Sanger sequencing is no longer always necessary based on a single-center validation of 1109 NGS variants in 825 clinical exomes.

Despite the improved accuracy of next-generation sequencing (NGS), it is widely accepted that variants need to be validated using Sanger sequencing before reporting. Validation of all NGS variants considerably increases the turnaround time and costs of clinical diagnosis. We comprehensively assessed this need in 1109 variants from 825 clinical exomes, the largest sample set to date assessed using Illumina chemistry reported. With a concordance of 100%, we conclude that Sanger sequencing can be very useful as an internal quality control, but not so much as a verification method for high-quality single-nucleotide and small insertion/deletions variants. Laboratories might validate and establish their own thresholds before discontinuing Sanger confirmation studies. We also expand and validate 23 copy number variations detected by exome sequencing in 20 samples, observing a concordance of 95.65% (22/23).

Pautas de prevención de defectos congénitos con especial referencia a los niveles primario y secundario. Guías de actuación preventiva desde la atención primaria / Guidelines for the prevention of congenital defects, particularly at primary and secondary level. Prevention guidelines from Primary Care

La prevención de defectos congénitos (DC) no difiere en esencia de la que se sigue para cualquier otra enfermedad. En el primer nivel, el de la prevención primaria, se trata de impedir que se produzca el trastorno. El segundo nivel se aplica cuando el DC ya se ha producido, y consiste en curar la enfermedad o, cuando ello no es posible, como en la mayoría de los DC, evitar que se agrave. Este nivel se basa en el diagnóstico precoz y correcto de la enfermedad, y en instaurar inmediatamente el tratamiento adecuado y las medidas correctoras o paliativas. El tercer nivel se instaura una vez que han fracasado los 2 anteriores y se centra en medidas que mejoren la autonomía y la calidad de vida del paciente (integración social y laboral de los afectados, supresión de barreras arquitectónicas, etc.). Por último, existe un «cuarto nivel de prevención» que consiste en evitar toda sobreactuación médica, en la que se someta al paciente a pruebas innecesarias que no sólo no le ayudan sino que, además, pueden generarle efectos adversos añadidos incluyendo problemas psíquicos. En este artículo se resumen las medidas más relevantes que se deberían implantar desde el colectivo de médicos de atención primaria, para conseguir todos los niveles de prevención de DC y, especialmente, de prevención primaria (AU)

There is essentially no difference in the prevention of congenital defects (CD) from that of any other disease. Primary prevention consists of preventing the causes that produce the disease. Secondary prevention is applied when the CD has already occurred, and consists of curing the disease, or when this is not possible, as in the majority of CD, to prevent it getting worse. This level is based on the early and correct diagnosis of the disease, and initiating immediate and appropriate treatment and corrective or palliative measures. The third level is started when the previous ones fail, and is focussed on measures that improve independence and quality of life (social and occupational integration of those affected, removal of architectural obstacles, etc.). Lastly, there is a “fourth level of prevention”, which consists of avoiding over-medication, in which the patient is subjected to unnecessary tests, which not only do not help the patient, but can also produce added adverse effects, including psychiatric problems. This article summarises the most important measures that Primary Care doctors should introduce to achieve all levels of CD prevention, and particularly primary prevention (AU)

Tratamiento farmacológico de la mujer embarazada: fármacos contraindicados durante la gestación / Pharmacological treatment in the pregnant woman: drugs contraindicated during pregnancy

Los médicos de atención primaria atienden a las mujeres embarazadas y en edad reproductiva, por lo que han de decidir sobre el tratamiento que deben seguir. Para ello, han de enfrentarse a la difícil situación de evaluar el riesgo que las diferentes alternativas terapéuticas pueden suponer para el desarrollo embrionario/fetal. Una evaluación que no es sencilla porque no se pueden establecer normas de aplicación general. De hecho, un mismo medicamento puede ser utilizado en algunas mujeres embarazadas y no ser adecuado en otras. Esto implica que la decisión sobre el tratamiento que se debe aplicar durante el embarazo requiera una evaluación individualizada en cada mujer. Por otra parte, la identificación del efecto de los diferentes medicamentos sobre el desarrollo embrionario y fetal humano es muy difícil y, además, está generalmente basada en estudios epidemiológicos observacionales. Esto supone una dificultad añadida porque en muchos casos este tipo de publicaciones no resultan fáciles de entender, lo que dificulta su traslación a la práctica clínica. Esto dio lugar en muchos países a la organización de servicios de información telefónica sobre teratógenos, atendidos por expertos tanto en evaluación de los riesgos para el embrión y feto, como sobre los procesos del desarrollo prenatal. No obstante, sabemos que hay fármacos que no parecen alterar el desarrollo y que pueden utilizarse durante el embarazo si se necesitan, otros que sí conllevan riesgo pero tienen que utilizarse para controlar la enfermedad materna y, por último se conocen otros cuya utilización en mujeres embarazadas o que planean estarlo está contraindicada. Estos últimos en mujeres en edad reproductiva han de utilizarse siguiendo unas estrictas normas para prevención de embarazos. En este artículo se ofrece una visión general sobre los tratamientos en mujeres embarazadas o que pueden estarlo, junto con sus potenciales efectos y se ofrece la lista de aquellos fármacos que se consideran seguros de utilizar durante la gestación y los que están contraindicados (AU)

As primary care doctors treat pregnant women and those of fertile age, they must decide which treatments they should follow. Therefore, they have to confront the difficult situation of assessing the risks that different alternative treatments may have on embryo/foetal development. An assessment that is not straightforward as established general guidelines may not be applicable. For example, one drug may be used in some pregnant women but may not be appropriate in others. This implies that the decision on treatments given during pregnancy requires an individualised assessment in each woman. On the other hand, identifying the effects of different drugs on human embryo and foetal development is very difficult, and is also mainly based on observational epidemiological studies. This makes it even more difficult as in many cases these publications are not easy to understand, making it difficult to apply in clinical practice. This has led to introducing Telephone Information Services on Teratogenics in many countries, which are answered by experts in the assessment of risks for the embryo and foetus, as well as on the processes of prenatal development. However, we know that there are drugs that do not seem to affect this development and can be used during pregnancy if required. Similarly, others are also known to be used in pregnant women or those planning a pregnancy are totally contraindicated. For this reason, women who take these have to follow strict guidelines to prevent becoming pregnant. This article provides a general view on treatments for pregnant women or those planning a pregnancy, together with their potential effects, as well as a list of those drugs that may be considered safe to use during pregnancy, and those that are contraindicated (AU)

[Characteristics of neonates with and without a single umbilical artery. Analysis of two consecutive series of neonates with and without congenital defects]. / Características de los neonatos con y sin arteria umbilical única. Análisis de dos series consecutivas de recién nacidos con y sin defectos congénitos.

BACKGROUND AND OBJECTIVE: The implications of the presence of a single umbilical artery (SUA) are unknown. Although most articles are based on selected samples, they suggest a relationship between SUA and malformations. Consequently, prenatal detection of SUA causes concern, since there are no definitive guidelines that can be followed after identification of this abnormality. The objective of this study was to comparatively analyze SUA in two series of consecutive births, with and without congenital defects. PATIENTS AND METHODS: A total of 19,909 cases and 19,148 controls from the Registry of the Spanish Collaborative Study on Congenital Malformations were studied. The variables analyzed were sex, birth weight, length, occipito-frontal circumference, gestational age, prematurity, delivery by caesarean section, umbilical cord length, placental weight, survival at 72 hours, primiparity, oligohydramnios, and polyhydramnios. Calculations included relative frequency, odds ratios (OR) and 95 % confidence intervals, the chi-square test, Fisher's p-value, and Student's t-test. RESULTS: SUA was found in 2.29 % of cases and in 1.03 % of controls (p = 0.0000001). These figures showed secular variation due to improvements in prenatal diagnosis and interruption of some pregnancies. When cases with and without SUA were compared, those with SUA had lower values of somatometry at birth, umbilical cord length and gestational age and had a higher risk for oligohydramnios, polyhydramnios, caesarean section, and death in the first 72 hours. Among controls, the only differences were a shorter umbilical cord and a higher frequency of oligohydramnios among infants with SUA. CONCLUSIONS: The results suggest that certain malformations associated with SUA could cause some of the differences among cases. Shortening of the umbilical cord and oligohydramnios could be related to SUA, as these abnormalities were found in both cases and controls. Comparison of cases and controls suggests that the etiopathogenesis of SUA could differ in the two groups.

Características de los neonatos con y sin arteria umbilical única. Análisis de dos series consecutivas de recién nacidos con y sin defectos congénitos / Characteristics of neonates with and without a single umbilical artery. Analysis of two consecutive series of neonates with and without congenital defects

Antecedentes y objetivo Se desconocen las implicaciones de la presencia de arteria umbilical única (AUU). Aunque la mayoría de los trabajos utilizan muestras seleccionadas, sugieren una relación entre la AUU y malformaciones. Esto supone una gran preocupación cuando se detecta una AUU prenatalmente, ya que no hay pautas de actuación tras su identificación. El objetivo de este trabajo es analizar comparativamente la AUU en dos series consecutivas de nacimientos, con y sin defectos congénitos. Pacientes y métodos Se utilizaron 19.909 casos y 19.148 controles del Registro del Estudio Colaborativo Español de Malformaciones Congénitas, y se analizaron: sexo, peso, talla, perímetro cefálico, edad gestacional, prematuridad, parto por cesárea, longitud del cordón umbilical, peso de la placenta, supervivencia a las 72 h, primiparidad, oligoamnios y polihidramnios. Se calculó la frecuencia relativa, el odds ratio (OR) e intervalos de confianza del 95 %, chi cuadrado, valor p de Fisher, y la t de Student. Resultados El 2,29 % de los casos y el 1,03 % de controles tenían AUU (p = 0,0000001), mostrando variación secular por la mejora del diagnóstico prenatal, e interrupciones del embarazo. Comparando casos con y sin AUU, los que tenían AUU presentaban menores valores de somatometría al nacimiento, longitud del cordón y edad gestacional, y mayor riesgo de oligohidramnios, polihidramnios, cesárea y muerte antes de las 72 h. Entre los controles, sólo diferían en que los que tenían AUU, presentaban cordón más corto y mayor frecuencia de oligoamnios. Conclusiones Los resultados sugieren que ciertas malformaciones asociadas a la AUU, podrían ser responsables de las diferencias entre los casos. El acortamiento del cordón y oligohidramnios podrían relacionarse con la AUU, porque se asocia tanto entre casos como entre controles. Comparando los casos con los controles se sugiere que la AUU podría tener diferente etiopatogenia en ambos grupos

Background and objective The implications of the presence of a single umbilical artery (SUA) are unknown. Although most articles are based on selected samples, they suggest a relationship between SUA and malformations. Consequently, prenatal detection of SUA causes concern, since there are no definitive guidelines that can be followed after identification of this abnormality. The objective of this study was to comparatively analyze SUA in two series of consecutive births, with and without congenital defects. Patients and methods A total of 19,909 cases and 19,148 controls from the Registry of the Spanish Collaborative Study on Congenital Malformations were studied. The variables analyzed were sex, birth weight, length, occipito-frontal circumference, gestational age, prematurity, delivery by caesarean section, umbilical cord length, placental weight, survival at 72 hours, primiparity, oligohydramnios, and polyhydramnios. Calculations included relative frequency, odds ratios (OR) and 95 % confidence intervals, the chi-square test, Fisher's p-value, and Student's t-test. Results SUA was found in 2.29 % of cases and in 1.03 % of controls (p = 0.0000001). These figures showed secular variation due to improvements in prenatal diagnosis and interruption of some pregnancies. When cases with and without SUA were compared, those with SUA had lower values of somatometry at birth, umbilical cord length and gestational age and had a higher risk for oligohydramnios, polyhydramnios, caesarean section, and death in the first 72 hours. Among controls, the only differences were a shorter umbilical cord and a higher frequency of oligohydramnios among infants with SUA. Conclusions The results suggest that certain malformations associated with SUA could cause some of the differences among cases. Shortening of the umbilical cord and oligohydramnios could be related to SUA, as these abnormalities were found in both cases and controls. Comparison of cases and controls suggests that the etiopathogenesis of SUA could differ in the two groups

Pre-gestational maternal body mass index predicts an increased risk of congenital malformations in infants of mothers with gestational diabetes.

AIMS: The aim of the present study was to identify characteristics in women diagnosed with gestational diabetes mellitus (GDM) that could be predictive of congenital malformations in their infants. METHODS: Using data from the Spanish Collaborative Study of Congenital Malformations (ECEMC), a hospital-based case-control study and surveillance system, we assessed the relationship between a number of maternal variables, including pre-gestational body mass index (BMI), and specific congenital malformations in their infants. RESULTS: The overall risk for a selected group of congenital malformations in an infant of an obese mother with GDM compared with an obese mother with normal glucose tolerance (NGT) was 2.78 (1.38-5.55, P < 0.001). Within the group of mothers with GDM, obesity (BMI > or = 30 kg/m2) was associated with a significantly increased risk of cardiovascular defects compared with non-obese women [OR = 2.82 (1.31-7.04), P < 0.01]. In mothers with NGT, pre-gestational BMI was not associated with congenital malformations. CONCLUSION: Pre-gestational obesity is a predictive variable for congenital malformations in infants of mothers with GDM. The greater their BMI, the higher the risk for congenital malformations in their offspring. Given the blastogenic origin of the congenital defects identified, and the relationship between obesity and Type 2 diabetes, it is probable that this increased risk is as a result of previously unidentified pre-gestational diabetes mellitus (PGD). It is important that overweight and obese women planning a pregnancy be evaluated for the presence of diabetes.

Diagnóstico prenatal temprano del síndrome de regresión caudal asociado con la diabetes mellitus / Early antenatal diagnosis of caudal regression syndrome associated with diabetes mellitus

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Epidemiological evidence that maternal diabetes does not appear to increase the risk for Down syndrome.

In 1997, Narchi and Kulaylat, studying the incidence of Down syndrome in infants of gestational diabetic mothers, concluded that maternal diabetes increases the risk for Down syndrome, but failed to control the maternal age in their analysis. Using data from the Spanish Collaborative Study of Congenital Malformations (ECEMC), we analyzed the relationship between Down syndrome and maternal diabetes mellitus, and maternal gestational diabetes, controlling the maternal age through the pair-matching analysis, stratifying by maternal age and logistic regression analysis. The analyses show that maternal age is related either to Down syndrome as well as to both types of maternal diabetes. Thus, the overall analysis could be confounded by maternal age. Once we controlled the maternal age, the risk of maternal diabetes mellitus for Down syndrome is: odds ratio (OR) = 0.92 (0.41-2.07); P = 0.83. Controlling maternal age in gestational diabetes, the risk is OR = 1.18 (0.61-2.35); P > 0.70. Based on our results, we conclude that Down syndrome is related to maternal age, but does not seem to be related to any type of maternal diabetes.

Periconceptional exposure to contraceptive pills and risk for Down syndrome.

OBJECTIVE: There are some studies which analyzed the relationship between prenatal exposure to oral contraceptives (OCs) and Down syndrome, with conflicting results even in women using OCs and conceiving at different intervals after discontinuing the use of contraceptive pills. We analyzed the risk for Down syndrome in infants of women who become pregnant while taking OC. STUDY DESIGN: We used the data from the Spanish Collaborative Study of Congenital Malformations (ECEMC). The ECEMC is a case-control study and surveillance system. For each malformed infant (case), the next non-malformed infant of the same sex born in the same hospital is selected as a control subject, from whom the collaborating physicians collected the same data as for the malformed infant. For the present study, we used two different approaches. First, the pair-matching analysis. Second, a case-control using the rest of the total of 17,183 controls from the ECEMC database with specified data on maternal use of OCs and maternal age. To control for maternal age, we used a logistic regression analysis. RESULTS: The results show an increased risk of 2.8-fold for infants with Down syndrome in women younger than 35 years of age if the mother became pregnant while she was taking OCs. We did not observe this result for women older than 34 years of age. CONCLUSION: Our results showed that the risk for Down syndrome in infants born to mothers with less than 35 years of age (as a group) who became pregnant while taking OCs is near the risk for Down syndrome of mothers with more than 34 years of age, women who are candidates for prenatal diagnosis. Thus, based on our results, one may consider the possibility of offering prenatal diagnosis for Down syndrome to young women who became pregnant while taking OCs.

Exstrophy of the cloaca and exstrophy of the bladder: two different expressions of a primary developmental field defect.

Exstrophy of the bladder (EB) and exstrophy of the cloaca (EC) are generally recognizable as distinct clinical entities. In patients with EB, the posterior bladder wall is exposed through a midline defect of the abdomen. The umbilicus is inferiorly displaced and located close to the superior margin of the exstrophic bladder. Genital abnormalities are common in boys and girls who may present epispadias and a small, split phallus or a split clitoris, a bifid uterus, and a duplicate or exstrophic vagina. In contrast to classic EB, EC is commonly associated with omphalocele, spinal defects, and incompletely formed external genitalia and is always associated with imperforate anus. Some authors state that EC and EB constitute two distinct disorders, but others consider them part of a "continuum," representing different levels of severity within the same spectrum. The use of the acronym OEIS to refer to the combination of omphalocele, exstrophy, imperforate anus, and spinal defects, in our opinion, has not helped to clarify the clinical definition, pathogenesis, or cause of this multiple congenital anomaly (MCA) pattern, mostly because the term makes no distinction between EC or EB. Here we present the epidemiological analysis of a group of characteristics in infants with EC and infants with EB to determine if they constitute two different entities. We also analyze if the different combinations of omphalocele, imperforate anus, and spinal defects are more frequent in infants with EC than in infants with MCA patterns other than EC and EB. The prevalence in our data for EC was 1:200,233 live births and 1:35,597 for EB. The clinical analysis indicated that the study defects (omphalocele, spine defects, spina bifida, and imperforate anus) tend to occur together in the same child with a higher frequency if the child has the EC defect than in infants with MCA patterns that did not include EC or EB. Our findings of low birth weight, twinning, single umbilical artery, and preferentially associated malformations suggest that EC is the result of damage occurring very early in development and that EC and EB are two different expressions of a primary polytopic developmental field defect.

High maternal fever during gestation and severe congenital limb disruptions.

Hyperthermia is defined as a temperature of at least 1.5 degrees C over the normal core body temperature. It is a proven teratogen in animals and in humans. The type of defects induced by hyperthermia in experimental animals are: anencephaly/exencephaly, encephalocele, microphthalmia, arthrogryposis, abdominal wall defects, limb deficiencies, embryonic death, and resorption. In humans it has been observed that infants prenatally exposed to hyperthermia presented with spina bifida, encephalocele, microphthalmia, micrognathia, external ear anomalies, cardiac defects, hypospadias, gastrointestinal defects, cleft lip and/or cleft palate, abdominal wall defects, diaphragmatic hernia, Hirschsprung disease, Möbius syndrome, oromandibular-limb hypogenesis spectrum, and spontaneous abortions. We describe an additional case with severe limb deficiencies whose mother had fever over 39 degrees C for 2 days in the second and in the fourth month of amenorrhoea. We conclude that, based on the degree of development of the humeri and the femora and the type of limb deficiencies, this case presents a disruption that most probably occurred in the fourth month of gestation.

Epidemiologic analysis of prenatal exposure to cough medicines containing dextromethorphan: no evidence of human teratogenicity.

BACKGROUND: In a recent experimental study on chick embryos, Andaloro et al. (1998, Pediatr. Res. 43:1-7) observed a relationship between neural crest/neural tube defects (NTDs) and prenatal exposure to dextromethorphan. These authors made an extrapolation of their results to the human embryo, indicating that this drug could produce NTDs in humans. Rosenquist (1999, Teratology 60:58-60) based on the results of the epidemiologic study performed by Ferencz et al. (1997, Perspect. Pediatr. Cardiol. 5:50-162), concluded that dextromethorphan could cause congenital heart defects in humans. Because this drug is an over-the-counter drug, the suggestion of those authors has led to great controversy and public concern about the possible teratogenic effect of this drug on the human embryo. METHODS: We present the results of a case-control study by using logistic regression analyses on the effect of prenatal exposure to drugs containing dextromethorphan only, or in combination with other drugs, on human development. We mostly analyzed dextromethorphan. The study was designed in part as hypothesis confirmation for NTDs and congenital heart defects and, in part, as hypotheses generation by testing the association with many other congenital defects. RESULTS: The results do not show a relation between the occurrence of NTDs and heart defects or other defects with exposure to drugs containing dextromethorphan. CONCLUSIONS: The usual use of dextromethorphan in cough medications during pregnancy does not increase the risk for congenital defects.

Anal atresia, vertebral, genital, and urinary tract anomalies: a primary polytopic developmental field defect identified through an epidemiological analysis of associations.

Anal atresia (AA) is observed per se or as part of different Mendelian or chromosomal syndromes, and as part of the VACTERL primary developmental field, CHARGE association, cloacal extrophy, in a mitochondrial cytopathy, and other multiple congenital anomaly patterns. There are only a few studies on the defects associated with AA, and in all of them it was observed that genitourinary defects are most frequent in infants with AA. Here we present the analysis of 28,410 malformed infants to study the frequency of 11 selected congenital defects in infants with AA in relation to their frequency in infants with multiple congenital anomaly patterns without AA. We conclude that the association of AA + spine defects + renal/urinary tract defects + genital defects constitutes a group of defects that tends to be present together in the same child because they are pathogenetically related, and since they are of blastogenetic origin they constitute a primary polytopic developmental field defect.

Body stalk defects, body wall defects, amniotic bands with and without body wall defects, and gastroschisis: comparative epidemiology.

The presence of body wall defects with "evisceration" of thoracic and/or abdominal organs associated with other congenital anomalies, with or without limb deficiencies, is considered to be the body wall complex (BWC). The BWC is different from gastroschisis, which is usually a small body wall defect lateral to the umbilical cord that is not covered by any membrane and, in most of the cases, is an isolated defect. For the present analysis we separated the BWC group into three subgroups. One group was that of body stalk anomalies characterized by severe defects of the abdominal wall with absence of, or very small, umbilical cord, or this is continuing with the placenta. The second group was made up of those infants with body wall defects without amniotic bands, and the third group was of those children with body wall defects produced by amniotic bands. We considered two additional groups in the analysis, one was of infants with gastroschisis and the other those infants with amniotic bands without body wall affectation. We also included the control group (nonmalformed infants) for comparisons. From the results of our epidemiological study, we can conclude that amniotic bands with body wall affectation and amniotic bands without body wall defects are two different entities. The results also suggest that the characteristics of infants with amniotic bands with body wall defects are more similar to the group of infants with body stalk anomalies. This may indicate that the former group is produced during the very early gestation.

Prenatal exposure to valproic acid during pregnancy and limb deficiencies: a case-control study.

We conducted a case-control study using data from the Spanish Collaborative Study of Congenital Malformations (ECEMC) on the relationship between prenatal exposure to valproic acid (VPA) and the presence of limb deficiencies in newborn infants. Among a total of 22,294 consecutive malformed infants (once we excluded genetic syndromes) and 21,937 control infants with specified data on antiepileptic drugs during gestation, 57 malformed infants and 10 control infants were exposed to VPA during the first trimester of pregnancy. Of the total of malformed infants exposed to VPA, 36.8% (21/57) presented with congenital limb defects of different types (including overlapping digits, talipes, clubfoot, clinodactyly, arachnodactyly, hip dislocation, pre- and postaxial polydactyly, etc.), three of them having limb deficiencies. The result of the case-control analysis shows a risk for limb deficiencies of odds ratio = 6.17 [confidence interval (CI) 1.28-29.66, P = 0.023], after controlling for potential confounder factors. If we consider that in our population the prevalence at birth of this type of defect is 6.88 per 10,000 livebirths (95% CI 6.43-7.36) we can estimate that the risk for women treated with VPA of having a baby with limb deficiencies would be around 0.42%. The limb deficiencies in the three patients exposed to VPA were the following: the first case was a newborn infant with hypoplasia of the left hand, the second patient was a newborn infant with unilateral forearm defect and hypoplastic first metacarpal bone in the left hand, and the third patient presented with short hands with hypoplastic first metacarpal bone, absent and hypoplastic phalanges, retrognathia, facial asymmetry, hypospadias, teleangiectatic angioma in skull, and hypotonia.