Congenital malformations and genetic diseases in Iranian infants

Summary Data of 13,037 live-born infants from a hospital in Tehran, Iran were analysed for congenital malformations and genetic diseases. The results showed that the rates of joint dislocation, eleft lip, cleft palate and finger anomalies are similar to those of the other populations. The rates of chromosomal, thorax and abdominal, external genital anomalies and other syndromes were higher compared with other populations, whereas the rates of multiple births and limb anomalies were lower.     

A neonatal case of left ventricular noncompaction associated with trisomy 18

A neonatal case of left ventricular non-compaction associated with trisomy 18: Left ventricular noncompaction (LVNC) is a rare congenital cardiomyopathy and exact etiology is still unknown. Trisomy 18 is the second most common autosomal trisomy in live-born infants. LVNC has been described in association with other dysmorphic features, association with trisomy 18 has not been reported previously in a neonate. LVNC broadens the cardiac anomalies associated with trisomy 18.     

Simultaneous screening of multiple mutations by invader assay improves molecular diagnosis of hereditary hearing loss: a multicenter study

Although etiological studies have shown genetic disorders to be a common cause of congenital/early-onset sensorineural hearing loss, there have been no detailed multicenter studies based on genetic testing. In the present report, 264 Japanese patients with bilateral sensorineural hearing loss from 33 ENT departments nationwide participated. For these patients, we first applied the Invader assay for screening 47 known mutations of 13 known deafness genes, followed by direct sequencing as necessary. A total of 78 (29.5%) subjects had at least one deafness gene mutation. Mutations were more frequently found in the patients with congenital or early-onset hearing loss, i.e., in those with an awareness age of 0-6 years, mutations were significantly higher (41.8%) than in patients with an older age of awareness (16.0%). Among the 13 genes, mutations in GJB2 and SLC26A4 were mainly found in congenital or early-onset patients, in contrast with mitochondrial mutations (12S rRNA m.1555A>G, tRNA(Leu(UUR)) m.3243A>G), which were predominantly found in older-onset patients. The present method of simultaneous screening of multiple deafness mutations by Invader assay followed by direct sequencing will enable us to detect deafness mutations in an efficient and practical manner for clinical use.     

Prevalence of congenital anomalies at birth among offspring of women at risk for a genetic disorder and with a normal second-trimester ultrasound.

The goal of this study was to determine the prevalence and the nature of congenital anomalies found at birth in offspring of women who had a normal second-trimester ultrasound and/or amniocentesis. Two groups of women were studied in our prenatal diagnosis clinic between 1991-1997. Group 1 consisted of pregnant women who had an amniocentesis for advanced maternal age (AMA), or for familial chromosomal or monogenic disorders. Group 2 consisted of pregnant women attending the prenatal diagnosis clinic and who had no indication for amniocentesis. Those with an abnormal ultrasound and/or amniocentesis were excluded. At the time of delivery, a questionnaire was sent pertaining to perinatal complications and the anomalies detected during the neonatal period. From a total of 15, 370 questionnaires sent from 1991-1997, 10,823 (group 1, n = 8,877; group 2, n = 1,946) were returned (overall response rate, 70.4%). Mean maternal age was 36 years in group 1 and 29 years in group 2. The prevalence of perinatal complications was similar in the two groups. In each group, the prevalence of all unforeseen anomalies was 2.9%. In group 1, the distribution of those anomalies was: major anomalies, 67.7%; minor anomalies, 23.9%; and multiple congenital anomalies (MCA), 8.3%. In group 2, the distribution was: major anomalies, 70.7%; minor anomalies, 24.1%; and MCA, 5.2%. In patients at risk for a genetic disease and consulting in a prenatal diagnosis clinic, the prevalence of all anomalies diagnosed at birth was 2.9%, even if the second-trimester ultrasound and amniocentesis results were normal. Therefore, it is important to inform those couples of this remaining risk.     

Granulomatous skin lesions complicating Varicella infection in a patient with Rothmund-Thomson syndrome and immune deficiency: case report

Acro-cardio-facial syndrome (ACFS) is a rare genetic disorder characterized by split-hand/split-foot malformation (SHFM), facial anomalies, cleft lip/palate, congenital heart defect (CHD), genital anomalies, and mental retardation. Up to now, 9 patients have been described, and most of the reported cases were not surviving the first days or months of age. The spectrum of defects occurring in ACFS is wide, and both interindividual variability and clinical differences among sibs have been reported. The diagnosis is based on clinical criteria, since the genetic mechanism underlying ACFS is still unknown. The differential diagnosis includes other disorders with ectrodactyly, and clefting conditions associated with genital anomalies and heart defects. An autosomal recessive pattern of inheritance has been suggested, based on parental consanguinity and disease's recurrence in sibs in some families. The more appropriate recurrence risk of transmitting the disease for the parents of an affected child seems to be up to one in four. Management of affected patients includes treatment of cardiac, respiratory, and feeding problems by neonatal pediatricians and other specialists. Prognosis of ACFS is poor.     

Clinical and diagnostic approach in unsolved CDG patients with a type 2 transferrin pattern

Dysmorphic features, multisystem disease, and central nervous system involvement are common symptoms in congenital disorders of glycosylation, including several recently discovered Golgi-related glycosylation defects. In search for discriminative features, we assessed eleven children suspected with a Golgi-related inborn error of glycosylation. We evaluated all genetically unsolved patients, diagnosed with a type 2 transferrin isofocusing pattern in the period of 1999-2009. By combining biochemical results with characteristic clinical symptoms, we used a diagnostic flow chart to approach the underlying defect in patients with congenital disorders of glycosylation-IIx. According to specific symptoms and laboratory results, we initiated additional, targeted biochemical and genetic studies. We found a distinctive spectrum of congenital disorders of glycosylation type 2-associated anomalies including sudden hearing loss, brain malformations, wrinkled skin, and epilepsy in combination with skeletal dysplasia, dilated cardiomyopathy, sudden cardiac arrest, abnormal copper and iron metabolism, and endocrine abnormalities in our patients. One patient with severe cortical malformations and mild skin abnormalities was diagnosed with a known genetic syndrome, due to an ATP6V0A2 defect. Here, we present unique congenital disorders of glycosylation type 2-associated anomalies, including both ATPase-related and unrelated cutis laxa and sensorineural hearing loss, a recently recognized symptom of congenital disorders of glycosylation. Based on our findings, we recommend clinicians to consider congenital disorders of glycosylation in patients with cardiac rhythm disorders, spondylodysplasia and biochemical abnormalities of the copper and iron metabolism even in absence of intellectual disability.     

Biochemical and genetic aspects of 7-dehydrocholesterol reductase and Smith-Lemli-Opitz syndrome

In recent years, several inherited human disorders caused by defects in cholesterol biosynthesis have been identified. These are characterized by malformations, multiple congenital anomalies, mental and growth retardation and/or skeletal and skin abnormalities indicating a pivotal role of cholesterol in morphogenesis and embryonic development. The first recognized and most common of these developmental disorders is Smith-Lemli-Opitz syndrome, an autosomal recessive trait caused by mutations in the DHCR7 gene resulting in a deficiency of the encoded sterol Delta(7)-reductase, alternatively called 7-dehydrocholesterol reductase (EC 1.3.1.21). This enzyme catalyzes the final step in cholesterol biosynthesis, which is the reduction of the Delta(7) double bond of 7-dehydrocholesterol to produce cholesterol.     

Genetic load of hereditary diseases in populations of the Krasnodar Krai]

Medico-genetical study of populations living in Krasnodar district was carried out. The mean value of genetic load contributed by autosomal dominant diseases composed 0.92 +/- 0.06, this value being 0.56 +/- 0.04 for autosomal recessive and 0.36 +/- 0.05 for X-linked recessive disorders per one thousand. Comparative analysis of genetical load in urban and rural populations demonstrated that they had no differences in relation to genetical load contributed by autosomal recessive and X-linked recessive disorders. At the same time, significant differences were noted between the populations concerning genetic load contributed by autosomal-dominant disorders.     

Transgenerational transmission of radiation- and chemically induced tumors and congenital anomalies in mice: studies of their possible relationship to induced chromosomal and molecular changes

This article provides a broad overview of our earlier studies on the induction of tumors and congenital anomalies in the progeny of X-irradiated or chemically treated mice and our subsequent (published, hitherto unpublished and on-going) investigations aimed at identifying potential relationships between genetic changes induced in germ cells and the adverse effects manifest as tumors and congenital anomalies using cytogenetic and molecular approaches. The earlier studies document the fact that tumors and congenital anomalies can be induced by irradiation or treatment with certain chemicals such as urethane and that these phenotypes are heritable i.e., transmitted to generations beyond the first generation. These findings support the view that transmissible induced genetic changes are involved. The induced rates of congenital abnormalities and tumors are about two orders of magnitude higher than those recorded in the literature from classical mutation studies with specific locus mutations. The cytogenetic studies addressed the question of whether there were any relationships between induced translocations and induced tumors. The available data permit the inference that gross chromosomal changes may not be involved but do not exclude smaller induced genetic changes that are beyond the resolution of the techniques used in these studies. Other work on possible relationship between visible chromosomal anomalies (in bone marrow preparations) and tumors were likewise negative. However, there were indications that some induced cytogenetic changes might underlie induced congenital anomalies, i.e., trisomies, deletions and inversions were observed in induced and transmissible congenital anomalies (such as dwarfs, tail anomalies). Studies that explored possible relationships between induction of minisatellite mutations at the Pc-3 locus and tumors were negative. However, gene expression analysis of tumor (hepatoma)-susceptible offspring of progeny descended from irradiated male mice showed abnormal expression of many genes. Of these, only very few were oncogenes. This lends some support to our hypothesis that cumulative changes in gene expression of many genes, which perform normal cellular functions, may contribute to the occurrence of tumors in the offspring of irradiated or chemically treated mice.     

Autosomal recessive cerebellar ataxias

Autosomal recessive cerebellar ataxias (ARCA) are a heterogeneous group of rare neurological disorders involving both central and peripheral nervous system, and in some case other systems and organs, and characterized by degeneration or abnormal development of cerebellum and spinal cord, autosomal recessive inheritance and, in most cases, early onset occurring before the age of 20 years. This group encompasses a large number of rare diseases, the most frequent in Caucasian population being Friedreich ataxia (estimated prevalence 2–4/100,000), ataxia-telangiectasia (1–2.5/100,000) and early onset cerebellar ataxia with retained tendon reflexes (1/100,000). Other forms ARCA are much less common. Based on clinicogenetic criteria, five main types ARCA can be distinguished: congenital ataxias (developmental disorder), ataxias associated with metabolic disorders, ataxias with a DNA repair defect, degenerative ataxias, and ataxia associated with other features. These diseases are due to mutations in specific genes, some of which have been identified, such as frataxin in Friedreich ataxia, α-tocopherol transfer protein in ataxia with vitamin E deficiency (AVED), aprataxin in ataxia with oculomotor apraxia (AOA1), and senataxin in ataxia with oculomotor apraxia (AOA2). Clinical diagnosis is confirmed by ancillary tests such as neuroimaging (magnetic resonance imaging, scanning), electrophysiological examination, and mutation analysis when the causative gene is identified. Correct clinical and genetic diagnosis is important for appropriate genetic counseling and prognosis and, in some instances, pharmacological treatment. Due to autosomal recessive inheritance, previous familial history of affected individuals is unlikely. For most ARCA there is no specific drug treatment except for coenzyme Q10 deficiency and abetalipoproteinemia.     

An epidemiologic study of congenital malformations of the anterior abdominal wall in more than half a million consecutive live births.

The records of an ongoing health surveillance registry that utilizes multiple sources of ascertainment were used to study the incidence rate of congenital malformations of the anterior abdominal wall in live-born children in British Columbia during the period 1964--1978 inclusive. No overall increase in incidence rate of these anomalies was detected during the study period. The estimated live-born incidence rates were: one in 4,175 live births for omphalocoele, one in 12,328 live births for gastroschisis, and one in 29,231 live births for prune belly. The data were analyzed with regard to sex and associated anomalies. Some practical implications regarding assessment of these infants are discussed.     

Genetics of Congenital Heart Disease: Past and Present

Congenital heart disease is the most common congenital anomaly, representing an important cause of infant morbidity and mortality. Congenital heart disease represents a group of heart anomalies that include septal defects, valve defects, and outflow tract anomalies. The exact genetic, epigenetic, or environmental basis of congenital heart disease remains poorly understood, although the exact mechanism is likely multifactorial. However, the development of new technologies including copy number variants, single-nucleotide polymorphism, next-generation sequencing are accelerating the detection of genetic causes of heart anomalies. Recent studies suggest a role of small non-coding RNAs, micro RNA, in congenital heart disease. The recently described epigenetic factors have also been found to contribute to cardiac morphogenesis. In this review, we present past and recent genetic discoveries in congenital heart disease.     

Evaluation of the anti-rubella immunity levels on a lot of 5,000 sera from women at procreative age, tested by HAI, in Romania

From the study performed on a lot of 5030 sera, prelevated from women between 15-40 years old, tested by hemagglutination inhibition reaction (HAI), divided in 5 age groups of 5 years each, resulted that the percentage of women that can be considered immunologically protected against rubella (with HAI antibody titers greater than or equal to 1/20) varied between 79.5% (15-20 years of age group), and 75.3% (31-35 years of age group). The average percentage for the total lot was 76.7. The geometrical means (MGx/divided by SG) of the individual HAI titers ranged between extreme values of 54.2 (x/divided by 4.1) for the Group I, and 40.7 (x/divided by 3.8) for the Group IV, presenting the value of 44.4 (x/divided by 3.9) for the total lot. The covering coefficients of the protection limit, estimated at the level of geometrical means of antibody titers, ranged between 2.7 and 2.0, according to the age group, while the estimations made at the levels of the limits of the statistical range of one geometric standard deviation (MG x/divided by SG), presented values comprised between 11-8 and 0.7-0.5, respectively. On the basis of some theoretical mathematical models proposed in the literature (and using data resulted from the study performed), an attempt was made to approximate the rate of fetal exposure as well as the presumptive risk of congenital rubella syndrome (to 0/0000 live-born).     

Patterns of infant mortality caused by major congenital anomalies

BACKGROUND: We assessed the impact of recent advances in perinatal care on infant mortality due to congenital anomaly. METHODS: Analysis of trends in congenital anomaly-attributed infant mortality, using the 1981-1995 Statistics Canada's birth and death records, with a total of 2,878,826 live births, 21,883 infant deaths, and 6, 908 infant deaths due to congenital anomalies. RESULTS: Infant mortality due to major congenital anomaly decreased from 3.11 per 1, 000 live births in 1981 to 1.89 per 1,000 live births in 1995. Cause-specific infant mortality rates for anencephaly, spina bifida, other central nervous system anomalies, cardiovascular system anomalies, respiratory system anomalies, digestive system anomalies, certain musculoskeleton anomalies, urinary system anomalies, chromosomal anomalies, and multiple congenital anomalies were 0.20, 0.23, 0.27, 1.04, 0.24, 0.08, 0.22, 0.16, 0.22, and 0.13 per 1,000 live births, respectively, in 1981-1983, whereas corresponding rates were 0.07, 0.07, 0.18, 0.73, 0.25, 0.03, 0.12, 0.12, 0.26, and 0.06 per 1,000 live births, respectively, in 1993-1995. CONCLUSIONS: Recent Canadian data show that infant deaths caused by major congenital anomalies have decreased significantly, but reductions varied substantially according to specific forms of anomalies.     

Genetic anticipation in Portuguese kindreds with familial amyloidotic polyneuropathy is unlikely to be caused by triplet repeat expansions

Familial amyloidotic polyneuropathy (FAP) is a lethal autosomal dominant type of amyloidosis resulting from the deposition of transthyretin (ATTR) variants in the peripheral and autonomic nervous systems. ATTR V30M-associated FAP exhibits marked genetic anticipation in some families, with clinical symptoms developing at an earlier age in successive generations. The genetic basis of this phenomenon in FAP is unknown. Anticipation has been associated with the dynamic expansion of trinucleotide repeats in several neurodegenerative disorders, such as Huntington disease, myotonic dystrophy, and fragile X syndrome. We have used the repeat expansion detection (RED) assay to screen affected members of Portuguese FAP kindreds for expansion of any of the ten possible trinucleotide repeats. Nine generational pairs with differences in their age of onset greater than 12 years and a control pair with identical ages of onset were tested. No major differences were found in the lengths of the ten trinucleotide repeats analyzed. The distribution of the maximal repeat sizes was consistent with reported studies in unrelated individuals with no known genetic disease. The present data do not support a role for trinucleotide repeat expansions as the molecular mechanism underlying anticipation in Portuguese FAP. Received: 13 December 1998 / Accepted: 23 March 1999     

Familial glaucoma iridogoniodysplasia maps to a 6p25 region implicated in primary congenital glaucoma and iridogoniodysgenesis anomaly.

Familial glaucoma iridogoniodysplasia (FGI) is a form of open-angle glaucoma in which developmental anomalies of the iris and irido-corneal angle are associated with a juvenile-onset glaucoma transmitted as an autosomal dominant trait. A single large family with this disorder was examined for genetic linkage to microsatellite markers. A peak LOD score of 11.63 at a recombination fraction of 0 was obtained with marker D6S967 mapping to chromosome 6p25. Haplotype analysis places the disease gene in a 6.4-cM interval between the markers D6S1713 and D6S1600. Two novel clinical appearances extend the phenotypic range and provide evidence of variable expressivity. The chromosome 6p25 region is now implicated in FGI, primary congenital glaucoma, and iridogoniodysgenesis anomaly. This may indicate the presence of a common causative gene or, alternatively, a cluster of genes involved in eye development/function.     

Genetic influence on human lifespan and longevity

There is an intense search for longevity genes in both animal models and humans. Human family studies have indicated that a modest amount of the overall variation in adult lifespan (approximately 20–30%) is accounted for by genetic factors. But it is not known if genetic factors become increasingly important for survival at the oldest ages. We study the genetic influence on human lifespan and how it varies with age using the almost extinct cohorts of Danish, Finnish and Swedish twins born between 1870 and 1910 comprising 20,502 individuals followed until 2003–2004. We first estimate mean lifespan of twins by lifespan of co-twin and then turn to the relative recurrence risk of surviving to a given age. Mean lifespan for male monozygotic (MZ) twins increases 0.39 [95% CI (0.28, 0.50)] years for every year his co-twin survives past age 60 years. This rate is significantly greater than the rate of 0.21 (0.11, 0.30) for dizygotic (DZ) males. Females and males have similar rates and these are negligible before age 60 for both MZ and DZ pairs. We moreover find that having a co-twin surviving to old ages substantially and significantly increases the chance of reaching the same old age and this chance is higher for MZ than for DZ twins. The relative recurrence risk of reaching age 92 is 4.8 (2.2, 7.5) for MZ males, which is significantly greater than the 1.8 (0.10, 3.4) for DZ males. The patterns for females and males are very similar, but with a shift of the female pattern with age that corresponds to the better female survival. Similar results arise when considering only those Nordic twins that survived past 75 years of age. The present large population based study shows genetic influence on human lifespan. While the estimated overall strength of genetic influence is compatible with previous studies, we find that genetic influences on lifespan are minimal prior to age 60 but increase thereafter. These findings provide a support for the search for genes affecting longevity in humans, especially at advanced ages.     

The Effect of Inbreeding on Mortality and Morbidity among Telugu-speaking Populations of Kharagpur, West Bengal, India

Increased mortality and morbidity including congenital malformations among the offspring of consanguineous marriages have been widely reported in human populations from different parts of the world. However, there are few studies on the effect of the intensity of inbreeding and different degrees of inbreeding on mortality and morbidity. The present study is an attempt to examine the effects of inbreeding on mortality and morbidity including congenital disorders in different levels of inbreeding among Telugu-speaking populations of Kharagpur, West Bengal, India, based on data collected through extensive pedigrees. The study reveals that the frequency of spontaneous abortions and stillbirths is higher in the offspring of consanguineous marriages than in that of non-consanguineous marriages. A similar effect is also observed in the infant mortality rate, which is known to have a genetic component, but is not seen in the mortality rate of children and juveniles. The rate of morbidity is consistently higher in the offspring of consanguineous marriages with a sex bias in favour of inbred females. The increased morbidity rates in inbred individuals tend to be inversely correlated with the increase in average autosomal inbreeding coefficient. This appears to strengthen Sanghvi’s hypothesis of a decline in the frequency of deleterious genes with intensification of inbreeding through generations. The present study also confirms an increase in genetic disorders with an increase in inbreeding in almost all populations.     

Prevalence of hereditary pathologies in residents of the Kirov Province]

Medical-genetic study was carried out in the population of Kirov Province (population size about 120.000). 203 families with 334 affected with hereditary disorders were registered. The correctness of pathology classification for the inheritance type was confirmed by segregational analysis. The load of hereditary diseases in the population was: 1.25 +/- 0.06 for autosomal dominant, 1.37 +/- 0.07 for autosomal recessive and 0.22 +/- 0.06 for X-linked recessive disorders. It is suggested that variability in the values of the load of autosomal recessive disorders is determined to the large extent by genetic structure of the population.