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PubMed1994

[Comprehensive evaluation of inheritance and environmental factors in the etiology of primary liver cancer].

A1:1 matched case-control study was carried out in 152 cases with primary liver cancer (PLC) and 152 controls to identify the risk factors associated with it and its cumulative mortality in their second- and third-degree relatives. Results showed cumulative mortality of PLC in the relatives of the cases (0.46%) was significantly higher than that of controls (0.07%). Cumulative mortality of PLC in consanguineous relatives of the cases (0.55%) was significantly higher than that in non-consanguineous ones (0.08%). Cumulative mortality of PLC decreased regularly with family relation (consanguinity) drifting apart. Genetic factors still played an important role independently in the etiology of PLC with multiple regression and stratification analyses studying genetic and environmental factors as a whole. This laid a theoretical basis to study further the association between genetic factors and PLC incidence.

Case-Control Studies↗

PubMed1993

A search for the primary abnormality in adult-onset type II citrullinemia.

Deficiency of argininosuccinate synthetase (ASS) causes citrullinemia in human beings. Type II citrullinemia is found in most patients with adult-onset citrullinemia in Japan, and ASS deficiency is found specifically in the liver. Previous studies have shown that the decrease of hepatic ASS activity is caused by a decrease in enzyme protein with normal kinetic properties and that there were no apparent abnormalities in the amount, translational activity, and gross structure of hepatic ASS mRNA. In the present work, we show by sequencing analysis that there was no mutation in the ASS mRNA from two patients with type II citrullinemia. We also report RFLP analysis of a consanguineous family with type II citrullinemia, by using three DNA polymorphisms located within the ASS gene locus. In spite of having consanguineous parents, the patient was not a homozygous haplotype for the ASS gene. The RFLP analysis of 16 affected patients from consanguineous parents showed that 5 of 16 patients had the heterozygous pattern for one of the three DNA probes and that the frequency of the heterozygous haplotype was not different from the control frequency. These results suggest that the primary defect of type II citrullinemia is not within the ASS gene locus.

Adolescent↗

PubMedDate not supplied

Mapping of Papillon-Lefevre syndrome to the chromosome 11q14 region.

Papillon-Lefevre syndrome (PLS) is an autosomal recessive disease which belongs to the palmo-plantar keratoderma (PPK) group. It is characterized by a premature loss of primary and permanent teeth and early onset periodontitis. High consanguinity has been observed in over one-third of PLS families. No candidate genes or gene localizations have been described to date for this disorder. A primary genome-wide search by homozygosity mapping using samples from a large consanguineous family in which 4 siblings were affected by the disease showed homozygosity and linkage in the region of 11q14. Linkage was confirmed in 4 additional families with diverse ethnic and geographic backgrounds, 2 of which were consanguineous. A maximum two-point lod score of 8.19 was obtained for the marker AFM063yg1 (D11S901= for theta = 0. Analysis of recombination events places the gene within a 7-cM interval between AFM063yg1 and AFM269yg9 (D11S4175). No shared haplotype was found for the 5 families analysed.

Chromosome Mapping↗

PubMed1997

Speech disorders in Israeli Arab children.

The aim of this work was to study the frequency of speech disorders in Israeli Arab children and its association with parental consanguinity. A questionnaire was sent to the parents of 1,495 Arab children attending kindergarten and the first two grades of the seven primary schools in the town of Taibe. Eight-six percent (1,282 parents) responded. The answers to the questionnaire revealed that 25% of the children reportedly had a speech and language disorder. Of the children identified by their parents as having a speech disorder, 44 were selected randomly for examination by a speech specialist. The disorders noted in this subgroup included errors in articulation (48.0%), poor language (18%), poor voice quality (15.9%); stuttering (13.6%), and other problems (4.5%). Rates of affected children of consanguineous and non-consanguineous marriages were 31% and 22.4%, respectively (p < 0.01). We conclude that speech disorders are an important problem among Israeli Arab schoolchildren. More comprehensive programs are needed to facilitate diagnosis and treatment.

Arabs↗

PubMed1998

[Analysis of the risk of congenital defects in different ethnic groups in Spain].

OBJECTIVE: The frequency of congenital defects is not the same in different populations and ethnic groups. Genetic factors, as well as differences in socio-cultural aspects (such as the frequency of consanguineous couples) between the groups could be responsible for some differences in the prevalence of congenital anomalies. However, some groups are made up of populations which live on the fringe of society in which several circumstances and related factors could increase the risk for congenital defects. PATIENTS AND METHODS: A total of 24,696 malformed infants were studied together with a similar group of controls, separated into the following ethnic groups: Gypsies, black, orientals, Arabic people and whites. Using different models of logistic regression analysis, controlling several factors related to the social-cultural level and with genetic aspects (such as consanguinity), we estimated the risk for 20 different congenital defects in the ethnic groups compared to the white population. RESULTS: The analysis showed that some ethnic groups have an increased risk for some congenital defects and that this increased risk is due to their high level of consanguinity. Other defects are due to different factors related with the low socio-cultural level. However, in black and Arabic people there is a high risk for some congenital defects that is not attributable to those genetic or socio-cultural factors studied. CONCLUSIONS: The results of the present study permit the estimation of the impact of congenital defects in these groups that have low socio-cultural level, as well as the need for health care. This is of great usefulness in establishing the necessary actions to provide proper assistance to prevent congenital defects in these populations.

Congenital Abnormalities↗

PubMed1998

Clinical and epidemiologic studies of familial hemophagocytic lymphohistiocytosis in Japan. Japan LCH Study Group.

BACKGROUND AND PROCEDURE: The etiology of familial hemophagocytic lymphohistiocytosis (FHL), which is characterized by fever, hepatosplenomegaly, pancytopenia, and coagulopathy, remains unknown. We analyzed 43 FHL patients, all with affected siblings, in 18 families who were identified during the period 1986-1995 in Japan. RESULTS: The presence of consanguinity was evident in two families (11%). The majority of families lived in western Japan, where the frequency of consanguineous marriage is high. The incidence of FHL was significantly higher in the western island, Kyushu, than in other areas. The segregation ratio calculated for these families was 0.35 by the Weinberg proband method, showing the autosomal-recessive inheritance of the disease. Since the diagnosis of an FHL patient without affected siblings (sporadic case) is quite difficult, we calculated the possible number of sporadic cases; approximately 122 patients could be identified as sporadic FHL cases during the same period in Japan. Most of the clinical and laboratory findings were not distinguishable from those of other types of lymphohistiocytosis. However, atypical lymphoid cells with azurophilic granules in peripheral blood were observed in half of the patients at diagnosis, suggesting the clinical importance of this parameter for early diagnosis. Despite intensive therapy, the prognosis of FHL was extremely poor; but 4 of the 8 patients who have survived had received bone marrow transplantation (BMT), indicating the effectiveness of BMT for this disorder. CONCLUSIONS: The distribution of FHL in areas of highly frequent consanguineous marriage and the segregation analysis indicated a genetic factor in FHL. The identification of the genes for FHL is expected to contribute to a cure for this disorder, and might also enable FHL carrier detection and donor selection for BMT.

Adolescent↗

PubMed2003

A whole genome screen for linkage in Turkish multiple sclerosis.

Factors exerting recessive effects on susceptibility to complex traits are expected to be over-represented in communities having a higher frequency of consanguineous marriage. Multiple sclerosis, a typical complex trait, is relatively common in Turkey where cultural factors also determine a high rate of consanguineous marriage. Previous genetic studies of multiple sclerosis in Turkey have been confined to the search for associations with candidate genes. In order to exploit the special genetic features of the Turkish population, we performed a whole genome screen for linkage in 43 Turkish multiplex families employing 392 microsatellite markers. Two genomic regions where maximum lod score (MLS) values were suggestive of linkage were identified (chromosomes 13q and 18q23) along with a further 14 regions of potential linkage. Parametric analysis of these data using a recessive model, appropriate for populations with a high frequency of consanguinity, increased the LOD scores in four regions.

Chromosome Mapping↗

PubMed2000

Etiology of deafness in Afyon school for the deaf in Turkey.

OBJECTIVE: Otolaryngologists play an important role in the evaluation of children with a hearing impairment. The group of unknown cause still has a high incidence. The purposes of this study were to determine the etiology of deafness in Afyon School for the Deaf in Turkey and to compare the results with the other studies from Turkey and other countries. METHODS: This study was a retrospective analysis of 130 deaf students, aged 5-16 years. Medical and family histories of the children were obtained. Clinical and laboratory examinations were carried out. RESULTS: Etiological groups showed the following distribution: febril convulsion, 26.9%; cause unknown, 26.1%; hereditary group, 23.8%; meningitis, 10%; measles, 6.1%; and miscellaneous, 6.6%. A total of 90.3% of the students with hereditary deafness were from consanguineous families. A marital consanguinity was noted in the parents of 64 (49.2%) of all children in the school and this rate was higher than the average in Turkey (P<0.05). Neither syndromic deafness nor maternal rubella was identified. A total of 27.6% of the cases were diagnosed after the age of 30 months. CONCLUSION: Febril convulsions and hereditary factors were the major causes of hearing loss in the present study. The high incidence of consanguineous marriage among the parents of the children with hereditary deafness seemed a strong evidence of genetic origin, indicating a close relationship between them. Congenital rubella syndrome did not appear as a significant etiology of deafness in Turkey.

Adolescent↗

PubMed2003

Risk factors for childhood epilepsy: a case-control study from Irbid, Jordan.

OBJECTIVE: The goal of this case-control study is to identify the significance of certain risk factors for epilepsy in a population of epileptic children in Northern Jordan. The risk factors examined are febrile convulsions, head trauma, central nervous system infections, abnormal perinatal history, family history and parental consanguinity. METHODOLOGY: We designed a case-control study for patients attending the outpatient neurology clinic of Princess Rahma Teaching Hospital in Irbid, Jordan during a 7-month period. Controls were selected, matched for age and sex, from a group of non-epileptic patients attending the general paediatrics outpatient clinic in the same hospital and during the same period. Data about the investigated risk factors were obtained by personal interview and review of the medical records and were analysed statistically for significance. RESULTS: The total number of participants was 200 patients and controls each. History of febrile convulsions, head trauma, abnormal perinatal history and family history showed a statistically significant increase risk for developing epilepsy. Central nervous system infections and parental consanguinity did not add to the risk of developing epilepsy. CONCLUSION: Positive family history for epilepsy, head trauma, febrile convulsions and abnormal perinatal history were shown to have a statistically significant association with epilepsy in patients attending Princess Rahma Teaching Hospital in Northern Jordan. Although consanguinity is widely practised in Jordan, it appears that it does not increase the risk of epilepsy probably due to the small contribution of monogenic recessive epilepsies to the population with epilepsy.

Case-Control Studies↗

PubMed2004

Risk of seizure recurrence after a first unprovoked seizure: a prospective study among Jordanian children.

PURPOSE: There is wide variation in the reported recurrence rate after a first unprovoked seizure in children. We investigated the risk of recurrence after a first unprovoked seizure in Jordanian children and the risk factors associated with increased recurrence rate. METHODS: All consecutive patients aged 3 months-14 years who presented with their first unprovoked seizures between January 1997 and 2000, were included in a prospective study and followed up for 3 years for possible recurrence. Of the patients studied, there was slight male predominance (56.6%) and 55% of them were 2-9 years of age. Generalised seizures were reported in 75% and the remaining 25% had partial seizures. The duration of seizure was 1-4 minutes in 59%. Family history of epilepsy was positive in 31% and parental consanguinity in 32%. The role of these factors in increasing the risk of recurrence was also investigated. RESULTS: Two hundred sixty-five patients were included in the study and continued follow up for 3 years. Ninety-eight (37%) of them experienced seizure recurrence. Among the predictor factors for recurrence, partial seizure (P = 0.003) and positive family history (P = 0.000) were associated with a statistically significant increased risk. Sex, age, duration of seizure and consanguinity were not associated with increased risk of recurrence. CONCLUSION: Thirty-seven percent of the children studied experienced a second attack after a first unprovoked seizure over the 3 years follows up period. The risk of recurrence was significantly higher in children with a partial seizure (55%) and among those with a positive family history of epilepsy (59%). Age at first seizure, sex, duration of seizure and consanguinity were not significantly related to the risk of recurrence.

Brain↗

PubMed1997

Effects of inbreeding on reproductive losses in Kota tribe.

Sanghvi's hypothesis on long term effects of inbreeding was tested in Kotas. Kota is a numerically small tribal population in the Nilgiri district, Tamil Nadu State, India. Consanguineous marriages are common in this tribe. A total of 95 couples were taken for this study and necessary data were collected on a set proforma. Of the 95 couples, 28 (29.5%) were consanguineously related. The inbreeding coefficient for autosomal genes is 0.022 and for sex-linked genes is 0.03. Inbreeding effects on reproductive losses were examined through an exponential regression model. Although the regression coefficient B values are positive, they are insignificant, suggesting no consistent relationship between degree of consanguinity and the reproductive losses. The estimates of genetic load is 1.8 lethal equivalents per gamete and the average B/A ratio is 5. These findings empirically support the Sanghvi's contention.

Ethnicity↗

PubMed2006

Genetic screening for autosomal recessive nonsyndromic mental retardation in an isolated population in Israel.

Nonsyndromic mental retardation (NSMR) is the diagnosis of exclusion in mentally retarded individuals without additional abnormalities. We have recently identified a protein-truncating mutation, G408fsX437, in the gene CC2D1A on chromosome 19p13.12 in nine consanguineous Israeli Arab families with severe autosomal recessive NSMR, and have developed a comprehensive prevention program among the at-risk population in the village. The subjects tested were healthy women who were invited to undergo the genetic screening test as a part of their routine pregnancy monitoring. One hundred and seventeen subjects reported a family history positive for mental retardation. We tested 524 pregnant or preconceptional women and found 47 carriers (approximately 1/11), whose spouses were then recommended to undergo testing. We identified eight carrier couples, who were given genetic counseling and offered prenatal diagnosis. Of all the marriages, 28.6% were consanguineous; 16.5% of the total were between first cousins. The high prevalence of the mutation can be explained both by the founder effect owing to the generally high consanguinity rate among the inhabitants of the village, and also because two families with excessive numbers of mentally retarded offspring were unacceptable as marriage partners by the rest of the families. This is the first example of the establishment of a large-scale genetic screening program for autosomal recessive NSMR, which was made possible owing to the high frequency of the specific causative mutation in this isolated population.

DNA-Binding Proteins↗

PubMed2003

Congenital secondary hypothyroidism due to a mutation C105Vfs114X thyrotropin-beta mutation: genetic study of five unrelated families from Switzerland and Argentina.

We identified five patients with congenital secondary hypothyroidism with isolated thyrotropin (TSH) deficiency originating from three and two unrelated Argentinean and Swiss families, respectively. The affected patients presented with both low TSH as well as low thyroid hormone levels. Further, TSH-releasing hormone (TRH) stimulation failed to increase serum TSH, whereas prolactin increased adequately. These affected children were homozygous for a 1-bp deletion (822delT) in the TSH-beta subunit gene leading to a cysteine 105 to valine conversion (C105V) and to a frameshift with a premature stop codon at position 114 (C105Vfs114X). In a total of 22 families five different mutations located within the coding region of the TSH-beta subunit gene responsible for congenital secondary hypothyroidism have been reported so far (E12X; G29R; Q49X; IVS2 +5, G --> A; C105Vfs114X). Importantly, out of 13 families, including our five families, the C105Vfs114X mutation has been described in 12 unrelated and non-consanguineous families, whereas the remaining four TSH-beta subunit gene mutations have been described in consanguineous families only. Therefore the C105Vfs114X mutation within the TSH-beta subunit gene is the most frequent alteration causing congenital secondary hypothyroidism (13 of 22; 59%) and occurs mainly in unrelated and non-consanguineous families (12 of 13; 92%). As we could exclude a common ancestry by microsatellite marker analysis in our five independent families we concluded that the codon 105 in the TSH-beta subunit gene might be a "hot spot," although a founder effect has been reported in certain cases clustered in a highly specific and restricted geographical area.

Adolescent↗

PubMed1998

Two frequent missense mutations in Pendred syndrome.

Pendred syndrome is an autosomal recessive disorder characterized by early childhood deafness and goiter. A century after its recognition as a syndrome by Vaughan Pendred, the disease gene ( PDS ) was mapped to chromosome 7q22-q31.1 and, recently, found to encode a putative sulfate transporter. We performed mutation analysis of the PDS gene in patients from 14 Pendred families originating from seven countries and identified all mutations. The mutations include three single base deletions, one splice site mutation and 10 missense mutations. One missense mutation (L236P) was found in a homozygous state in two consanguineous families and in a heterozygous state in five additional non-consanguineous families. Another missense mutation (T416P) was found in a homozygous state in one family and in a heterozygous state in four families. Pendred patients in three non-consanguineous families were shown to be compound heterozygotes for L236P and T416P. In total, one or both of these mutations were found in nine of the 14 families analyzed. The identification of two frequent PDS mutations will facilitate the molecular diagnosis of Pendred syndrome.

Adolescent↗

PubMed2002

Major birth defects among infants with Down's syndrome in Alexandria, Egypt (1995-2000).

A case-control study of 514 infants with confirmed Down's syndrome (DS) was carried out during the period 1 July 1995-30 June 2000 to investigate the risk factors for the occurrence of congenital anomalies among DS cases. Our results showed that the significant risk factors for developing any type of congenital anomalies among DS were: parental consanguinity, grand-maternal consanguinity, use of antibiotics, use of oral contraceptive pills, diabetes mellitus, and maternal fever. The interaction between trisomy 21 genes and consanguinity and/or environmental factors can increase the risk of several additional birth defects.

Abnormalities, Multiple↗

PubMed2003

How are deleterious mutations purged? Drift versus nonrandom mating.

Accumulation of deleterious mutations has important consequences for the evolution of mating systems and the persistence of small populations. It is well established that consanguineous mating can purge a part of the mutation load and that lethal mutations can also be purged in small populations. However, the efficiency of purging in natural populations, due to either consanguineous mating or to reduced population size, has been questioned. Consequences of consanguineous mating systems and small population size are often equated under "inbreeding" because both increase homozygosity, and selection is though to be more efficient against homozygous deleterious alleles. I show that two processes of purging that I call "purging by drift" and "purging by nonrandom mating" have to be distinguished. Conditions under which the two ways of purging are effective are derived. Nonrandom mating can purge deleterious mutations regardless of their dominance level, whereas only highly recessive mutations can be purged by drift. Both types of purging are limited by population size, and sharp thresholds separate domains where purging is either effective or not. The limitations derived here on the efficiency of purging are compatible with some experimental studies. Implications of these results for conservation and evolution of mating systems are discussed.

Biological Evolution↗

PubMed2003

A novel missense mutation in the gene encoding SLURP-1 in patients with Mal de Meleda from northern Tunisia.

BACKGROUND: Mal de Meleda (MDM) is a rare autosomal recessive skin disorder which belongs to the clinically and genetically heterogeneous group of palmoplantar keratodermas (PPK). Clinically, MDM is characterized by erythema and hyperkeratosis of the palms and soles with sharp demarcation that appears soon after birth and progressively extends to the dorsal surface of the hands and feet. OBJECTIVES: Except for the molecular study reported in Algerian families, MDM has not yet been investigated in the Maghrebian population, characterized by its heterogeneous ethnic background and a high rate of consanguinity. In this study we report genetic and molecular investigations of eight unrelated consanguineous Tunisian families including 17 affected individuals. METHODS: Eight large consanguineous MDM families who originated from cities of northern Tunisia, with a total of 17 patients and 22 unaffected family members were investigated. Families were genotyped with the following microsatellite markers: CNG003, D8S1751 and D8S1836. Mutation analyses were performed in affected patients, in both parents and in unaffected individuals. Linkage analysis was also performed. RESULTS: All the clinical features of MDM were constantly present. Nevertheless variable severity was noted among patients. Histological details were recorded. The haplotype analysis of markers CNG003, D8S1751 and D8S1836 revealed that all affected offspring were homozygous by descent for the three polymorphic markers. The maximum lod score value, 3.22, confirmed the evidence for linkage to the ARS gene. Three haplotypes were observed, and the findings suggest that at least three different mutations within the ARS gene segregate with these haplotypes. Three different mutations were identified, the 82delT mutation previously described and two novel missense mutations. CONCLUSIONS: The results suggest that the ARS gene is likely to be responsible for MDM in the eight Tunisian families. The clinical variability in the expression of PPK in MDM Tunisian patients might be accounted for by the intervention of modifier genes influencing the MDM phenotype.

Antigens, Ly↗

PubMed1990

Epilepsy and other convulsive disorders in Saudi Arabia: a prospective study of 1,000 consecutive cases.

The pattern of epilepsy and other convulsive disorders in 1,000 consecutive Saudi nationals is described. These disorders were common with a hospital frequency rate of 8 per 1,000. Men were more frequently affected than women and 60% of the patients were under 10 years old at the onset of their illness. The epilepsies were the commonest type (74%). Febrile convulsions (20%) presented mainly between the ages of one and five years. Isolated seizures (3%) and acute symptomatic convulsions (3%) were uncommon. In the epileptic group, generalised seizures (71%) were more frequent than partial (29%) and complex partial seizures occurred mainly in those above 21 years old. Absences (4%), infantile spasms (3%) and atonic seizures (3%) were uncommon. No specific etiology of the epilepsy was determined in the majority of the cases (63%). The identified major etiologic factors of the epilepsies were perinatal encephalopathy (21%), cerebral trauma (11%), sequelae of meningitis or encephalitis (2%), brain tumors (0.5%), and vascular lesions such as stroke and arteriovenous malformation. Perinatal encephalopathy accounted for 40% of the epilepsies in children less than 5 years old, and trauma for 20% of those above 20 years old. A family history of epilepsy in close relations was obtained in 23% of the cases, and the consanguinity rate among the parents was 53%. The high incidence of associated perinatal encephalopathy found in this study suggests that perinatal factors play a major role in the pathogenesis of epilepsy in Saudi Arabia. The high frequency of cerebral trauma was also striking. Although consanguinity of the parents appeared not to be a major factor in the genetics of convulsive disorders in this environment, it might have potentiated the tendency of familial aggregation of convulsive disorders in this community. Consanguinity may be an important factor in the production of some of these disorders but its precise role has not been determined.

Adolescent↗