Genetic epidemiology of lipoprotein lipase deficiency in Saguenay-Lac-St-Jean (Québec, Canada).

Familial hyperchylomicronemia due to the lipoprotein lipase (LPL) activity deficiency (Type I hyperlipoproteinemia) is an autosomal recessive disorder with a prevalence estimated at one case per million. Thirty-four type I individuals are known in Saguenay-Lac-St-Jean (SLSJ), a geographically isolated region of Quebec. The prevalence of type I and LPL deficient heterozygote in this region was estimated at 1/6382 and 1/46 inhabitants respectively. The mean inbreeding coefficient was slightly elevated in the type I group compared with three control groups. The mean kinship coefficient was 15.1 times higher in the type I group than in the control groups. The high prevalence of type I in SLSJ appears to be the result of the emigration of carriers of LPL deficiency from Charlevoix, another isolated region of quebec to the SLSJ region. Endogamy also played a crucial role in increasing the prevalence of type I in SLSJ.     

Population genetics of hereditary hemochromatosis in Saguenay Lac-Saint-Jean (Quebec, Canada).

Hereditary hemochromatosis (HH) is an autosomal recessive disorder that has a high prevalence in Caucasian populations. Based on HLA typing in 18 families, the gene frequency was estimated 0.12. The homozygote frequency was 0.014 and the heterozygote frequency was 0.21 in Saguenay Lac-Saint-Jean (SLSJ), a geographically isolated region of northeastern Quebec. The genealogical reconstruction showed that 15 of the 57 obligate carriers of the HH gene could be traced back to a unique ancestor in the 18th century. The mean coefficients of inbreeding and kinship were 17 and 15 times, respectively, higher in the HH group than in three control groups. The values of both coefficients were much higher than those found in other HH populations and in most of the other recessive disorders prevalent in SLSJ.     

Genetic epidemiology of hereditary tyrosinemia in Quebec and in Saguenay-Lac-St-Jean.

Hereditary tyrosinemia type I is an autosomal recessive disorder that was recognized in Saguenay-Lac-St-Jean (SLSJ) (Quebec) in 1967. Ninety-eight tyrosinemic children, including some of the 113 children born in the SLSJ region, have been screened by the Quebec Network of Genetic Medicine in the whole province since 1970. The geographical distribution of the 98 children screened showed the majority of them to have been born in the northeastern part of Quebec. The prevalence at birth was estimated at 1/1,846 live borns, and the carrier rate was estimated at 1/20 inhabitants in the SLSJ region. Three control groups matched to the tyrosinemic obligate-carrier couples were generated using the population register of the SLSJ region kept at SOREP. The mean coefficient of inbreeding was only slightly elevated in the tyrosinemic group compared with the control groups and was due to remote consanguinity. The mean kinship coefficient was 2.3 times higher in the tyrosinemic group than in the control groups. In the SLSJ region the places of origin of the tyrosinemic children and their parents did not show a clustered nonuniform distribution. Endogamy was not found to be higher in the tyrosinemic group than in the control groups. All these results support both the hypothesis of a founder effect for tyrosinemia and a high gene frequency in northeastern Quebec.     

Inbreeding in Saguenay-Lac-St-Jean (Quebec, Canada): a study of Catholic Church dispensations 1842-1971.

Saguenay-Lac-St-Jean (SLSJ) is a rather geographically isolated region of Quebec which shows a high occurrence of hereditary disorders. It has been suggested that high inbreeding might explain this situation. We studied the inbreeding in the SLSJ region by 10-year periods from 1842 till 1971 using the Catholic Church dispensations. The values of the mean inbreeding coefficient were found to be low during the whole period, reaching a peak of 22.94 x 10(-4) during the period 1902-1911. The values observed in the SLSJ were lower than those found in most regions of Quebec and similar to those reported in European populations.     

Hereditary nonspherocytic hemolytic anemia due to pyruvate kinase deficiency: a prevalence study in Quebec (Canada).

Fifty-eight cases of hereditary nonspherocytic hemolytic anemia due to pyruvate kinase deficiency were collected from both laboratories that have performed the assay since 1972 and from attending physicians in the province of Quebec. Using the postal addresses of the probands, a prevalence map was constructed according to the administrative regions of the province of Quebec. The prevalence was found to be higher in eastern Quebec (1/81,838) than in western Quebec (1/139,086). Fifty probands were of French Canadian origin whereas the remaining 6 were recent immigrants.     

Location score and haplotype analyses of the locus for autosomal recessive spastic ataxia of Charlevoix-Saguenay, in chromosome region 13q11

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a clinically homogeneous form of early-onset familial spastic ataxia with prominent myelinated retinal nerve fibers. More than 300 patients have been identified, and most of their families originated in the Charlevoix-Saguenay region of northeastern Quebec, where the carrier prevalence has been estimated to be 1/22. Consistent with the hypothesis of a founder effect, we observed excess shared homozygosity at 13q11, among patients in a genomewide scan of 12 families. Analysis of 19 pedigrees demonstrated very tight linkage between the ARSACS locus and an intragenic polymorphism of the gamma-sarcoglycan (SGCG) gene, but genomic DNA sequence analysis of all eight exons of SGCG revealed no disease-causing mutation. On the basis of haplotypes composed of seven marker loci that spanned 11.1 cM, the most likely position of the ARSACS locus was 0.42 cM distal to the SGCG polymorphism. Two groups of ARSACS-associated haplotypes were identified: a large group that carries a common SGCG allele and a small group that carries a rare SGCG allele. The haplotype groups do not appear to be closely related. Therefore, although chromosomes within each haplotype group may harbor a single ARSACS mutation identical by descent, the two mutations could have independent origins.     

The tyrosinase-positive oculocutaneous albinism locus maps to chromosome 15q11.2-q12.

Tyrosinase-positive oculocutaneous albinism (ty-pos OCA), an autosomal recessive disorder of the melanin biosynthetic pathway, is the most common type of albinism occurring worldwide. In southern African Bantu-speaking negroids it has an overall prevalence of about 1/3,900. Since the basic biochemical defect is unknown, a linkage study with candidate loci, candidate chromosomal regions, and random loci was undertaken. The ty-pos OCA locus was found to be linked to two arbitrary loci, D15S10 and D15S13, in the Prader-Willi/Angelman chromosomal region on chromosome 15q11.2-q12. The pink-eyed dilute locus, p, on mouse chromosome 7, maps close to a region of homology on human chromosome 15q, and we postulate that the ty-pos OCA and p loci are homologous.     

Medico-genetic studies of the Kostroma oblast population. X. Load of hereditary diseases in the population of Kostroma

Medical-genetic study of the population of Kostroma (the total size of the population analysed approx. 250,000) was carried on. The load of hereditary diseases in the population (per 1000) was 0.75 for autosomal dominant, 0.49 for autosomal recessive and 0.17 for X-linked recessive disorders. Significant differences in the prevalence of autosomal recessive hereditary disorders between rural populations and the population of Kostroma were observed. The dependence of the load of autosomal recessive pathology on random inbreeding was shown for the whole Kostroma province.     

Clinical, metabolic, and genetic aspects of cytochrome C oxidase deficiency in Saguenay-Lac-Saint-Jean.

Thirty-four children with lactic acidosis and Leigh encephalopathy due to cytochrome C oxidase (COX) deficiency distributed in 28 families have recently been identified in northeastern Quebec, particularly in the Saguenay-Lac-Saint-Jean (SLSJ) region. The segregation analysis was consistent with an autosomal recessive mode of inheritance. The incidence was estimated at 1/2,063 live births between 1979 and 1990, and the carrier rate was estimated at 1/23 inhabitants in SLSJ. In SLSJ, the places of origin of the COX-deficient children and their parents did not show a clustered nonuniform distribution. The genealogical reconstruction of 54 obligate carriers identified 26 ancestors common to all of them. Twenty-two were 17th-century Europeans, suggesting that the COX-deficient gene was introduced in the French-Canadian population by early settlers. These results support the hypothesis of a founder effect for COX deficiency in northeastern Quebec. Clinical findings are reported for 15 of these COX-deficient patients, age 6 mo to 11 years. Moderate developmental delay, hypotonia, ataxia, strabismus, and mild facial dysmorphism were frequent. Eleven children died in episodes of fulminant metabolic acidosis. The patients had elevated blood and cerebrospinal fluid lactate levels, decreased blood bicarbonate levels, and normal blood pH. Leigh disease and microvesicular steatosis of the liver were present in all affected patients for whom postmortem examination was performed. This biochemically uniform group of patients showed a wide range of clinical severity.     

Homozygosity for a missense mutation in the 67 kDa isoform of glutamate decarboxylase in a family with autosomal recessive spastic cerebral palsy: parallels with Stiff-Person Syndrome and other movement disorders

Background  

Cerebral palsy (CP) is an heterogeneous group of neurological disorders of movement and/or posture, with an estimated incidence of 1 in 1000 live births. Non-progressive forms of symmetrical, spastic CP have been identified, which show a Mendelian autosomal recessive pattern of inheritance. We recently described the mapping of a recessive spastic CP locus to a 5 cM chromosomal region located at 2q24-31.1, in rare consanguineous families.     

Genetic epidemiology of sensorimotor polyneuropathy with or without agenesis of the corpus callosum in northeastern Quebec

Sensorimotor polyneuropathy with or without agenesis of the corpus callosum (McKusick number 218000) is a disorder that has a high frequency in Saguenay-Lac-St-Jean (SLSJ), a geographically isolated region of northeastern Quebec. The incidence at birth and the carrier rate were estimated, respectively, at 1/2117 liveborns and 1/23 inhabitants. Remote consanguinity was found in several polyneuropathic families while the mean kinship coefficient was 2.7 times higher in the polyneuropathic group than in control groups. The birth places of the individuals with sensorimotor polyneuropathy and their parents did not show a clustered nonuniform distribution. The genealogical reconstruction suggests that the high incidence of polyneuropathy in SLSJ is likely to be the result of a founder effect. It also suggests that a unique mutation accounts for most, if not all, of the cases of sensorimotor polyneuropathy known in this region.     

Medico-genetical study of the population of the Kostroma Region. IV. Genetic load and diversity of hereditary pathology in 5 districts

Data on the prevalence of hereditary diseases in five regions of the Kostroma province were obtained and analysed. 28 autosomal recessive, 25 autosomal dominant and 4 X-linked recessive disorders were found. Segregation analysis proved the rightness of the material subdivision, according to the type of inheritance. The load of hereditary diseases in five regions was: 0.86 +/- 0.09 X 10(3) for autosomal recessive, 0.97 +/- 0.1 X 10(3) for autosomal dominant and 0.36 +/- 0.09 X 10(3) for X-linked recessive disorders. The problems of prevalence of hereditary diseases connected with population structure is discussed.     

Founder effect in familial hyperchylomicronemia among French Canadians of Quebec

Familial hyperchylomicronemia has reached a high prevalence in the French Canadian population of eastern Quebec. The birth places of 58 carriers identified through the birth of one affected child clustered in three regions. The genealogies of these 58 individuals showed that no founder was common to all of them. Three sets of founders were found, one for each region, with little overlapping between two regions. These results strongly suggest that more than one mutation, introduced by the French migrants in the 17th century, are segregating in the French Canadian population. Perche, a region situated between Paris and Normandy, appeared to be the most likely putative center of diffusion of at least one mutation in the lipoprotein lipase gene segregating in the modern-day French Canadian population of Quebec.     

The Load of Hereditary Diseases in the Population of Republic of Sakha (Yakutia)

Summarized data of medical genetic survey of the population of Republic of Sakha (Yakutia) are presented. The number of the population examined constituted 1 000 700 individuals (including 424 500 of urban and 576 200 of rural population, respectively). Regarding the ethnicity, 33 regions of the Republic examined were at most inhabited by Yakuts (36%) and Russians (55%). A total of 400 families (606 patients) with autosomal dominant, 274 families (369 patients) with autosomal recessive, and 42 families (53 patients) with X-linked pathologies were detected. The segregation analysis performed showed good correlation with the expected type of inheritance for both dominant and recessive diseases. The prevalence rate of monogenic hereditary diseases for rural and urban populations, as well as for solely Yakuts, was calculated. It was shown that weighted average prevalence of dominant (0.68; 1.44) and recessive (0.43; 0.86) disorders in Yakuts was two times higher than in total population examined.     

A genomewide linkage-disequilibrium scan localizes the Saguenay-Lac-Saint-Jean cytochrome oxidase deficiency to 2p16

Leigh syndrome (LS) affects 1/40,000 newborn infants in the worldwide population and is characterized by the presence of developmental delay and lactic acidosis and by a mean life expectancy variously estimated at 3-5 years. Saguenay-Lac-Saint-Jean (SLSJ) cytochrome oxidase (COX) deficiency (LS French-Canadian type [LSFC] [MIM 220111]), an autosomal recessive form of congenital lactic acidosis, presents with developmental delay and hypotonia. It is an LS variant that is found in a geographically isolated region of Quebec and that occurs in 1/2,178 live births. Patients with LSFC show a phenotype similar to that of patients with LS, but the two groups differ in clinical presentation. We studied DNA samples from 14 patients with LSFC and from their parents, representing a total of 13 families. Because of founder effects in the SLSJ region, considerable linkage disequilibrium (LD) was expected to surround the LSFC mutation. We therefore performed a genomewide screen for LD, using 290 autosomal microsatellite markers. A single marker, D2S1356, located on 2p16, showed significant (P < 10(-5)) genomewide LD. Using high-resolution genetic mapping with additional markers and four additional families with LSFC, we were able to identify a common ancestral haplotype and to limit the critical region to approximately 2 cM between D2S119 and D2S2174. COX7AR, a gene encoding a COX7a-related protein, had previously been mapped to this region. We determined the genomic structure and resequenced this gene in patients with LSFC and in controls but found no functional mutations. Although the LSFC gene remains to be elucidated, the present study demonstrates the feasibility of using a genomewide LD strategy to localize the critical region for a rare genetic disease in a founder population.     

Prevalence of gestational diabetes mellitus among James Bay Cree women in northern Quebec

BACKGROUND: The prevalence of gestational diabetes mellitus has been reported to vary widely in aboriginal populations. Most of the data have come from the United States. To help determine the extent of gestational diabetes in Canada''s aboriginal population, the authors assessed the prevalence in a population of Cree women in northern Quebec. METHODS: A cross-sectional study was conducted using the National Diabetes Data Group (NDDG) criteria. Information was obtained from patient charts on pregnancies between January 1995 and December 1996 among women residing in 9 Cree communities in the eastern James Bay region of northern Quebec. Women who were not Cree, had pre-existing diabetes, had spontaneous abortion or were receiving glucocorticoid treatment were excluded. RESULTS: Data on 654 pregnancies that met the inclusion criteria were available. Results of the screening oral glucose challenge test were available for 579 of the pregnancies; the remaining 75 were excluded. The mean gestational age at screening was 28.3 (standard deviation 2.6) weeks. The prevalence of gestational diabetes was 12.8% (74/579) (95% confidence interval [CI] 10.1%-15.5%). The prevalence in the inland communities was twice as high as that in the coastal communities (18.0% v. 9.3%, p = 0.002). Women with gestational diabetes or impaired glucose tolerance tended to be older, have had more pregnancies, weigh more before pregnancy and have heavier babies than those with a normal glycemic status. INTERPRETATION: The prevalence of gestational diabetes among James Bay Cree women in northern Quebec is twice as high as that among women in the general North American population and the second highest reported in an aboriginal group worldwide.     

Population genetic studies of retinitis pigmentosa.

A questionnaire survey characterized a sample of 670 probands with retinitis pigmentosa (RP) and allied disorders. Segregation analysis provided some evidence for a small proportion of sporadic cases and for decreased segregation ratios of the dominant and recessive genotypes, which could be attributed to delayed age of onset in some cases. The overall incidence of RP was indirectly calculated to be approximately 1 in 3,700, while the incidence of autosomal recessive RP, including at least two genocopies, was estimated to be about 1 in 4,450. Family data analysis included the calculation of the likelihood that each family represented autosomal recessive, autosomal dominant, and X-linked inheritance patterns. These likelihoods were then converted to relative probabilities and summed over the sample population to yield estimates of the proportions of the three Mendelian types. This large, heterogeneous sample indicated that approximately 84% of the cases in the United States may be autosomal recessive, while about 10% are dominant and 6% X-linked recessive.     

Hereditary deafness in Kirov oblast: a genetic epidemiological study

The results of a genetic epidemiological study of hereditary deafness (HD) in ten raions (districts) of Kirov oblast (administrative region), Russia, are presented. A total of 122 075 people have been examined. Segregation analysis of all families with diagnosed HD has demonstrated a good fit to either the autosomal dominant (AD) or autosomal recessive (AR) mode of inheritance. The total prevalence rates of AD and AR HDs, as well as the specific prevalence rates of nonsyndromic and syndromic forms of HD, have been calculated for the population often raions. The HD prevalence rate in Kirov oblast has been found to be 1 : 1043 people (1 : 1453 and 1 : 3699 for the nonsyndromic and syndromic forms, respectively). This value has been found to vary in different raions, which is explained by differences in the genetic subdivision levels of the populations studied; the correlation coefficient between the HD load and random inbreeding (F(ST)) in district populations is r = 0.81 +/- 0.22. The diversity of syndromic hearing disorders is described.     

Prevalence of Helicobacter pylori pathogenicity-associated cagA and vacA genotypes among Pakistani dyspeptic patients

The cytotoxin-associated gene A ( cagA ), and the vacuolating cytotoxin gene A ( vacA ) products are considered the most important pathogenic determinants of Helicobacter pylori , a gram-negative bacterium causing gastrointestinal disorders such as duodenal ulcers, gastritis and mucosa-associated lymphoid tissue disease. A higher prevalence of H. pylori has been reported in various regions in the Pakistani population; however, no data are available about the virulence-associated genetic determinants. The objective of this study was to determine the prevalence of virulence-associated genes, cagA, vacA and particularly vacA allelic variants among dyspeptic patients from Pakistan. Gastric biopsy samples were obtained from 78 adult patients presenting dyspepsia symptoms. DNA was isolated and analyzed for the presence of H. pylori and its genotypes by PCR. Genus-specific PCR involving 16S rRNA gene revealed that 66 of the 78 patients were positive for H. pylori , an overall prevalence of 84.6% for this particular study. The most common vacA genotype was s1b/m2 (54.5%) followed by s1a/m1 (19.7%). cagA was positive in 24.2% of the cases and strongly associated with s1a/m1, vacA . The prevalence of virulent cagA , and vacA allelic form s1a/m1 was lower than that reported from neighboring countries.     

A Cytogenetic Analysis of Chromosomal Region 31 of Drosophila Melanogaster

Cytogenetic region 31 of the second chromosome of Drosophila melanogaster was screened for recessive lethal mutations. One hundred and thirty nine new recessive lethal alleles were isolated that fail to complement Df(2L)J2 (31A-32A). These new alleles, combined with preexisting mutations in the region, define 52 complementation groups, 35 of which have not previously been described. Among the new mutations were alleles of the cdc2 and mfs(2)31 genes. Six new deficiencies were also isolated and characterized identifying 16 deficiency subintervals within region 31. The new deficiencies were used to further localize three loci believed to encode non-histone chromosomal proteins. Suvar(2)1/Su(var)214, a dominant suppressor of position-effect variegation (PEV), maps to 31A-B, while the recessive suppressors of PEV mfs(2)31 and wdl were localized to regions 31E and 31F-32A, respectively. In addition, the cytological position of several mutations that interact with heterochromatin were more precisely defined.