similar to those in the patients developed in the embryos of Haao-null or Kynu-null mice owing to NAD deficiency. In null mice, the prevention of NAD deficiency during gestation averted defects. CONCLUSIONS: Disruption of NAD synthesis caused a deficiency of NAD and congenital malformations in humans and mice. Niacin supplementation during gestation prevented the malformations in mice. (Funded by the National Health and Medical Research Council of Australia and others.).

Effect of Race on the Prevalence of Congenital Malformations among Newborns in the United States.

BACKGROUND: Racial variability in certain prenatal risk factors, such as prenatal vitamin supplementation and termination of pregnancy for fetal anomaly, has altered the racial prevalence of congenital malformation (CM). Analysis of a single large representative population is required to analyze current racial differences in prevalence of CM in the United States. METHOD: This is a population-based cross-sectional study to analyze racial differences in prevalence of CM diagnoses. We reviewed all live births in the 2008 Nationwide Inpatient Sample (NIS) database and determined birth prevalence of 55 selected CM diagnoses in Caucasians. We then calculated the relative risk of these CM diagnoses in African American, Hispanics and Asians relative to Caucasians. RESULT: Overall CM prevalence was 29.2 per 1,000 in a cohort of 1,048,252 live births of which 51% were Caucasians. Compared to Caucasian, risk of overall CM was lower in African Americans (RR = .9, CI .8-9) and Hispanics (RR = .9, CI .8-.9). Risk of overall CM was similar in Caucasians and Asians. Relative to the Caucasians, African Americans had lower risk of cardiac, genitourinary, and craniofacial malformations but higher risk of musculoskeletal malformations. Hispanics had lower risk of genitourinary and gastrointestinal malformation. Asians had higher risk of craniofacial and musculoskeletal malformation. CONCLUSIONS: This is a comprehensive description of racial difference in risk of CM in the United States. Observed racial differences in risk of CM may be related to genetic susceptibilities, to cultural or social differences that could modify exposures, or to the many potential combinations between susceptibilities and exposures.

Midwives' perceptions of communication during videotaped counseling for prenatal anomaly tests: how do they relate to clients' perceptions and independent observations?

OBJECTIVE: This study aimed to provide insight into Dutch midwives' self-evaluation of prenatal counseling for anomaly screening in real life practice and, the degree of congruence of midwives' self-assessments with clients' perceptions and with observed performance. METHODS: Counseling sessions were videotaped. We used the QUOTE(prenatal) questionnaire to have each midwife (N = 20) and her client (N = 240) rate the prenatal counseling that they had together. We used an adapted version of the RIAS video-coding system to assess actual counseling during videotaped prenatal counseling (N = 240). RESULTS: Midwives perceived the following functions of counseling performed well: 100% of Client-Counselor relation (CCR); 80% of Health Education (HE); and 17% Decision-Making Support (DMS). Congruence on HE of midwives with observers and with clients was ≥ 75%; congruence on DMS was higher between midwives and observers (80%) compared to midwives and clients (62%). CONCLUSION: Midwives perceive that during prenatal counseling the CCR and HE functions of counseling were performed well, whereas DMS was not. Furthermore, this study shows incongruence between midwives and clients about the discussion during DMS, indicating DMS is more difficult to assess than HE. PRACTICE IMPLICATIONS: The best way to measure prenatal counseling practice might be by using assessments of different sources within one study.

Prenatal screening, reproductive choice, and public health.

One widely held view of prenatal screening (PNS) is that its foremost aim is, or should be, to enable reproductive choice; this is the Pure Choice view. The article critiques this position by comparing it with an alternative: Public Health Pluralism. It is argued that there are good reasons to prefer the latter, including the following. (1) Public Health Pluralism does not, as is often supposed, render PNS more vulnerable to eugenics-objections. (2) The Pure Choice view, if followed through to its logical conclusions, may have unpalatable implications, such as extending choice well beyond health screening. (3) Any sensible version of Public Health Pluralism will be capable of taking on board the moral seriousness of abortion and will advocate, where practicable, alternative means of reducing the prevalence of disease and disability. (4) Public Health Pluralism is at least as well-equipped as the Pure Choice model to deal with autonomy and consent issues.

A new ethical landscape of prenatal testing: individualizing choice to serve autonomy and promote public health: a radical proposal.

A new landscape of prenatal testing (PNT) is presently developing, including new techniques for risk-reducing, non-invasive sampling of foetal DNA and drastically enhanced possibilities of what may be rapidly and precisely analysed, surrounded by a growing commercial genetic testing industry and a general trend of individualization in healthcare policies. This article applies a set of established ethical notions from past debates on PNT for analysing PNT screening-programmes in this new situation. While some basic challenges of PNT stay untouched, the new development supports a radical individualization of how PNT screening is organized. This reformation is, at the same time, difficult to reconcile with responsible spending of resources in a publicly funded healthcare context. Thus, while the ethical imperative of individualization holds and applies to PNT, the new landscape of PNT provides reasons to start rolling back the type of mass-screening programmes currently established in many countries. Instead, more limited offers are suggested, based on considerations of severity of conditions and optimized to simultaneously serve reproductive autonomy and public health within an acceptable frame of priorities. The new landscape of PNT furthermore underscores the ethical importance of supporting and including people with disabilities. For the very same reason, no ban on what may be analysed using PNT in the new landscape should be applied, although private offers must, of course, conform to strict requirements of respecting reproductive autonomy and what that means in terms of counselling.

Prenatal screening: an ethical agenda for the near future.

Prenatal screening for foetal abnormalities such as Down's syndrome differs from other forms of population screening in that the usual aim of achieving health gains through treatment or prevention does not seem to apply. This type of screening leads to no other options but the choice between continuing or terminating the pregnancy and can only be morally justified if its aim is to provide meaningful options for reproductive choice to pregnant women and their partners. However, this aim should not be understood as maximizing reproductive choice per se. Only if understood as allowing prospective parents to avoid suffering related to living with (a child with) serious disorders and handicaps can prenatal screening be a publicly or collectively funded programme. The alternative of moving prenatal testing outside the healthcare system into the private sector is problematic, as it makes these tests accessible only to those who can afford to pay for it. New developments in prenatal screening will have to be assessed in terms of whether and to what extent they either contribute to or undermine the stated aim of providing meaningful options for reproductive choice. In the light of this criterion, this article discusses the introduction of the new non-invasive prenatal test (NIPT), the tendency to widen the scope of follow-up testing, as well as the possible future scenarios of genome-wide screening and 'prenatal personalised medicine'. The article ends with recommendations for further debate, research and analysis.

Prenatal screening for congenital anomalies: exploring midwives' perceptions of counseling clients with religious backgrounds.

BACKGROUND: In the Netherlands, prenatal screening follows an opting in system and comprises two non-invasive tests: the combined test to screen for trisomy 21 at 12 weeks of gestation and the fetal anomaly scan to detect structural anomalies at 20 weeks. Midwives counsel about prenatal screening tests for congenital anomalies and they are increasingly having to counsel women from religious backgrounds beyond their experience. This study assessed midwives' perceptions and practices regarding taking client's religious backgrounds into account during counseling. As Islam is the commonest non-western religion, we were particularly interested in midwives' knowledge of whether pregnancy termination is allowed in Islam. METHODS: This exploratory study is part of the DELIVER study, which evaluated primary care midwifery in The Netherlands between September 2009 and January 2011. A questionnaire was sent to all 108 midwives of the twenty practices participating in the study. RESULTS: Of 98 respondents (response rate 92%), 68 (69%) said they took account of the client's religion. The two main reasons for not doing so were that religion was considered irrelevant in the decision-making process and that it should be up to clients to initiate such discussions. Midwives' own religious backgrounds were independent of whether they paid attention to the clients' religious backgrounds. Eighty midwives (82%) said they did not counsel Muslim women differently from other women. Although midwives with relatively many Muslim clients had more knowledge of Islamic attitudes to terminating pregnancy in general than midwives with relatively fewer Muslim clients, the specific knowledge of termination regarding trisomy 21 and other congenital anomalies was limited in both groups. CONCLUSION: While many midwives took client's religion into account, few knew much about Islamic beliefs on prenatal screening for congenital anomalies. Midwives identified a need for additional education. To meet the needs of the changing client population, counselors need more knowledge of religious opinions about the termination of pregnancy and the skills to approach religious issues with clients.

Management of vaginal agenesis.

PURPOSE OF REVIEW: Mayer-Rokitansky-Küster-Hauser syndrome is undergoing new research outcomes involving genetics and management. RECENT FINDINGS: Recent literature supports a polygenic multifactorial genetic basis for the syndrome. Management is now predominantly by vaginal dilators and nonsurgical, but holistic. The future of uterine transplantation is discussed. SUMMARY: New developments open new possibilities for understanding the genetic basis of the disease, and research in this area will continue. Management in terms of fertility may have an added dimension if uterine transplantation and successful pregnancy outcome can be proven.

[Diagnostics of genetic malformations in small ruminants]. / Diagnostik kongenitaler Missbildungen beim kleinen Wiederkäuer.

The epidemic occurrence of the Schmallenberg virus has induced numerous congenital malformations in small ruminants. Because of this high incidence of malformed lambs, an overview of the different causes of congenital malformations is provided. The most frequent infectious and physical causes as well as mineral and vitamin deficiencies and toxic agents which can induce congenital malformations are indicated. This list is supplemented by advice on sampling and laboratory diagnosis for an etiological diagnosis of the malformations.

Polymorphisms in folate-metabolizing genes and risk of having an offspring with congenital anomalies in the West Siberian region of Russia: a case-control study.

OBJECTIVE: Periconceptional folate supplementation prevents a number of congenital anomalies (CA). The aim of our study was to investigate the association of 11 polymorphisms in the folate-metabolizing genes with the risk of having an offspring with CA in the Russian ethnic group. METHOD: We genotyped 280 mothers having a CA-affected pregnancy and 390 control mothers. The most common malformations among the cases were CA of the nervous, urinary, and cardiovascular systems, and these groups were analyzed separately. RESULTS: In the whole group of CA, we revealed the associations of MTHFR C677T and MTR A2756G loci with increased risk of CA-affected pregnancy. In the group of CA of the cardiovascular system, we observed an association of MTHFR A1298C with decreased risk and an association of MTR A2756G with increased risk of CA. After the Bonferroni correction, only the association between the genotype MTR 2756GG and the risk of having a fetus with CA of the cardiovascular system remained statistically significant (OR = 4.99, P = 0.03). CONCLUSION: These findings indicate that locus A2756G in the MTR gene may play a role in susceptibility to CA of the cardiovascular system in West Siberia, but further research is necessary to confirm the association.

Three generations of matrilineal excess of birth defects in Irish families with neural tube defects.

BACKGROUND: Neural tube defects (NTDs) and birth defects overall are more likely to occur among maternal compared to paternal relatives in two generations (uncles/aunts and first cousins) of Irish families where an individual has been born with an NTD. AIMS: The aim of this study was to determine if the matrilineal excess persisted into the third generation. METHODS: First cousins were interviewed about their pregnancy outcomes and their offsprings' health. RESULTS: Maternal first cousins once removed (FCOR) were more likely to have birth defects than paternal FCOR: 6.7 versus 3.5% (adjusted odds ratio 1.49, 95% CI 0.57, 3.89). No NTDs occurred. Folic acid supplementation significantly reduced the risk of birth defects (P = 0.04). CONCLUSIONS: This study demonstrates an excess of birth defects among maternal relatives in three consecutive generations of NTD families, and supports the hypothesis that an underlying mechanism links distant maternal relatives in at least some NTD families.

Socioeconomic status in relation to selected birth defects in a large multicentered US case-control study.

This study examined individual and household socioeconomic status (SES) in relation to phenotypes of neural tube defects, orafacial clefts, and conotruncal heart defects using data from the National Birth Defects Prevention Study with 2,551 nonmalformed liveborn controls and 1,841 cases delivered in 1997-2000. The individual SES was measured by maternal and paternal education, occupation, and household income. All individual SES measures were combined to create a household SES index. Elevated risks were found for maternal low education in association with anencephaly and dextrotransposition of the great arteries (dTGA) (adjusted odds ratios (AORs) > or = 1.4); paternal low education in association with anencephaly, cleft palate, tetralogy of Fallot (TOF), and dTGA (AORs > or = 1.4); low household income in association with TOF (AOR = 1.4, 95% confidence interval (CI): 0.8, 2.5); maternal operator/laborer occupation in association with cleft palate, TOF, and dTGA (AORs > or = 1.4); paternal operator/laborer occupation in association with spina bifida (AOR = 1.4, 95% CI: 1.0, 2.0); and either parent's unemployment in association with dTGA (AOR > or = 1.4). Subjects with the lowest household SES index had the greatest risks of all selected birth defects except TOF. This study reveals consistently increased risks of selected birth defects in association with household SES index but not individual SES measures.

Folate supplementation in three genetic models: implications for understanding folate-dependent developmental pathways.

Supplementation of a pregnant mother's diet with folate has been shown to protect the developing embryo from birth defects in humans as well as rodent animal models. Folate supplementation not only reverses a potential nutritional deficiency; folate effectively prevents defects even when the mother's nutritional status is normal. These findings indicate that folate is able to interact with the molecular pathways that control normal embryonic development. Supplementation studies in animals provide the experimental starting point for the identification of such folate-responsive pathways. This review summarizes the progress to date in understanding the folate response in genetic models of birth defects in the mouse.

[Active screening for genetic pathology in newborns. I. Registration of congenital abnormalities]. / Aktiven skrining za genetichna patologiia sred novorodeni. I. Registratsiia na vrodeni anomalii.

Active screening for genetic pathology over a period of 12 years (1990-2001) involved examination of 29,629 newborns at the Clinic of Obstetrics and Gynaecology. Congenital anomalies were detected in 1244 cases (live-, stillbirths and terminated pregnancies) which gives an average incidence rate of 42.0 per 1000 among the studied population. Congenital cardiac anomalies and CA of the central nervous system were the most common types of isolated CA. They provided frequencies of 7.76 per 1000 and 6.85 per 1000 cases respectively. The incidence of the neural tube defects (NTD), particularly, varied throughout the years (t = 2.69; p < 0.01) but stated high--on average 2.12 per 1000 with the highest rate of 3.89 per 1000 in 1993. A reduction in the incidence of NTD is possible with a recommendation of periconceptional folic acid supplementation. Registration of CA is a strategy for identifying families at risk to give births of child with CA. This approach enabled us to provide more accurate genetic counselling and prenatal diagnosis for genetic pathology. Active screening of newborn population is likely to be an effective and necessary service.

Human Phenome based on traditional Chinese medicine--a solution to congenital syndromology.

The occurrence of many congenital syndromes has long been an enigma. Clinically, the phenotype of any given genetic defect usually varies to some extent, whilst, pathogenetically, features within each syndrome are probably interconnected, albeit by largely unknown mechanisms. Through its unique theories such as the Jing-Mai (variously translated as the Channels, Vessels or Meridians), Zang-Fu (the Yin and Yang internal organs) and Wu-Xing (translated as the Five-Phase Correspondence or Five-Element theory), traditional Chinese medicine (TCM) seems to have comprehensively summarized the makeup of the human phenotypes. By combining the above TCM theories with modem medical knowledge, the intrinsic mechanisms between various aspects of the phenotypic makeup of the human individual, i.e. the Human Phenome, may be deduced. Analysis of congenital syndromes in light of the Human Phenome seems to suggest that various genetic defects may cause diseases in a similar fashion; i.e. primarily with structural abnormalities distributed along the four Jing-Mai connected with the Kidneys (midline defects) as well as "Marrow" aberrations (anomalies of hematology/immunology, endocrine, central nervous system and the bones). The derived Human Phenome may thereby enable a better understanding of such conditions and provide a model for the study of multigenic traits. On the other hand, blind spots of clinical observation and unknown aspects of human nature, e.g. circuits formed by the JingMai, symmetries of the Jing-Mai and Zang-Fu, and correspondences between body physiques, spiritual factors and the external world may also be deduced. The TCM-based Human Phenome may thereby offer a fresh view for genotype-phenotype correlations, insights into genedevelopment mechanisms, as well as potential directions for the development of new treatments.

Prevention of developmental abnormalities with particular emphasis of primary prevention.

The Hungarian total (birth + fetal) prevalences of different developmental abnormalities offer a possibility to estimate the proportion of preventable development abnormalities. The effectiveness of primary, secondary and tertiary preventive methods are evaluated with a particular emphasis of primary prevention based on periconceptional folic acid or folic acid-containing multivitamin supplementation. The total prevalence of informative offspring with developmental abnormalities is 66.83 per 1,000 in Hungary and within this major DAs have 27.01 per 1,000 rate. The latter can be reduced by 26.6% by primary preventive methods due to mainly periconceptional folic acid/multivitamin supplementation. Secondary prevention particularly neonatal orthopedic screening is very effective for deformities such as congenital dislocation of the hip. Antenatal diagnoses followed by termination of pregnancy can avoid the birth of malformed newborn infants in 8.7% of DAs, however, this figure is 20 and 27% among major and multiple developmental abnormalities, respectively. Early surgical intervention can achieve a complete recovery in 33.5% of cases with developmental abnormalities. Thus there are two major conclusions: at present the major part of developmental abnormalities are preventable, however, different developmental abnormalities do not represent a single pathological category therefore there is no single strategy for their prevention.

5,10-Methylenetetrahydrofolate reductase gene variants and congenital anomalies: a HuGE review.

The enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR) is involved in folate metabolism. The MTHFR gene is located on chromosome 1 (1p36.3), and two common alleles, the C677T (thermolabile) allele and the A1298C allele, have been described. The population frequency of C677T homozygosity ranges from 1% or less among Blacks from Africa and the United States to 20% or more among Italians and US Hispanics. C677T homozygosity in infants is associated with a moderately increased risk for spina bifida (pooled odds ratio = 1.8; 95% confidence interval: 1.4, 2.2). Maternal C677T homozygosity also appears to be a moderate risk factor (pooled odds ratio = 2.0; 95% confidence interval: 1.5, 2.8). The A 1298C allele combined with the C677T allele also could be associated with an increased risk for spina bifida. Some data suggest that the risk for spina bifida associated with C677T homozygosity may depend on nutritional status (e.g., blood folate levels, intake of vitamins) or on the genotype of other folate-related genes (e.g., cystathionine-beta-synthase and methionine synthase reductase). Studies of the C677T allele in relation to oral clefts, Down syndrome, and fetal anticonvulsant syndrome either have yielded conflicting results or have not been yet replicated.

Birth malformations in Babylon and Assyria.

In this paper, we intend to study the oldest systematic descriptions of birth malformations in the history of medicine, as they appear in cuneiform texts written four millennia ago in the land between the two rivers, Mesopotamia, the cradle of civilization, the land of Assyro-Babylonian culture. The core of our work will be an omen text, which was published in 1970 and, since then, has remained confined to the field of Assyriological studies; thus, the history of medicine and disease have not taken advantage of its knowledge. This text is known in Assyriology by its Akkadian name: "shumma izbu" (Izbu), "if an anomaly" [Leichty, 1970: The Omen series shumma izbu, Texts from Cuneiform Sources IV].