Novel PKU mutation on haplotype 2 in French-Canadians.

We analyzed DNA from nine French-Canadian probands from eastern Quebec province; all had hyperphenylalaninemia (phenylketonuria [PKU] or non-PKU forms) caused by mutations at the phenylalanine hydroxylase locus. Analysis of RFLP haplotypes and mutations revealed a novel mutation, an A-to-G transition (met----val) in codon 1 (the translation-initiation codon). It occurred on 5 of the 18 mutant chromosomes and was associated each time with haplotype 2. A proband homozygous for this mutation had the PKU phenotype. In other probands, the codon 1 mutation was inherited once with the splice junction mutation in exon 12 (on haplotype 3), conferring PKU, and was inherited twice with a mutation on haplotype 1, conferring PKU in one proband and non-PKU hyperphenylalaninemia in the other. The other five probands carried mutations, conferring PKU, on the following haplotype combinations: 1/3 (twice), 1/9, 3/4, and 1/1. The mutations on haplotypes 1, 4, and 9 are not yet characterized. This preliminary study reveals a novel PKU mutation and considerable genetic heterogeneity at the phenylalanine hydroxylase locus in French-Canadians.     

The French Canadian Tay-Sachs disease deletion mutation: identification of probable founders

Summary Tay-Sachs disease (TSD) is an inherited neurodegenerative ganglioside storage disorder caused by deficiency of the hexosaminidase A enzyme. A deletion allele (FCD) at the HEXA locus has attained high frequency in the French Canadian population. The distribution of affected probands shows a likely center of diffusion for this mutation located in the Bas-St.-Laurent and Gaspésie regions of the province of Quebec. We have reconstructed the genealogies of 15 obligate carriers of the FCD allele to an average depth of 12 generations identifying 60 ancestors and 80 European founders common to all of them. The ancestral origins of the European founders show a significantly greater number of individuals born in the French provinces of Normandy and Perche than expected based on information regarding the origins of the 8,500 immigrants who settled the colony of New France during the French regime. We have identified common ancestors among the 10 who were born in Quebec who appear to be likely candidates for the origin of the FCD mutation. One such couple had 11 children, 5 of whom settled in regions of Quebec or New Brunswick that today have elevated heterozygote frequencies for the FCD. The five offspring are ancestors of all known carriers. By contrast, the absence of FCD alleles among TSD probands in France suggests that the mutation did not occur in a European founder.     

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.     

Hereditary disorders in Saguenay-Lac-St-Jean (Quebec, Canada)

Saguenay-Lac-St-Jean is a geographically isolated region located in northeastern Quebec. Opened to the white settlement in 1938, its immigrants mainly came from Charlevoix, another isolated region of Quebec. The prevalence and/or incidence of several autosomal dominant and recessive disorders are very high. The overall birth prevalence of the recessive disorders was calculated at 1/207 living births and the overall carrier rate at 1/7 inhabitants. This situation may be explained by migration and social factors.     

Mutation profiles of phenylketonuria in Quebec populations: evidence of stratification and novel mutations.

Independent phenylketonuria (PKU) chromosomes (n = 109) representing 80% of a proband cohort in Quebec province carry 18 different identified mutations in 20 different mutation/haplotype combinations. The study reported here, the third in a series on Quebec populations, was done in the Montreal region and predominantly on French Canadians. It has identified three novel mutations (A309D, D338Y, and 1054/1055delG[352fs]) and one unusual mutation/RFLP haplotype combination (E280K on Hp 2). The relative frequencies and distribution of PKU mutations were then compared in three regions and population subsets (eastern Quebec, French Canadian; western Quebec, French Canadian; and Montreal, non-French Canadian). The distributions of the prevalent and rare mutations are nonrandom and provide evidence for genetic stratification. The latter and the presence of eight unusual mutation/haplotype combinations in Quebec families with European ancestries (the aforementioned four and M1V, I65T, S349P, and R408W on Hp 1) corroborate demographic and anthropologic evidence, from elsewhere, for different origins of French Canadians in eastern and western Quebec.     

Type II diabetes of early onset: a distinct clinical and genetic syndrome?

The inheritance of non-insulin-dependent (type II) diabetes was studied by a continuous infusion of glucose test in all available first degree relatives of 48 diabetic probands of various ages and with differing severity of disease. In an initial study of 38 type II diabetic subjects and their first degree relatives six islet cell antibody negative patients with early onset disease (aged 25-40 at diagnosis) were found to have a particularly high familial prevalence of diabetes or glucose intolerance. Nine of 10 parents available for study either had type II diabetes or were glucose intolerant. A high prevalence of diabetes or glucose intolerance was also found in their siblings (11/16;69%). In a second study of the families of a further 10 young diabetic probands (presenting age 25-40) whose islet cell antibody state was unknown a similar high prevalence of diabetes or glucose intolerance was found among parents of the five islet cell antibody negative probands (8/9; 89%) but not among parents of the five islet cell antibody positive probands (3/8;38%). Islet cell antibody negative diabetics with early onset type II disease may have inherited a diabetogenic gene or genes from both parents. They commonly need insulin to maintain adequate glycaemic control and may develop severe diabetic complications. Early onset type II diabetes may represent a syndrome in which characteristic pedigrees, clinical severity, and absence of islet autoimmunity make it distinct from either type I diabetes, maturity onset diabetes of the young, or late onset type II diabetes.     

Prevalence of hepatitis B virus infection in pregnant women in the Montreal area.

From January 1982 to June 1984, 30,315 serum specimens from pregnant women at nine hospitals in the Montreal area were screened for hepatitis B surface antigen (HBsAg). Of the specimens 103, from 98 women, were positive, a prevalence rate of 3.4 per 1000. The ethnic origin of the 98 women and the number who were also positive for e antigen (HBeAg) were as follows: French-Canadian, 29 (3 HBeAg-positive); Asian, 28 (14); Haitian, 32 (0); other, 7 (0); and unknown, 2 (0). The prevalence rates of HBsAg positivity according to ethnic origin at one of the hospitals were 73.9 in Asians, 33.1 in Haitians, 0.9 in French Canadians and 8.0 in women of other extraction. If the prevalence rate found in this study is true for the 95 000 live births that occur yearly in the province of Quebec, there are an estimated 323 infants at risk for hepatitis B virus (HBV) infection each year in the province. Screening programs for detecting HBV carriage in pregnant women should be instituted, since recent studies have shown combined active-passive immunization to be effective in preventing perinatal transmission of HBV infection.     

Familial Aggregation of Morbid Obesity

Recent studies have shown major gene effects for obesity in randomly ascertained families. To investigate the familial aggregation of a specific subset of obesity, which is particularly prone to medical complications, families with morbid obesity were studied. This condition occurs in 1%-2%of the population and is defined as 45.5 kg (100 pounds) or more over ideal weight. First-degree relatives of 221 morbidly obese probands (1560 adults) were identified, and height and weight (current and greatest) were obtained from each family member. Morbid obesity occurred in the family members of the probands 8 times more often than in the general population. Of the morbidly obese probands, 48% had one or more first-degree relatives who were also morbidly obese compared to a 6% population estimate. By the ages of 20–24, 12% of the morbidly obese probands were already 45.5 kg or more overweight, and 45% were 22.7 kg (50 pounds) or more overweight. There was little difference in the prevalence of familial morbid obesity by the gender of the probands: 47% of the male probands and 48% of the female probands had another morbidly obese relative, while 67% and 53% of the early onset (before age 25) male and female probands, respectively, had one or more first-degree relatives who were also morbidly obese. In addition to the extreme degree of familial aggregation, the prevalence of morbid obesity in parent-offspring sets was calculated within the morbidly obese families. Morbidly obese families who have one or two morbidly obese parents have a 2.6 times increased risk (p<0.002) of having one or more morbidly obese adult offspring, compared to families who have neither parent morbidly obese. Evidence for trimodality of the body mass index distribution was found for each gender (p = 0.0006 for male relatives and p = 0.075 for female relatives). The strong familial aggregation of morbid obesity indicates the need for further understanding of the genetic determinants of this extreme clinical disorder and how environmental factors affect the genetic expression of the trait. (OBESITY RESEARCH 1993;1:261–270)     

Activity of California encephalitis group viruses in Entrelacs (province of Quebec, Canada)

During the summer of 1979, indicator rabbits were placed in three sites in Entrelacs (Laurentian area, province of Quebec) and mosquitoes were collected in order to monitor arbovirus activity in the area. Eight seroconversions to California encephalitis (CE) group viruses were detected in rabbits during June, July, and August. Twenty-five strains identified as members of the CE group were isolated: 3 were obtained from viremic rabbit sera, 1 from adult Aedes communis reared in the laboratory from field-collected larvae, and 21 from mosquito pools. Twenty-two of these were typed as snowshoe hare (SSH) virus. No evidence of La Crosse (LAC) virus was detected but three strains belonging to the CE group showed antigenic properties different from reference SSH, LAC, or Jamestown Canyon (JC) viruses. One isolate identified as Flanders virus was obtained from Culex pipiens. Three mosquito species (A. communis, A. punctor, and A. excrucians) were involved in the transmission cycle of SSH virus in Entrelacs. This is the first report, in the province of Quebec, of SSH isolation from animal sera and the first demonstration of its transovarial transmission.     

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.     

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.     

Drug addiction among Quebec physicians.

Data collected by the Quebec Board of Physicians show that during the 5 years from 1974 to 1978 the prevalence of addiction to opiates among Quebec physicians was 2.8/1000. The physician addicts had greater mobility and a higher attrition rate than their peers. The typical addict was male, a general practitioner and married. He often suffered from pain, fatigue, overwork, and financial and marital difficulties. His addiction had begun at approximately 35 years of age and had become evident about 3 1/2 years later. Meperidine was the preferred opiate. Some of the physicians lost their licences to practise for variable periods of time; for these the prognosis was gloomy. Depression was the main psychiatric disorder diagnosed.     

Prevalence and distribution of genetic diseases in Quebec: impact of the past on the present

The prevalence and distribution of genetic diseases in the province of Quebec has been influenced by its population history. The current French Canadian population stems from 8,500 pioneers who left France for Nouvelle-France between 1608 and 1759. After the English conquest of Nouvelle-France in 1759, the French Canadian population remained mostly genetically isolated, for linguistic, cultural, and religious reasons. The migration of a small number of French individuals to Nouvelle-France created a founder effect. Subsequent migrations inland have created smaller regional founder effects. The limited size of the population favoured genetic drift, and the social context encouraged endogamy, i.e. unions between French Canadians with little admixture with English and other immigrants. Founder effects, genetic drift, and endogamy have all played a role in the current prevalence and distribution of genetic diseases now found in Quebec. The prevalence and distribution of genetic diseases in Quebec need to be taken into account in clinical practice. When clinicians are knowledgeable about the genetic diseases prevalent in the population they treat, they know to consider these diseases in differential diagnoses when appropriate and prioritize investigations accordingly. When developing a new diagnostic test for a genetic disease, the prevalence of the disease and the nature of the mutations found in the target population need to be taken into account. The performance of the test will depend on how well it accounts for the particularities of the disease in that population. In other words, how well does it detect the mutations found in that population? Interpretation of individual genetic test results will also depend on how well the test is expected to perform in the individual's population.     

Heritable risk factors associated with language impairments

There is a strong genetic contribution to children's language and literacy impairments. The aim of this study was to determine which aspects of the phenotype are familial by comparing 34 parents of probands with language/literacy impairments and 33 parents of typically developing probands. The parents responded to questionnaires regarding previous history for language/reading impairment and participated in psychometric testing. The psychometric test battery consisted of tests assessing non-verbal IQ, short-term memory, articulation, receptive grammar, reading abilities and spelling. Self-report measures demonstrated a higher prevalence of language and literacy impairments in parents of affected probands (32%) compared with parents of unaffected probands (6%). The two groups of parents differed significantly in their performance on the non-word repetition, oromotor and digit span tasks. Non-word repetition gave the best discrimination between the parent groups even when the data from the parents who actually were impaired as ascertained by direct testing or self-report were removed from the analyses. This suggests that non-word repetition serves as a marker of a family risk for language impairment. The paper concludes with a discussion of issues associated with ascertainment of specific language impairment (SLI).     

Increased prevalence of seizures in boys who were probands with the <Emphasis Type="Italic">FMR1</Emphasis> premutation and co-morbid autism spectrum disorder

Seizures are a common co-occurring condition in those with fragile X syndrome (FXS), and in those with idiopathic autism spectrum disorder (ASD). Seizures are also associated with ASD in those with FXS. However, little is known about the rate of seizures and how commonly these problems co-occur with ASD in boys with the FMR1 premutation. We, therefore, determined the prevalence of seizures and ASD in boys with the FMR1 premutation compared with their sibling counterparts and population prevalence estimates. Fifty premutation boys who presented as clinical probands (N = 25), or non-probands (identified by cascade testing after the proband was found) (N = 25), and 32 non-carrier controls were enrolled. History of seizures was documented and ASD was diagnosed by standardized measures followed by a team consensus of ASD diagnosis. Seizures (28%) and ASD (68%) were more prevalent in probands compared with non-probands (0 and 28%), controls (0 and 0%), and population estimates (1 and 1.7%). Seizures occurred more frequently in those with the premutation and co-morbid ASD particularly in probands compared with those with the premutation alone (25 vs. 3.85%, p = 0.045). Although cognitive and adaptive functioning in non-probands were similar to controls, non-probands were more likely to meet the diagnosis of ASD than controls (28 vs. 0%, p < 0.0001). In conclusion, seizures were relatively more common in premutation carriers who presented clinically as probands of the family and seizures were commonly associated with ASD in these boys. Therefore, boys with the premutation, particularly if they are probands should be assessed carefully for both ASD and seizures.     

Prevalence of the fragile X syndrome in four birth cohorts of children of school age

Summary The prevalence of the fragile X syndrome among 12,882 children (6594 boys and 6288 girls) born during the years 1969–1972 in Kuopio province in eastern central Finland has been studied retrospectively. Mentally retarded children were selected from normal schools by using school achievement tests and from registers of mentally retarded individuals. In the present study fragile X syndrome was found in 6/111 mentally retarded children (5.4%), in 4/61 boys and in 2/50 girls, respectively. It was not detected in the control group of 85 healthy children. The corrected prevalence of fragile X syndrome among boys in four successive birth cohorts was estimated to the 1 in 1210 or 0.8/1000, and that among girls, 1 in 2418 or 0.4/1000. The overall prevalence was calculated to be 1 in 1612 or 0.6/1000 children.     

Association of macrosomia with perinatal and postneonatal mortality among First Nations people in Quebec

Background

High prevalence of infant macrosomia (up to 36%, the highest in the world) has been reported in some First Nations communities in the Canadian province of Quebec and the eastern area of the province of Ontario. We aimed to assess whether infant macrosomia was associated with elevated risks of perinatal and postneonatal mortality among First Nations people in Quebec.

Methods

We calculated risk ratios (RRs) of perinatal and postneonatal mortality by birthweight for gestational age, comparing births to First Nations women (n = 5193) versus women whose mother tongue is French (n = 653 424, the majority reference group) in Quebec 1991–2000.

Results

The prevalence of infant macrosomia (birthweight for gestational age > 90th percentile) was 27.5% among births to First Nations women, which was 3.3 times (confidence interval [CI] 3.2–3.5) higher than the prevalence (8.3%) among births to women whose mother tongue is French. Risk ratios for perinatal mortality among births to First Nations women were 1.8 (95% CI 1.3–2.5) for births with weight appropriate for gestational age, 4.1 (95% CI 2.4–7.0) for small-for-gestational-age (< 10th percentile) births and < 1 (not significant) for macrosomic births compared to births among women whose mother tongue is French. The RRs for postneonatal mortality were 4.3 (95% CI 2.7–6.7) for infants with appropriate-for-gestational-age birthweight and 8.3 (95% CI 4.0–17.0) for infants with macrosomia.

Interpretation

Macrosomia was associated with a generally protective effect against perinatal death, but substantially greater risks of postneonatal death among births to First Nations women in Quebec versus women whose mother tongue is French.A trend toward higher birthweights has emerged in recent decades.^1–3 Reflected in this trend is a rise in the prevalence of infant macrosomia, commonly defined as either a birthweight greater than 4000 g or a birthweight for gestational age greater than the 90th percentile relative to a fetal growth standard.^4–8 Maternal obesity, impaired glucose tolerance and gestational diabetes mellitus are important risk factors for infant macrosomia^9,10 and are known to afflict a much higher proportion of people in Aboriginal populations than in the general population.^11–14 This is true especially for Aboriginal populations in which a traditional lifestyle has changed to a less physically active, modern lifestyle in recent decades. A high prevalence of infant macrosomia (up to 36%, which, to the best of our knowledge, is the highest in the world) has been reported in some First Nations communities of Quebec and eastern Ontario in Canada.^15–17 However, little is known about the implications of this high prevalence for perinatal and infant health of First Nations people in these regions. We examined whether infant macrosomia was associated with increased risk for perinatal and postneonatal death among First Nations infants in Quebec.     

Differential rates of frameshift alterations in four repeat sequences of hereditary nonpolyposis colorectal cancer tumors

In some Palestinian communities, the prevalence of inherited prelingual deafness is among the highest in the world. As an initial step towards understanding the genetic causes of hearing loss in the Palestinian population, 48 independently ascertained probands with non-syndromic hearing loss were evaluated for mutations in the connexin 26 gene. Of the 48 deaf probands, 11 (23%) were homozygous or compound heterozygous for mutations in GJB2. Five different mutations were identified: ivs1(+1) G-->A, 35delG, 167delT, T229C, 235delC. Nine deaf probands were homozygous and only two compound heterozygous. Among 400 hearing Palestinian controls, one carrier was observed (for 167delT). We show that GJB2 ivs1(+1) G-->A disrupts splicing, yielding no detectable message. Linkage disequilibrium analysis suggests, in the Palestinian and Israeli populations, a common origin of the 35delG mutation, which is worldwide, and of 167delT, which appears specific to Israeli Ashkenazi and Palestinian populations. A high prevalence of deafness, high frequency of homozygosity rather than compound heterozygosity among deaf, and low mutation carrier frequency together reflect the high levels of consanguinity of many extended Palestinian families. Some of the 25 families with multiple cases of inherited prelingual deafness and wildtype GJB2 sequences may represent as-yet-unknown genes for inherited hearing loss.     

The Prevalence of Human T-Lymphotropic Virus Infection among Blood Donors in Southeast China, 2004-2013

Background

The human T-lymphotropic virus type 1 (HTLV-1) which is associated with the diseases of adult T-cell leukemia/lymphoma, HTLV-1 associated myelopathy / tropical spastic paraparesis (HAM/TSP) and HTLV-associated uveitis, can cause transfusion-transmitted infections. Although HTLV screening of blood donors was already routinely performed in developed countries, little is know about the HTLV prevalence among blood donors in developing countries which do not perform HTLV screening, such as China.

Objectives &Aims

To systematically characterize the prevalence of HTLV infection among bloods in southeast China.

Methods

A 10-year survey for HTLV prevalence in blood donors was performed in Xiamen, southeast China, during 2004-2013. The HTLV-1/2 of blood donations were screened by enzyme-linked immunosorbent assay, following with confirmation by western blot assay and 9nucleic acid testing. The HTLV-1 prevalences in donors from different cities were calculated. Viral sequences derived from identified HTLV-positive cases were sequenced and analyzed.

Results

Among 253,855 blood donors, 43 were confirmed to be seropositive for HTLV-1 (16.9 per 100,000 95% CI: 12.3-22.8) and none HTLV-2 infection was found. The HTLV-1 prevalence varied significantly in donors from different cities. Donors from cities in Fujian province (24.3 per 100,000, 95%CI: 17.4-33.1) had a significantly higher (p=0.001) HTLV-1 seroprevalence than those who were born in non-Fujian cities (3.4 per 100,000, 95%CI: 0.7-9.8). Among nine cities in Fujian province, the highest prevalence was found in blood donors from Ningde (171.3 per 100,000, 95%CI: 91.3-292.8) which is a coastal city in the northeast of Fujian. Molecular characterization of viral sequences from 27 HTLV-1 carriers revealed 25 were Transcontinental subtype of genotype A and 2 were Japanese subtype of genotype A. Interestingly, 12 of 25 Transcontinental subtype sequences harbored a characteristic L55P mutation in viral gp46 protein, which was only presented in the Transcontinental subtype sequences from Japan and Taiwan but not in that from other countries.

Conclusions

Although China is considered to be a non-endemic region for HTLV, the HTLV-1 prevalence in blood donors is significantly higher in Fujian province, southeast China. A higher prevalence of HTLV-1 in the Fujian may be attributed to endemic foci in the city of Ningde.