Frequency of the Ivs12+5g→a Splice Mutation of the Fumarylacetoacetate Hydrolase Gene in Carriers of Hereditary Tyrosinaemia in the French Canadian Population of Saguenay-Lac-St-Jean

Poudrier, Jacques; St‐Louis, Maryse; Lettre, Francine; Gibson, Karine; Prévost, Claude; Larochelle, J; Tanguay, Robert M.

doi:10.1002/(sici)1097-0223(199601)16:1<59::aid-pd810>3.0.co;2-d

Cited by 28 publications

(8 citation statements)

References 15 publications

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“…Founder effects have been described in SLSJ for several genetic disorders [12-18], which is not unexpected given its unique population history [9]. Here, we report a single PEX6 mutation in all ZS cases in French-Canadians from the SLSJ region.…”

Section: Discussionsupporting

confidence: 58%

“…SLSJ has remained relatively geographically isolated and has a current population size of approximately 285,000 individuals [9]. As a consequence of this history, founder effects have been described for several genetic disorders including tyrosinemia type I (MIM# 276700) [12,13], autosomal recessive spastic ataxia of Charlevoix-Saguenay (MIM# 270550) [14,15], sensorimotor polyneuropathy with or without agenesis of corpus callosum (MIM# 218000) [16,17] and Leigh syndrome, French Canadian type (MIM# 220111) [18]. Each of these genetic conditions shows a low genetic complexity in French-Canadians of SLSJ, with one or two mutations contributing to the disease frequency.…”

Section: Introductionmentioning

confidence: 99%

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A founder mutation in the PEX6 gene is responsible for increased incidence of Zellweger syndrome in a French Canadian population

et al. 2012

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BackgroundZellweger syndrome (ZS) is a peroxisome biogenesis disorder due to mutations in any one of 13 PEX genes. Increased incidence of ZS has been suspected in French-Canadians of the Saguenay-Lac-St-Jean region (SLSJ) of Quebec, but this remains unsolved.MethodsWe identified 5 ZS patients from SLSJ diagnosed by peroxisome dysfunction between 1990–2010 and sequenced all coding exons of known PEX genes in one patient using Next Generation Sequencing (NGS) for diagnostic confirmation.ResultsA homozygous mutation (c.802_815del, p.[Val207_Gln294del, Val76_Gln294del]) in PEX6 was identified and then shown in 4 other patients. Parental heterozygosity was confirmed in all. Incidence of ZS was estimated to 1 in 12,191 live births, with a carrier frequency of 1 in 55. In addition, we present data suggesting that this mutation abolishes a SF2/ASF splice enhancer binding site, resulting in the use of two alternative cryptic donor splice sites and predicted to encode an internally deleted in-frame protein.ConclusionWe report increased incidence of ZS in French-Canadians of SLSJ caused by a PEX6 founder mutation. To our knowledge, this is the highest reported incidence of ZS worldwide. These findings have implications for carrier screening and support the utility of NGS for molecular confirmation of peroxisomal disorders.

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Section: Discussionsupporting

confidence: 58%

Section: Introductionmentioning

confidence: 99%

A founder mutation in the PEX6 gene is responsible for increased incidence of Zellweger syndrome in a French Canadian population

et al. 2012

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“…It is caused by mutations in the fumarylacetoacetate hydrolase gene on chromosome 15q23-25. One mutation, IVS12þ5G!A accounts for 95.4% of mutant alleles in French Canadians (48). A therapeutic agent, nitisinone (NTBC), effectively prevents acute hepatic and neurologic crises (49).…”

Section: Diseases With Higher Frequency In French Canadiansmentioning

confidence: 99%

Population history and its impact on medical genetics in Quebec

et al. 2005

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Knowledge of the genetic demography of Quebec is useful for gene mapping, diagnosis, treatment, community genetics and public health. The French-Canadian population of Quebec, currently about 6 million people, descends from about 8500 French settlers who arrived in Nouvelle-France between 1608 and 1759. The migrations of those settlers and their descendants led to a series of regional founder effects, reflected in the geographical distribution of genetic diseases in Quebec. This review describes elements of population history and clinical genetics pertinent to the treatment of French Canadians and other population groups from Quebec and summarizes the cardinal features of over 30 conditions reported in French Canadians. Some were discovered in French Canadians, such as autosomal recessive ataxia of the Charlevoix-Saguenay (MIM 270550), agenesis of corpus callosum and peripheral neuropathy (MIM 218000) and French-Canadian-type Leigh syndrome (MIM 220111). Other conditions are particularly frequent or have special genetic characteristics in French Canadians, including oculopharyngeal muscular dystrophy, hepatorenal tyrosinaemia, cystic fibrosis, Leber hereditary optic neuropathy and familial hypercholesterolaemia. Three genetic diseases of Quebec First Nations children are also discussed: Cree encephalitis (MIM 608505), Cree leukoencephalopathy (MIM 603896) and North American Indian childhood cirrhosis (MIM 604901).

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“…44 The IVS12+5ga allele accounts for about 90% of mutant FAH alleles in the Saguenay-Lac St-Jean area of Quebec. 56,57 IVS12+5ga and IVS6-1gt are frequent in patients of diverse ethnic origins. 58 In addition, W262X is prevalent in Finns, 59 Neonatal screening • Measurement of succinylacetone in a dried blood spot, using tandem mass spectrometry: 46,49,50,[63][64][65] Screening using blood tyrosine as a marker leads to many false-positive results, in newborns with transient tyrosinemia, in those with other hereditary tyrosinemias, and occasionally in children with hepatic problems other than hepatorenal tyrosinemia; 23 more importantly, false-negative results may be obtained in children affected with hepatorenal tyrosinemia, 44 particularly in this era of low neonatal protein intake (breast-feeding, humanized formulas) and early hospital discharge, two factors that reduce the levels of blood tyrosine in predischarge samples.…”

Section: Biochemical Investigationsmentioning

confidence: 99%

Current management options for tyrosinemia

El‐Shabrawi¹,

Kamal²

2013

ODRR

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Hypertyrosinemia is observed in three inherited disorders of tyrosine metabolism. Hereditary Tyrosinemia Type I (HTT-I), or hepatorenal tyrosinemia, is an autosomal recessive disorder caused by mutation in the fumarylacetoacetate hydrolase (FAH) gene. HTT-I is associated with severe involvement of the liver, kidneys, and central nervous system, and is due to toxic accumulation of metabolites of tyrosine, such as succinylacetone. HTT-I is the inborn error with the highest incidence of progression to hepatocellular carcinoma. Elevated succinylacetone, in dried filter paper blood samples, or in plasma or urine, is pathognomonic and diagnostic for HTT-I and is the most reliable neonatal screening method. Liver transplantation is the definitive management, but the need for this is markedly decreased by the combined dietary and drug management. A diet low in tyrosine and phenylalanine, plus nitisinone (2-[2-nitro-4-trifluoromethylbenzoyl]-1,3-cyclohexanedione) (NCTB) are considered the gold standard management options. Carnitine and 1,25-OH-vitamin D are adjuvant therapy. Strict follow up with succinylacetone level for monitoring of treatment should be done. Abdominal ultrasonography and abdominal computerized tomography scan or magnetic resonance imaging should also be done for surveillance of the possible development of hepatocellular carcinoma.

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Frequency of the Ivs12+5g→a Splice Mutation of the Fumarylacetoacetate Hydrolase Gene in Carriers of Hereditary Tyrosinaemia in the French Canadian Population of Saguenay-Lac-St-Jean

Cited by 28 publications

References 15 publications

A founder mutation in the PEX6 gene is responsible for increased incidence of Zellweger syndrome in a French Canadian population

A founder mutation in the PEX6 gene is responsible for increased incidence of Zellweger syndrome in a French Canadian population

Population history and its impact on medical genetics in Quebec

Current management options for tyrosinemia

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